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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/07/13" /><meta name="citation_author" content="Nancy D Leslie" /><meta name="citation_author" content="Sofia Saenz-Ayala" /><meta name="citation_pmid" content="20301763" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK6816/" /><meta name="citation_keywords" content="Very Long-Chain Acyl-CoA Dehydrogenase Deficiency" /><meta name="citation_keywords" content="VLCAD Deficiency" /><meta name="citation_keywords" content="VLCAD Deficiency" /><meta name="citation_keywords" content="Very Long-Chain Acyl-CoA Dehydrogenase Deficiency" /><meta name="citation_keywords" content="ACADVL-Related Severe Early-Onset Cardiac and Multiorgan Failure" /><meta name="citation_keywords" content="ACADVL-Related Hepatic or Hypoketotic Hypoglycemia" /><meta name="citation_keywords" content="ACADVL-Related Later-Onset Episodic Myopathy with Intermittent Rhabdomyolysis" /><meta name="citation_keywords" content="Very long-chain specific acyl-CoA dehydrogenase, mitochondrial" /><meta name="citation_keywords" content="ACADVL" /><meta name="citation_keywords" content="Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Nancy D Leslie" /><meta name="DC.Contributor" content="Sofia Saenz-Ayala" /><meta name="DC.Date" content="2023/07/13" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK6816/" /><meta name="description" content="Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. 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The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK6816_"><span class="title" itemprop="name">Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency, VLCAD Deficiency</div><div class="contrib half_rhythm"><span itemprop="author">Nancy D Leslie</span>, MD<div class="affiliation small">Professor of Clinical Pediatrics<br />Division of Human Genetics<br />Cincinnati Children's Hospital Medical Center<br />Cincinnati, Ohio<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.cmhcc@eilsel.ycnan" class="oemail">gro.cmhcc@eilsel.ycnan</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Sofia Saenz-Ayala</span>, MD<div class="affiliation small">Cincinnati Children's Hospital Medical Center<br />Cincinnati, Ohio</div></div><p class="small">Initial Posting: <span itemprop="datePublished">May 28, 2009</span>; Last Revision: <span itemprop="dateModified">July 13, 2023</span>.</p><p><em>Estimated reading time: 37 minutes</em></p></div><div class="body-content whole_rhythm" itemprop="text"><div id="vlcad.Summary" itemprop="description"><h2 id="_vlcad_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in <i>ACADVL</i> on molecular genetic testing. If one <i>ACADVL</i> pathogenic variant is found and suspicion of VLCAD deficiency is high, specialized biochemical testing using cultured fibroblasts or lymphocytes may be needed for confirmation of the diagnosis.</p></div><div><h4 class="inline">Management.</h4><p>
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<i>Treatment of manifestations:</i>
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</p><ul><li class="half_rhythm"><div><b>Routine daily treatment.</b> Low-fat formula or low long-chain fat / high medium-chain triglyceride (MCT) medical food, with 13%-39% of calories as total fat; total dietary protein above the dietary reference intake for age; MCT oil or triheptanoin supplementation; carnitine supplementation; consider supplementation with linoleic acid, arachidonic acid, alpha-linolenic acid, and docosahexaenoic acid; frequent feeding in infants and a bedtime snack high in complex carbohydrates in children and adults; nasogastric tube feeding for those with feeding issues; guided exercise and avoidance of severe exercise to address exercise intolerance in older individuals; standard treatment of cardiomyopathy; supportive developmental therapies as needed.</div></li><li class="half_rhythm"><div><b>Emergency outpatient treatment.</b> Consider a trial outpatient treatment at home for up to 12 hours, including frequent high carbohydrate feedings, reduced fasting duration time, antipyretics, and antiemetics.</div></li><li class="half_rhythm"><div><b>Acute inpatient treatment.</b> Administration of high-energy fluids (≥10% IV dextrose) with electrolytes at a rate of at least 1.5 times maintenance (minimum of 8 mg/kg/min of glucose) while avoiding the use of L-carnitine and IV lipids; standard treatment for cardiomyopathy / cardiac failure; ample hydration and alkalization of the urine for those with rhabdomyolysis.</div></li></ul><p><i>Prevention of secondary complications:</i> Acute rhabdomyolysis is treated with ample hydration and alkalization of the urine to protect kidney function and to prevent acute kidney failure secondary to myoglobinuria; if a surgery or procedure is required, notify designated metabolic center in advance of the procedure to discuss perioperative management with surgeons and anesthesiologists; some anesthetics may be contraindicated.</p><p><i>Surveillance:</i> Measurement of growth parameters (including head circumference) and assessment of feeding skills (in infants/toddlers) at each visit; plasma carnitine panel, acylcarnitine profile, and creatine kinase level every three months for the first year of life, every three to six months for those between age one and seven years, and every six to 12 months for those older than age seven years; red blood cell or plasma essential fatty acids every six months for those on long-chain fat restriction; measurement of vitamins A, D, and E annually or as clinically indicated for those on long-chain fat restriction; echocardiogram at least annually or as clinically indicated; DXA scan every five years in adults; measurement of complete blood count, ferritin level, comprehensive metabolic panel, troponin, and B-type natriuretic protein as clinically indicated.</p><p><i>Agents/circumstances to avoid:</i> Fasting; myocardial irritation; dehydration; high-fat diet; and volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate.</p><p><i>Evaluation of relatives at risk:</i> Evaluation of all at-risk sibs of any age is warranted to identify those who would benefit from treatment and preventive measures.</p><p><i>Pregnancy management:</i> Labor and postpartum periods are catabolic states and place the mother at higher risk for rhabdomyolysis and subsequent myoglobinuria. A management plan for labor and delivery is necessary for the affected pregnant woman. In addition to regular assessment by a cardiologist and maternal fetal medicine specialist, the following are recommended: visit with a nutritionist familiar with VLCAD deficiency monthly or at least in each trimester; measurement of plasma carnitine panel (total, free, esters) and creatine kinase level at each visit; plasma acylcarnitine profile weekly to monthly; red blood cell or plasma essential fatty acids (for those on long-chain fat restriction) at least once during pregnancy; echocardiogram either prior to conception or as soon as a pregnancy is recognized; measurement of vitamins A, D, and E (for those on long-chain fat restriction), complete blood count, ferritin level, and metabolic panel as a baseline or as clinically indicated.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>VLCAD deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an <i>ACADVL</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Molecular genetic carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.</p></div></div><div id="vlcad.GeneReview_Scope"><h2 id="_vlcad_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="vlcad.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_vlcad.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Severe early-onset cardiac and multiorgan failure</div></li><li class="half_rhythm"><div>Hepatic or hypoketotic hypoglycemia</div></li><li class="half_rhythm"><div>Later-onset episodic myopathy with intermittent rhabdomyolysis</div></li></ul>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="vlcad.TF.c.1"><p class="no_margin">For other genetic causes of these phenotypes, see <a href="#vlcad.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></div></div></div></div><div id="vlcad.Diagnosis"><h2 id="_vlcad_Diagnosis_">Diagnosis</h2><p>Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons.</p><div id="vlcad.Suggestive_Findings"><h3>Suggestive Findings</h3><div id="vlcad.Scenario_1_Abnormal_Newborn_Screen"><h4>Scenario 1: Abnormal Newborn Screening (NBS) Result</h4><p>NBS for VLCAD deficiency is primarily based on quantification of various acylcarnitine levels (C14:1, C14:2, C14, and C12:1) and ratios of acylcarnitine levels (C14:1/C2, C14:1/C16) on dried blood spots.</p><p><b>Acylcarnitine values and ratios</b> above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, which typically includes a confirmatory acylcarnitine profile.</p><ul><li class="half_rhythm"><div>Although cutoff/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 µmol/L [<a class="bk_pop" href="#vlcad.REF.miller.2015.139">Miller et al 2015</a>] on an initial NBS test strongly suggests VLCAD deficiency. Individuals with this level or higher should be assumed to have VLCAD deficiency.</div></li><li class="half_rhythm"><div>Levels of C14:1 greater than 0.8 µmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no <i>ACADVL</i> pathogenic variants.</div></li><li class="half_rhythm"><div>Postanalytic tools, such as those developed by the Region 4 Stork (R4S/CLIR) collaborative, may contribute to refinement of NBS cutoffs and inform clinicians regarding the likelihood of a true positive diagnosis of VLCAD deficiency in individual newborns [<a class="bk_pop" href="#vlcad.REF.hall.2014.889">Hall et al 2014</a>, <a class="bk_pop" href="#vlcad.REF.merritt.2014.484">Merritt et al 2014</a>]. In Georgia, postanalytic tools have been used to triage abnormal NBS results for follow up. For example, when a case on the dual scatter plot is in the "indeterminate" quadrant or the "affected" quadrant, the child is referred for testing, including sequence analysis, while other cases are referred for repeat screens [<a class="bk_pop" href="#vlcad.REF.hall.2020.20">Hall et al 2020</a>].</div></li><li class="half_rhythm"><div>A significant number of individuals with an abnormal NBS result have one <i>ACADVL</i> pathogenic variant and are likely heterozygotes (i.e., carriers) who have been detected because of the low specificity of the initial NBS acylcarnitine screening assay unless multiple marker calculations are applied [<a class="bk_pop" href="#vlcad.REF.diekman.2016.101">Diekman et al 2016</a>].</div></li><li class="half_rhythm"><div>If the follow-up biochemical testing supports the likelihood of VLCAD deficiency, additional testing is required to establish the diagnosis (see <a href="#vlcad.Establishing_the_Diagnosis">Establishing the Diagnosis</a>).</div></li><li class="half_rhythm"><div>Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion, or if the episode prompting concern has resolved. (2) NBS data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Severe body weight loss at the sampling day of NBS could cause false positive elevation of C14:1 and C14:1/C2.</div></li></ul><p>The following <b>medical interventions</b> need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether it is a true positive NBS result and to establish the diagnosis of VLCAD deficiency definitively:</p><ul><li class="half_rhythm"><div class="half_rhythm">Evaluation of the newborn to ascertain clinical status</div></li><li class="half_rhythm"><div class="half_rhythm">Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy</div></li><li class="half_rhythm"><div class="half_rhythm">Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including:</div><ul><li class="half_rhythm"><div>Admission to the hospital</div></li><li class="half_rhythm"><div>Fluid resuscitation</div></li><li class="half_rhythm"><div>Infusion of IV glucose</div></li><li class="half_rhythm"><div>Nutritional evaluation</div></li><li class="half_rhythm"><div>Institution of enteral nutrition with supplementation of medium-chain fat</div></li><li class="half_rhythm"><div>Cardiac evaluation</div></li></ul><div class="half_rhythm">See also <a href="#vlcad.Management">Management</a>.</div></li></ul></div><div id="vlcad.Scenario_2_Symptomatic_Individual"><h4>Scenario 2: Symptomatic Individual</h4><p>A symptomatic individual may have either: findings associated with later-onset VLCAD deficiency; or untreated infantile-onset VLCAD deficiency resulting from any of the following: NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment following a positive NBS result.</p><p>Supportive – but nonspecific– clinical findings by age and preliminary laboratory findings can include the following.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Newborn/infant:</div><ul><li class="half_rhythm"><div>Severe hypertrophic or dilated cardiomyopathy</div></li><li class="half_rhythm"><div>Pericardial effusion</div></li><li class="half_rhythm"><div>Arrhythmias</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Hepatomegaly</div></li><li class="half_rhythm"><div>Multiorgan failure</div></li></ul></li><li class="half_rhythm"><div>Older child / adult:</div><ul><li class="half_rhythm"><div>Myopathy associated with exercise intolerance</div></li><li class="half_rhythm"><div>Muscle cramps and/or pain</div></li><li class="half_rhythm"><div>Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever</div></li></ul></li></ul><p>
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<b>Preliminary laboratory findings</b>
|
||
</p><ul><li class="half_rhythm"><div>Newborn/infant:</div><ul><li class="half_rhythm"><div>Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine</div></li><li class="half_rhythm"><div>Elevated liver transaminases</div></li><li class="half_rhythm"><div>Altered hepatic synthetic liver function</div></li></ul></li><li class="half_rhythm"><div>Older child / adult: intermittent elevations in creatine phosphokinase with return to normal between episodes</div></li></ul><p><b>Family history</b> is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.</p></div></div><div id="vlcad.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of VLCAD deficiency <b>is established</b> in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or biallelic pathogenic (or likely pathogenic) variants in <i>ACADVL</i> identified on <a href="#vlcad.Molecular_Genetic_Testing">molecular genetic testing</a> (see <a href="/books/NBK6816/table/vlcad.T.molecular_genetic_testing_used_i/?report=objectonly" target="object" rid-ob="figobvlcadTmoleculargenetictestingusedi">Table 1</a>). If one <i>ACADVL</i> pathogenic variant is found and suspicion of VLCAD deficiency is high, <a href="#vlcad.Specialized_Biochemical_Testing">specialized biochemical testing</a> using cultured fibroblasts or lymphocytes may be needed for confirmation of the diagnosis.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#vlcad.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of biallelic <i>ACADVL</i> variants of uncertain significance (or of one known <i>ACADVL</i> pathogenic variant and one <i>ACADVL</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><div id="vlcad.Molecular_Genetic_Testing"><h4>Molecular Genetic Testing</h4><p><b>Scenario 1: Abnormal NBS result.</b> When NBS results and other laboratory findings suggest the diagnosis of VLCAD deficiency, molecular genetic testing approaches typically include <b>single-gene testing</b>. Sequence analysis of <i>ACADVL</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.</p><p><b>Scenario 2: Genetic testing options for a symptomatic individual</b> who has atypical findings associated with later-onset VLCAD deficiency or untreated infantile-onset VLCAD deficiency (resulting from NBS not performed or false negative NBS result) typically include a <b>multigene panel</b> or, less commonly, <b>comprehensive genomic testing</b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>A fatty acid oxidation or rhabdomyolysis multigene panel</b> that includes <i>ACADVL</i> and other genes of interest (see <a href="#vlcad.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm">When the diagnosis of VLCAD deficiency has not been considered, <b>comprehensive</b>
|
||
<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is an option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</div><div class="half_rhythm">For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</div></li></ul><div id="vlcad.T.molecular_genetic_testing_used_i" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.molecular_genetic_testing_used_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.molecular_genetic_testing_used_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ACADVL</i>
|
||
</td><td headers="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">95%-97% <sup>4</sup></td></tr><tr><td headers="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_vlcad.T.molecular_genetic_testing_used_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare; 1 reported <sup>6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="vlcad.TF.1.1"><p class="no_margin">See <a href="/books/NBK6816/#vlcad.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.1.2"><p class="no_margin">See <a href="#vlcad.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd><dt>3. </dt><dd><div id="vlcad.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="vlcad.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#vlcad.REF.liebig.2006.343">Liebig et al [2006]</a>, <a class="bk_pop" href="#vlcad.REF.merritt.2014.484">Merritt et al [2014]</a>, <a class="bk_pop" href="#vlcad.REF.evans.2016.282">Evans et al [2016]</a>, <a class="bk_pop" href="#vlcad.REF.pena.2016.272">Pena et al [2016]</a>, and <a class="bk_pop" href="#vlcad.REF.hesse.2018.1169">Hesse et al [2018]</a> report a total of 307 individuals with clinically diagnosed VLCAD, most ascertained by newborn screening. The number of observed vs expected sequence variants across the entire group is 97%. However, only <a class="bk_pop" href="#vlcad.REF.hesse.2018.1169">Hesse et al [2018]</a> performed systematic enzyme assays in their entire study population of 108 individuals. For the 55 individuals with enzyme activity that was 0%-24% of control, all pathogenic variants were identified through sequence analysis. For the smaller group, which was designated as an overlap affected/carrier group (n=7) with enzyme activity 25%-27% of control, only 57% had two variants identified through sequence analysis. In this table, the 95% reflects only the data reported by <a class="bk_pop" href="#vlcad.REF.hesse.2018.1169">Hesse et al [2018]</a>, calculated across both subgroups. Note: The <a class="bk_pop" href="#vlcad.REF.hesse.2018.1169">Hesse et al [2018]</a> article does not state that all individuals in the overlap group are affected; that is, some individuals may have only one pathogenic variant, not biallelic pathogenic variants.</p></div></dd><dt>5. </dt><dd><div id="vlcad.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="vlcad.TF.1.6"><p class="no_margin"><a class="bk_pop" href="#vlcad.REF.pervaiz.2011.29">Pervaiz et al [2011]</a>, <a class="bk_pop" href="#vlcad.REF.miller.2015.139">Miller et al [2015]</a></p></div></dd></dl></div></div></div></div><div id="vlcad.Specialized_Biochemical_Testing"><h4>Specialized Biochemical Testing</h4><p>Specialized biochemical testing may be used to clarify the diagnosis, particularly when molecular testing reveals only one pathogenic variant.</p><p><b>Analysis of fatty acid beta-oxidation in cultured fibroblasts.</b> In vitro incubation of cultured fibroblasts with C13-palmitate or unlabeled palmitate and carnitine may provide indirect evidence of impaired beta-oxidation. Individuals with severe VLCAD deficiency typically accumulate excess tetradecanoyl (C14) carnitine, whereas individuals with less severe phenotypes may shift accumulation toward dodecanoyl (C12) carnitine. This test is often called the "in vitro probe study" and is available clinically.</p><p><b>Analysis of VLCAD enzyme activity.</b> Measurement of VLCAD enzyme activity in leukocytes, cultured fibroblasts, liver, heart, skeletal muscle, or amniocytes by the electron transfer flavoprotein or ferricineum reduction assay can be used to confirm the diagnosis of VLCAD deficiency. Better specificity has been noted when the products are separated and quantitated by high-performance liquid chromatography or tandem mass spectrometry (MS/MS). The clinical availability of this assay has varied with time.</p></div></div></div><div id="vlcad.Clinical_Characteristics"><h2 id="_vlcad_Clinical_Characteristics_">Clinical Characteristics</h2><div id="vlcad.Clinical_Description"><h3>Clinical Description</h3><p>Depending on the severity of very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency, individuals can present with hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, and myopathy with recurrent rhabdomyolysis, triggered by a catabolic state. Therefore, the condition has been divided into three clinical subgroups, including a severe early-onset cardiac and multiorgan failure form, a hepatic or hypoketotic hypoglycemic form, and a later-onset myopathic form [<a class="bk_pop" href="#vlcad.REF.andresen.1999.479">Andresen et al 1999</a>]. Most affected individuals identified by newborn screening (NBS) are asymptomatic at the time of diagnosis [<a class="bk_pop" href="#vlcad.REF.spiekerkoetter.2010.527">Spiekerkoetter 2010</a>, <a class="bk_pop" href="#vlcad.REF.baruteau.2013.795">Baruteau et al 2013</a>].</p><p><b>Scenario 1: Abnormal NBS result and prompt initiation of appropriate management in neonatal period.</b> With early intensive supportive care and diet modification (see <a href="#vlcad.Management">Management</a>), normal cognitive outcome has been reported.</p><ul><li class="half_rhythm"><div>Developmental and intelligence quotient (IQ) scores were similar to those seen in the general population (developmental quotient / IQ ≥85) [<a class="bk_pop" href="#vlcad.REF.brown.2014.278">Brown et al 2014</a>, <a class="bk_pop" href="#vlcad.REF.landau.2017.209">Landau et al 2017</a>].</div></li><li class="half_rhythm"><div>However, motor and speech delays were reported [<a class="bk_pop" href="#vlcad.REF.waisbren.2013.260">Waisbren et al 2013</a>].</div></li></ul><p>Both <a class="bk_pop" href="#vlcad.REF.pena.2016.272">Pena et al [2016]</a> and <a class="bk_pop" href="#vlcad.REF.vockley.2016.223">Vockley et al [2016]</a> reported individuals who developed cardiomyopathy while being treated with a medium-chain triglyceride oil-based diet.</p><p><a class="bk_pop" href="#vlcad.REF.bleeker.2019.414">Bleeker et al [2019]</a> and <a class="bk_pop" href="#vlcad.REF.marsden.2021.816">Marsden et al [2021]</a> reported that NBS results in prevention of hypoglycemic events in those with some residual enzyme activity, but not prevention of hypoglycemia or cardiac complications in affected individuals with very low residual enzyme activity.</p><p>
|
||
<b>Scenario 2: Symptomatic individual associated with later-onset VLCAD deficiency or untreated infantile-onset VLCAD deficiency (resulting from NBS not performed or false negative NBS result)</b>
|
||
</p><ul><li class="half_rhythm"><div><b>Severe early-onset cardiac and multiorgan failure VLCAD deficiency</b> typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia.</div><ul><li class="half_rhythm"><div>Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [<a class="bk_pop" href="#vlcad.REF.bonnet.1999.2248">Bonnet et al 1999</a>].</div></li><li class="half_rhythm"><div>Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.</div></li><li class="half_rhythm"><div><a class="bk_pop" href="#vlcad.REF.cox.1998.247">Cox et al [1998]</a> reported normal cognitive outcome at age four years in an affected individual diagnosed clinically with VLCAD deficiency who had severe hypertrophic cardiomyopathy at age five months.</div></li></ul></li><li class="half_rhythm"><div><b>Hepatic or hypoketotic hypoglycemic VLCAD</b>
|
||
<b>deficiency</b> typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly (similar to medium-chain acyl-coenzyme A dehydrogenase deficiency) but without cardiomyopathy. Hypoglycemia and poor feeding during the newborn period have been reported in neonates who were later diagnosed with VLCAD deficiency [<a class="bk_pop" href="#vlcad.REF.pena.2016.272">Pena et al 2016</a>].</div></li><li class="half_rhythm"><div><b>Later-onset episodic myopathic</b>
|
||
<b>VLCAD</b>
|
||
<b>deficiency,</b> probably the most common phenotype, presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptom onset in these individuals. Ascertainment in adulthood has been reported [<a class="bk_pop" href="#vlcad.REF.hoffman.2006.657">Hoffman et al 2006</a>].</div></li></ul></div><div id="vlcad.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>As a general rule, strong genotype-phenotype correlations exist in VLCAD deficiency [<a class="bk_pop" href="#vlcad.REF.andresen.1999.479">Andresen et al 1999</a>]:</p><ul><li class="half_rhythm"><div>Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in <i>ACADVL</i> are associated with the severe early-onset form [<a class="bk_pop" href="#vlcad.REF.andresen.1999.479">Andresen et al 1999</a>].</div></li><li class="half_rhythm"><div>A specific homozygous missense pathogenic variant (c.709T>C;<a href="/books/NBK6816/table/vlcad.T.notable_acadvl_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobvlcadTnotableacadvlpathogenicvarian">p.Cys237Arg</a>) leading to low long-chain fatty acid oxidation flux may also be associated with cardiac disease [<a class="bk_pop" href="#vlcad.REF.diekman.2015.989">Diekman et al 2015</a>].</div></li><li class="half_rhythm"><div>Milder childhood and adult forms are often associated with residual enzyme activity. The common <a href="/books/NBK6816/table/vlcad.T.notable_acadvl_pathogenic_varian/?report=objectonly" target="object" rid-ob="figobvlcadTnotableacadvlpathogenicvarian">p.Val283Ala</a> variant, in both homozygous and compound heterozygous genotypes, is typically associated with the non-cardiac phenotypes [<a class="bk_pop" href="#vlcad.REF.spiekerkoetter.2009.498">Spiekerkoetter et al 2009</a>, <a class="bk_pop" href="#vlcad.REF.diekman.2015.989">Diekman et al 2015</a>, <a class="bk_pop" href="#vlcad.REF.miller.2015.139">Miller et al 2015</a>].</div></li></ul></div><div id="vlcad.Prevalence"><h3>Prevalence</h3><p>Complete ascertainment by NBS is not assured, but the incidence of VLCAD deficiency is now estimated at 1:30,000 to 1:100,000 births.</p><p>NBS has demonstrated that VLCAD deficiency is more prevalent than previously suspected; however, the majority of children ascertained by NBS are asymptomatic during the first few years of observation, suggesting that these individuals may have gone undiagnosed prior to the advent of population-based screening.</p></div></div><div id="vlcad.Genetically_Related_Allelic_Disord"><h2 id="_vlcad_Genetically_Related_Allelic_Disord_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>ACADVL</i>.</p></div><div id="vlcad.Differential_Diagnosis"><h2 id="_vlcad_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Infantile cardiomyopathy</b> with evidence of abnormal fatty acid oxidation may be seen in the autosomal recessive disorders summarized in <a href="/books/NBK6816/table/vlcad.T.disorders_in_the_differential_di/?report=objectonly" target="object" rid-ob="figobvlcadTdisordersinthedifferentialdi">Table 2</a> [<a class="bk_pop" href="#vlcad.REF.roe.2006.40">Roe et al 2006</a>].</p><div id="vlcad.T.disorders_in_the_differential_di" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders in the Differential Diagnosis of Severe Early-Onset VLCAD</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.disorders_in_the_differential_di/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.disorders_in_the_differential_di_lrgtbl__"><table><thead><tr><th id="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Biochemical Phenotype</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CPT2</i>
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||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/cpt2/">Carnitine palmitoyltransferase (CPT) II deficiency</a> – severe infantile hepatocardiomuscular form</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓ CPT enzyme activity in muscles</td></tr><tr><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ETFA</i>
|
||
<br />
|
||
<i>ETFB</i>
|
||
<br />
|
||
<i>ETFDH</i>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe forms of <a href="/books/n/gene/madd/">multiple acyl-coenzyme A dehydrogenase deficiency</a></td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ multiple acylcarnitine species of different length size in blood in combination w/↑ excretion of multiple organic acids in urine</td></tr><tr><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>HADHA</i>
|
||
<br />
|
||
<i>HADHB</i>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/lchad/">Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) / trifunctional protein deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ C16OH, C18OH, C18:1OH</td></tr><tr><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC22A5</i>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/cdsp/">Systemic primary carnitine deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Extremely ↓ plasma free carnitine (C0) levels</td></tr><tr><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC25A20</i>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/cact-def/">Carnitine-acylcarnitine translocase deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ C16, C16:1, C18, & C18:1</td></tr><tr><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TANGO2</i>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/tango2-mea/"><i>TANGO2</i>-related metabolic encephalopathy & arrhythmias</a>
|
||
</td><td headers="hd_h_vlcad.T.disorders_in_the_differential_di_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent episodes of acute metabolic crises (hypoglycemia, ↑ lactate, mild hyperammonemia)</td></tr></tbody></table></div></div><p><b>The hepatic hypoglycemic form</b> of VLCAD deficiency may have clinical features similar to <a href="/books/n/gene/mcad/">medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency</a>, or to the electron transfer flavoprotein (ETF) / ETF ubiquinone (coenzyme Q) oxidoreductase defects that produce <a href="/books/n/gene/madd/">multiple acyl-coenzyme A dehydrogenase deficiencies</a>; however, the biochemical phenotypes are distinct.</p><p><b>Intermittent rhabdomyolysis</b> is a feature of <a href="/books/n/gene/gsd5/">glycogen storage disease type V</a> (McArdle disease), <a href="/books/n/gene/cpt2/">carnitine palmitoyltransferase (CPT) II deficiency</a>, some primary myopathies, and <a href="/books/n/gene/lchad/">trifunctional protein deficiency</a> (see <a href="/books/NBK6816/table/vlcad.T.selected_metabolic_myopathies_in/?report=objectonly" target="object" rid-ob="figobvlcadTselectedmetabolicmyopathiesin">Table 3</a>). Rhabdomyolysis is also seen in LPIN1 deficiency, though often at younger ages than in VLCAD deficiency and typically provoked by illness rather than exercise.</p><div id="vlcad.T.selected_metabolic_myopathies_in" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Selected Metabolic Myopathies in the Differential Diagnosis of Later-Onset Episodic Myopathic VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.selected_metabolic_myopathies_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.selected_metabolic_myopathies_in_lrgtbl__"><table><thead><tr><th id="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder Type</th><th id="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Selected Examples</th><th id="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Characteristics</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Fatty acid oxidation disorders</b>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/madd/">Multiple acyl-coenzyme A dehydrogenase deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ETFA</i>
|
||
<br />
|
||
<i>ETFB</i>
|
||
<br />
|
||
<i>ETFDH</i>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_4" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">Manifest w/endurance-type activity or under fasting or other metabolically stressful conditions</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/cpt2/">Carnitine palmitoyltransferase (CPT) II deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>CPT2</i>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/cdsp/">Systemic primary carnitine deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SLC22A5</i>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/lchad/">Trifunctional protein deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>HADHB</i>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/lchad/">Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>HADHA</i>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Glycogen storage disorders (GSD)</b>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/gsd5/">GSD V</a> (McArdle disease)</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PYGM</i>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_4" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">Muscular hypotonia, muscle weakness w/limb girdle distribution, high-intensity exercise intolerance</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/gsd2/">GSD II</a> (Pompe disease)</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GAA</i>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/gsd3/">GSD III</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>AGL</i>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/gsd4/">GSD IV</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>GBE1</i>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Lipid metabolism disorders</b>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LPIN1 deficiency (OMIM <a href="https://omim.org/entry/268200" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">268200</a>)</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>LPIN1</i>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Episodic rhabdomyolysis triggered by fasting, infection/fever, or prolonged exercise</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Mitochondrial myopathies</b>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/tk2-mtddepl/"><i>TK2</i>-related mitochondrial DNA maintenance defect, myopathic form</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>TK2</i>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Impaired use of available oxygen assoc w/muscle fatigue & lactic acidosis at low levels of physical activity</td></tr><tr><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/sucla2-def/"><i>SUCLA2</i>-related mitochondrial DNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria</a>
|
||
</td><td headers="hd_h_vlcad.T.selected_metabolic_myopathies_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SUCLA2</i>
|
||
</td></tr></tbody></table></div></div></div><div id="vlcad.Management"><h2 id="_vlcad_Management_">Management</h2><p>Clinical guidelines for the nutritional management of very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency at various ages have been published [<a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al 2020</a>] (<a href="https://www.sciencedirect.com/science/article/pii/S1096719220302018?via%3Dihub" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">full text</a>). Guidelines can be accessed from the <a href="https://gmdi.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Genetic Metabolic Dietitians International</a> and <a href="https://southeastgenetics.org/for-professionals/nutrition-management-guidelines/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Southeast Regional Genetics Network</a> websites.</p><p>When VLCAD deficiency is suspected during the diagnostic evaluation – for example, as a result of a suggestive acylcarnitine profile (see <a href="#vlcad.Scenario_2_Symptomatic_Individual">Suggestive Findings</a>) – fasting precautions should be implemented immediately. In asymptomatic neonates, maternal breast milk without supplemental medium-chain triglycerides can continue as long as fasting precautions are taken [<a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al 2020</a>].</p><p>Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (e.g., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.</p><div id="vlcad.Evaluations_Following_Initial_Diag"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with VLCAD deficiency, the evaluations summarized in <a href="/books/NBK6816/table/vlcad.T.recommended_evaluations_followin/?report=objectonly" target="object" rid-ob="figobvlcadTrecommendedevaluationsfollowin">Tables 4</a> or <a href="/books/NBK6816/table/vlcad.T.recommended_evaluations_followin_1/?report=objectonly" target="object" rid-ob="figobvlcadTrecommendedevaluationsfollowin1">5</a> (depending on the age at diagnosis) are recommended, if not previously performed as part of the evaluation that led to the diagnosis.</p><div id="vlcad.T.recommended_evaluations_followin" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis of VLCAD Deficiency in a Neonate or Infant</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.recommended_evaluations_followin/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.recommended_evaluations_followin_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian <sup>1</sup></td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.</div></li><li class="half_rhythm"><div>Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for crises).</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline laboratory studies</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl serum creatine kinase concentration, liver transaminases, & blood glucose concentrations</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Electrocardiogram</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for arrhythmias</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for cardiomyopathy & cardiac dysfunction</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nutrition / feeding team eval</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl eval of feeding skills, anthropometric measures, & nutritional status</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/psychologist &/or social worker</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To ensure understanding of diagnosis & assess parental / affected person's coping skills & <a href="#vlcad.Resources">resources</a></td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Genetic counseling by genetics professionals <sup>2</sup></td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & families re nature, MOI, & implications of VLCAD deficiency to facilitate medical & personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance</p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.4.1"><p class="no_margin">After a new diagnosis of VLCAD deficiency in a neonate or infant, the closest hospital and local pediatrician should also be informed.</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.4.2"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div><div id="vlcad.T.recommended_evaluations_followin_1" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis of VLCAD Deficiency in an Older Child or Adult</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.recommended_evaluations_followin_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.recommended_evaluations_followin_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Baseline laboratory studies</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl serum creatine kinase concentration & liver transaminases</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam of abdomen</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for hepatomegaly</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routine neurodevelopmental assessment</td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/psychologist &/or social worker</td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To ensure understanding of diagnosis & assess parental / affected person's coping skills & <a href="#vlcad.Resources">resources</a></td></tr><tr><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Genetic counseling by genetics professionals <sup>1</sup></td><td headers="hd_h_vlcad.T.recommended_evaluations_followin_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & families re nature, MOI, & implications of VLCAD deficiency to facilitate medical & personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance</p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.5.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="vlcad.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Frequently updated, succinct emergency care plans should detail the typical clinical issues (either those already experienced by the affected individual or those anticipated based on the diagnosis) and the importance of early management (e.g., use of IV glucose as an energy source, monitoring for cardiac rhythm disturbance, and monitoring of rhabdomyolysis) and avoidance of triggers (fasting, long-chain fats, and irritation of the myocardium) [<a class="bk_pop" href="#vlcad.REF.arnold.2009.85">Arnold et al 2009</a>].</p><p>Cardiac dysfunction may be reversible with early, intensive supportive care (occasionally including extracorporeal membrane oxygenation) and diet modification.</p><p><b>Triheptanoin (C7).</b> This odd medium-chain fatty acid was approved by the FDA in June 2020 for the treatment of pediatric and adult individuals with VLCAD deficiency.</p><ul><li class="half_rhythm"><div>The use of triheptanoin is based on its action as an anaplerotic molecule that can correct the secondary depletion of TCA cycle intermediates occurring in these disorders.</div></li><li class="half_rhythm"><div>Benefits include decrease in total days of hospitalization per year and reduction in episodes of rhabdomyolysis [<a class="bk_pop" href="#vlcad.REF.roe.2015.260">Roe & Brunengraber 2015</a>, <a class="bk_pop" href="#vlcad.REF.z_ggeler.2021.28">Zöggeler et al 2021</a>]. Improvement in cardiomyopathy, hepatomegaly, and hypoglycemia was reported in those treated with triheptanoin compared to pretreatment [<a class="bk_pop" href="#vlcad.REF.roe.2015.260">Roe & Brunengraber 2015</a>, <a class="bk_pop" href="#vlcad.REF.vockley.2015.53">Vockley et al 2015</a>, <a class="bk_pop" href="#vlcad.REF.vockley.2016.223">Vockley et al 2016</a>, <a class="bk_pop" href="#vlcad.REF.gillingham.2017.831">Gillingham et al 2017</a>, <a class="bk_pop" href="#vlcad.REF.vockley.2017.370">Vockley et al 2017</a>, <a class="bk_pop" href="#vlcad.REF.calvert.2018.1074">Calvert et al 2018</a>].</div></li><li class="half_rhythm"><div>Triheptanoin was less effective in reducing rhabdomyolysis post treatment compared to its effect on other symptoms of VLCAD deficiency, suggesting a role for other pathophysiologic mechanisms and demonstrating the need for additional therapies (see <a href="#vlcad.Therapies_Under_Investigation">Therapies Under Investigation</a>) [<a class="bk_pop" href="#vlcad.REF.sklirou.2021.598760">Sklirou et al 2021</a>].</div></li><li class="half_rhythm"><div>Adverse events in all of the clinical trials were similar for C7 and C8 treatment and predominantly consisted of gastrointestinal symptoms (abdominal pain, diarrhea) [<a class="bk_pop" href="#vlcad.REF.sklirou.2021.598760">Sklirou et al 2021</a>, <a class="bk_pop" href="#vlcad.REF.z_ggeler.2021.28">Zöggeler et al 2021</a>].</div></li></ul><div id="vlcad.T.routine_daily_treatment_in_indiv" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Routine Daily Treatment in Individuals with VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.routine_daily_treatment_in_indiv/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.routine_daily_treatment_in_indiv_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Principle/<br />Manifestation</th><th id="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Restriction of long-chain fats in persons w/severe disease <sup>1</sup></td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low-fat formula <sup>2, 3</sup> or low long-chain fat / high MCT medical food</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ranging from 13% to 39% of calories as total fat (See <a href="/books/NBK6816/table/vlcad.T.baseline_1_recommended_total_lon/?report=objectonly" target="object" rid-ob="figobvlcadTbaseline1recommendedtotallon">Table 7</a>.)</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">MCT oil OR triheptanoin (Dojolvi<sup>®</sup>) supplementation <sup>4, 5</sup></td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>For MCT oil: to provide an addl 15%-18% of calories (See <a href="/books/NBK6816/table/vlcad.T.baseline_1_recommended_total_lon/?report=objectonly" target="object" rid-ob="figobvlcadTbaseline1recommendedtotallon">Table 7</a>.)</div></li><li class="half_rhythm"><div>For triheptanoin: to provide 30% of daily caloric intake <sup>6</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Total dietary protein at or above the DRI for age</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">The Institute of Medicine EER calculation for physical activity & age can be used to predict energy needs. <sup>7</sup></td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In infants & children who are gaining weight & are otherwise healthy</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider supplementation w/:
|
||
<ul><li class="half_rhythm"><div>LA (3%-4% of total energy)</div></li><li class="half_rhythm"><div>ARA (0.5%-1.2% of total energy)</div></li><li class="half_rhythm"><div>ALA (0.5% of total energy)</div></li><li class="half_rhythm"><div>DHA (infants/toddlers: 60 mg/day; older persons: 100 mg/day)</div></li></ul>
|
||
</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For those requiring long-chain fat restriction</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Prevention of catabolism from overnight fasting</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequent feeding, incl awakening an infant for feeding or overnight enteral feeding if necessary</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In infants</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Consider bedtime snack high in complex carbohydrates.</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For children & adults</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Exercise intolerance in older persons</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>MCT oil at 0.5 g/kg lean body weight 20 min prior to exercise <sup>8</sup></div></li><li class="half_rhythm"><div>Exercise guided by affected person's tolerance level</div></li></ul>
|
||
</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Avoidance of severe exercise (e.g., military training)</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Which may unmask symptoms in previously asymptomatic adults <sup>9</sup> (See <a href="#vlcad.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a>.)</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Secondary carnitine deficiency</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Initial oral dosage of 10-25 mg L-carnitine/kg/day divided into 3-4 doses is typical.</div></li><li class="half_rhythm"><div>Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.</div></li></ul>
|
||
</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Supplemental carnitine may not be required but should be considered in those w/free carnitine concentration <10 µmol/L.</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per cardiologist</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">W/appropriate dietary modification & cardiac support (incl use of ECMO when appropriate), cardiac dysfunction may be reversible.</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ energy/caloric demands</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nasogastric tube feeding to address feeding issues</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adequate provision of info & education to parents, affected persons, & caregivers</td></tr><tr><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech / gross<br />motor delay</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Speech therapy</div></li><li class="half_rhythm"><div>Physical therapy</div></li><li class="half_rhythm"><div>Rehab therapy</div></li></ul>
|
||
</td><td headers="hd_h_vlcad.T.routine_daily_treatment_in_indiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ALA = alpha-linolenic acid; ARA = arachidonic acid; DHA = docosahexaenoic acid; DRI = dietary reference intake; ECMO = extracorporeal membrane oxygenation; EER = estimated energy requirement; LA = linoleic acid; MCT = medium-chain triglycerides</p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.6.1"><p class="no_margin"><a class="bk_pop" href="#vlcad.REF.solis.2002.1800">Solis & Singh [2002]</a>, <a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al [2020]</a></p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.6.2"><p class="no_margin">Breast-feeding (or using expressed breast milk) without MCT oil supplements may be considered in asymptomatic neonates predicted to have mild VLCAD deficiency who are growing well, as long as fasting precautions are followed.</p></div></dd><dt>3. </dt><dd><div id="vlcad.TF.6.3"><p class="no_margin">In asymptomatic infants with moderate VLCAD deficiency, breast-feeding (or using expressed breast milk) can be used with consideration of supplementation with a low long-chain fat / high MCT medical food [<a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al 2020</a>].</p></div></dd><dt>4. </dt><dd><div id="vlcad.TF.6.4"><p class="no_margin">Triheptanoin, a synthetic seven odd medium-chain fatty acid triglyceride, was approved by the FDA in June 2020 [<a class="bk_pop" href="#vlcad.REF.sklirou.2021.598760">Sklirou et al 2021</a>, <a class="bk_pop" href="#vlcad.REF.z_ggeler.2021.28">Zöggeler et al 2021</a>].</p></div></dd><dt>5. </dt><dd><div id="vlcad.TF.6.5"><p class="no_margin">The FDA recommends discontinuing MCT products prior to initiation of triheptanoin therapy. In the retrospective study by <a class="bk_pop" href="#vlcad.REF.z_ggeler.2021.28">Zöggeler et al [2021]</a>, affected individuals were given parallel administration of MCT oil and triheptanoin.</p></div></dd><dt>6. </dt><dd><div id="vlcad.TF.6.6"><p class="no_margin"><a class="bk_pop" href="#vlcad.REF.calvert.2018.1074">Calvert et al [2018]</a>, <a class="bk_pop" href="#vlcad.REF.vockley.2019.169">Vockley et al [2019]</a></p></div></dd><dt>7. </dt><dd><div id="vlcad.TF.6.7"><p class="no_margin">
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||
<a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al [2020]</a>
|
||
</p></div></dd><dt>8. </dt><dd><div id="vlcad.TF.6.8"><p class="no_margin"><a class="bk_pop" href="#vlcad.REF.gillingham.2006.58">Gillingham et al [2006]</a>, <a class="bk_pop" href="#vlcad.REF.behrend.2012.110">Behrend et al [2012]</a></p></div></dd><dt>9. </dt><dd><div id="vlcad.TF.6.9"><p class="no_margin"><a class="bk_pop" href="#vlcad.REF.hoffman.2006.657">Hoffman et al [2006]</a>, <a class="bk_pop" href="#vlcad.REF.lafor_t.2009.324">Laforêt et al [2009]</a></p></div></dd></dl></div></div></div><div id="vlcad.T.baseline_1_recommended_total_lon" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Baseline <sup>1</sup> Recommended Total, Long-Chain, and Medium-Chain Fat Intake and Estimated Energy Requirement By Age and Pregnancy/Lactation Status in Individuals with VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.baseline_1_recommended_total_lon/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.baseline_1_recommended_total_lon_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" style="text-align:left;vertical-align:middle;">Age</th><th id="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" style="text-align:left;vertical-align:middle;">Disease Severity</th><th id="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3" colspan="3" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">% of Total Energy</th><th id="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_4" style="text-align:left;vertical-align:middle;">Method of Calculating Energy Requirement</th></tr><tr><th headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3" id="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">From Total Fat</th><th headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3" id="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">From Long-Chain Fat</th><th headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3" id="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">From Medium-Chain Fat</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>0-6 mos</b>
|
||
</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">40-55</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-15</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30-45</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_4" rowspan="9" colspan="1" style="text-align:left;vertical-align:middle;">EER <sup>2</sup></td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">15-30</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-30</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">30-55</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-20</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>7-12 mos</b>
|
||
</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">35-45</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-15</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25-30</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">15-30</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-25</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">30-40</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-10</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>1-3 yrs</b>
|
||
</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">30-40</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-15</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-30</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">20-30</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-20</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">20-40</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-10</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>4-18 yrs</b>
|
||
</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">25-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15-25</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_4" rowspan="6" colspan="1" style="text-align:left;vertical-align:middle;">EER w/PAL</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">15-25</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-20</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">20-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-10</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>>19 yrs</b>
|
||
</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">20-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-25</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">15-20</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-20</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">20-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-10</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Pregnancy</b>
|
||
</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">20-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-25</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">EER per trimester</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">15-20</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-20</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">20-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-10</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Lactation</b>
|
||
</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">20-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-25</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">EER</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">15-25</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10-20</td></tr><tr><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">20-35</td><td headers="hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_1_3 hd_h_vlcad.T.baseline_1_recommended_total_lon_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0-10</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al [2020]</a>
|
||
<a href="https://www.sciencedirect.com/science/article/pii/S1096719220302018?via%3Dihub#t0010" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Table 2</a></p></div></dd><dt></dt><dd><div><p class="no_margin">EER = estimated energy requirement; PAL = physical activity level</p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.7.1"><p class="no_margin">When an affected individual is clinically well.</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.7.2"><p class="no_margin">The estimated energy requirement calculated based on age or pregnancy trimester was published by the <a class="bk_pop" href="#vlcad.REF20">Institute of Medicine [2005]</a>.</p></div></dd></dl></div></div></div><div id="vlcad.T.emergency_outpatient_treatment_i" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Emergency Outpatient Treatment in Individuals with VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.emergency_outpatient_treatment_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.emergency_outpatient_treatment_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation</th><th id="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mildly ↑ catabolism <sup>1</sup></td><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Frequent high-carbohydrate feedings <sup>2</sup></div></li><li class="half_rhythm"><div>Fasting duration time should be ↓ compared to when person is well.</div></li></ul>
|
||
</td><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Trial of outpatient treatment at home for up to 12 hrs</div></li><li class="half_rhythm"><div>Reassessment frequently for clinical changes</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fever</td><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Administer antipyretics (acetaminophen, ibuprofen) if temperature >38.5 °C.</td><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Occasional vomiting</td><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Antiemetics <sup>3</sup></td><td headers="hd_h_vlcad.T.emergency_outpatient_treatment_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="vlcad.TF.8.1"><p class="no_margin">Fever <38.5 °C (101 °F); enteral feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability)</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.8.2"><p class="no_margin">Focusing on foods that will provide glucose polymers, or simple or complex carbohydrates [<a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al 2020</a>]</p></div></dd><dt>3. </dt><dd><div id="vlcad.TF.8.3"><p class="no_margin">Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to a hospital.</p></div></dd></dl></div></div></div><div id="vlcad.T.acute_inpatient_treatment_in_ind" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Acute Inpatient Treatment in Individuals with VLCAD Deficiency <sup>1</sup></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.acute_inpatient_treatment_in_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.acute_inpatient_treatment_in_ind_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation</th><th id="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consideration/Other</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ catabolism (due to fever, perioperative/peri-interventional fasting periods, repeated vomiting/diarrhea)</td><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Administer high-energy fluids (at least 10% IV dextrose) w/electrolytes at rate of ≥1.5x maintenance (minimum of 8 mg/kg/min of glucose). <sup>2</sup></td><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Avoid use of L-carnitine during acute illness.</div></li><li class="half_rhythm"><div>Avoid use of IV lipids.</div></li><li class="half_rhythm"><div>A source of essential fatty acids should be provided after 7 days.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy /<br />Cardiac failure</td><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fluid amounts may require adjustment based on cardiac status w/o compromising caloric provisions.</td></tr><tr><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rhabdomyolysis</td><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ample hydration & alkalization of urine</td><td headers="hd_h_vlcad.T.acute_inpatient_treatment_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To protect kidney function & prevent acute kidney failure secondary to myoglobinuria</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al [2020]</a></p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.9.1"><p class="no_margin">Inpatient emergency treatment should (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.9.2"><p class="no_margin">Total fluid volumes may need to be adjusted if the affected individual has cardiomyopathy; however, caloric provision should not be compromised. If necessary, decreasing IV fluid rates and increasing dextrose concentration (with supplemental insulin, if necessary, to avoid acute hyperglycemia) is required.</p></div></dd></dl></div></div></div><p><b>Transitional care from pediatric to adult-centered multidisciplinary care settings.</b> As a lifelong disorder with varying implications according to age, smooth transition of care from the pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Standardized procedures for transitional care do not exist for VLCAD deficiency because of the absence of multidisciplinary outpatient departments.</p><ul><li class="half_rhythm"><div>Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with VLCAD deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.</div></li><li class="half_rhythm"><div>As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.</div></li></ul></div><div id="vlcad.Prevention_of_Primary_Manifestatio"><h3>Prevention of Primary Manifestations</h3><p>See Management, <a href="#vlcad.Treatment_of_Manifestations">Treatment of Manifestations</a>, <a href="/books/NBK6816/table/vlcad.T.routine_daily_treatment_in_indiv/?report=objectonly" target="object" rid-ob="figobvlcadTroutinedailytreatmentinindiv">Table 6</a>.</p></div><div id="vlcad.Prevention_of_Secondary_Complicati"><h3>Prevention of Secondary Complications</h3><p>One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation results in management that can be administered expediently in the setting of intercurrent illness or other catabolic stressors.</p><div id="vlcad.T.prevention_of_secondary_manifest" class="table"><h3><span class="label">Table 10. </span></h3><div class="caption"><p>Prevention of Secondary Manifestations in Individuals with VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.prevention_of_secondary_manifest/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.prevention_of_secondary_manifest_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Situation</th><th id="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prevention</th><th id="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Acute decompensation /<br />Rhabdomyolysis</td><td headers="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute decompensation / rhabdomyolysis</div></li><li class="half_rhythm"><div>Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home</div></li><li class="half_rhythm"><div>Medical alert bracelets/pendants, or car seat stickers</div></li></ul>
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</td><td headers="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff. <sup>1, 2</sup></div></li><li class="half_rhythm"><div>Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for VLCAD deficiency & containing contact info for primary treating metabolic center.</div></li><li class="half_rhythm"><div>For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.</div></li></ul>
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</td></tr><tr><td headers="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgery or procedure<br />(incl dental procedures)</td><td headers="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. <sup>3</sup></div></li><li class="half_rhythm"><div>Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).</div></li><li class="half_rhythm"><div>Some anesthetics may be contraindicated (see <a href="#vlcad.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a>).</div></li></ul>
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</td><td headers="hd_h_vlcad.T.prevention_of_secondary_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider placing a "flag" in affected person's medical record so that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in setting of certain procedures.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="vlcad.TF.10.1"><p class="no_margin">Essential information including written treatment protocols should be provided <i>before</i> inpatient emergency treatment may be necessary.</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.10.2"><p class="no_margin">Parents or local hospitals should immediately inform the designated metabolic center if (1) temperature rises above 38.5 °C, (2) vomiting/diarrhea or other symptoms of intercurrent illness develop, or (3) new neurologic symptoms occur.</p></div></dd><dt>3. </dt><dd><div id="vlcad.TF.10.3"><p class="no_margin">For affected individuals deemed to be high risk for perioperative complications, perioperative/perianesthetic management precautions may include an evaluation at a specialty anesthetic clinic.</p></div></dd></dl></div></div></div></div><div id="vlcad.Surveillance"><h3>Surveillance</h3><p>In addition to regular evaluations by a metabolic specialist and metabolic dietician, the surveillance evaluations summarized in <a href="/books/NBK6816/table/vlcad.T.recommended_surveillance_for_ind/?report=objectonly" target="object" rid-ob="figobvlcadTrecommendedsurveillanceforind">Table 11</a> are recommended.</p><div id="vlcad.T.recommended_surveillance_for_ind" class="table"><h3><span class="label">Table 11. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.recommended_surveillance_for_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.recommended_surveillance_for_ind_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation</th><th id="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency/Comment</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Abnormal growth /<br />Assessment of nutritional deficiencies /<br />Feeding issues</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Measurement of growth (w/special attention to obesity) <sup>1</sup> & head circumference</div></li><li class="half_rhythm"><div>Assessment of feeding skills in infants/toddlers</div></li></ul>
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</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Abnormal biochemical laboratory parameters</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Plasma carnitine panel (total, free, esters)</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Every 3 mos for 1st yr of life</div></li><li class="half_rhythm"><div>Every 6-12 mos for those age >1 yr</div></li></ul>
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</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Plasma acylcarnitine profile</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Every 3 mos for 1st yr of life</div></li><li class="half_rhythm"><div>Every 3-6 mos for those age 1-7 yrs</div></li><li class="half_rhythm"><div>Every 6-12 mos for those age >7 yrs</div></li></ul>
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</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Creatine kinase level</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">RBC or plasma essential fatty acids (for persons on long-chain fat restriction)</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6 mos</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Vitamins A, D, & E (for persons on long-chain fat restriction)</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually or as clinically indicated</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CBC, ferritin level, comprehensive metabolic panel <sup>2</sup></td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As clinically indicated</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least annually or as clinically indicated <sup>3</sup></td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Measurement of troponin & BNP</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As clinically indicated</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓ bone mineral density</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DXA scan</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 5 yrs in adults <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al [2020]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">BNP = B-type natriuretic protein; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; RBC = red blood cell</p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.11.1"><p class="no_margin">Obesity can become a significant problem, and is not easy to remedy in individuals with exercise intolerance and requirement for active management of fasting.</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.11.2"><p class="no_margin">To include electrolytes, kidney function, liver function, and glucose</p></div></dd><dt>3. </dt><dd><div id="vlcad.TF.11.3"><p class="no_margin">Particularly in individuals with previous cardiac dysfunction or those with significant exercise intolerance</p></div></dd><dt>4. </dt><dd><div id="vlcad.TF.11.4"><p class="no_margin">Decreased bone mineral density is not a primary feature of VLCAD deficiency but can occur in those who have nutritional deficiencies, such as low total 25-hydroxyvitamine D concentrations.</p></div></dd></dl></div></div></div></div><div id="vlcad.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Avoid the following:</p><ul><li class="half_rhythm"><div>Fasting, including periods of preparation and recovery from planned surgery or sedation [<a class="bk_pop" href="#vlcad.REF.vellekoop.2011.96">Vellekoop et al 2011</a>]</div></li><li class="half_rhythm"><div>Myocardial irritation (e.g., cardiac catheterization)</div></li><li class="half_rhythm"><div>Dehydration (risk for acute tubular necrosis)</div></li><li class="half_rhythm"><div>High-fat diet (long-chain fats) including ketogenic or carbohydrate-restricted diets for the purpose of weight loss. Careful weight reduction has been accomplished by restricting long-chain fats and calories, supplementing with calories provided through medium-chain triglycerides, and limiting overnight catabolism with uncooked cornstarch [<a class="bk_pop" href="#vlcad.REF.zweers.2012.127">Zweers et al 2012</a>].</div></li><li class="half_rhythm"><div>Volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate [<a class="bk_pop" href="#vlcad.REF.vellekoop.2011.96">Vellekoop et al 2011</a>]. However, the use of propofol for short-duration procedures has been evaluated in individuals with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency and was not found to cause adverse events [<a class="bk_pop" href="#vlcad.REF.martin.2014.139">Martin et al 2014</a>].</div></li></ul></div><div id="vlcad.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>Testing of all at-risk sibs of any age is warranted to identify as early as possible those who would benefit from institution of treatment and preventive measures (see Management, <a href="#vlcad.Treatment_of_Manifestations">Treatment of Manifestations</a>).</p><ul><li class="half_rhythm"><div>If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.</div></li><li class="half_rhythm"><div>If the pathogenic variants in the family are not known, plasma or dried blood spot acylcarnitine analysis may not be sufficiently sensitive, and direct VLCAD assay of lymphocytes or fatty acid oxidation probe studies of cultured fibroblasts may be required.</div></li></ul><p>For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening either test for the familial <i>ACADVL</i> pathogenic variants or measure an acylcarnitine profile.</p><p>See <a href="#vlcad.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="vlcad.Pregnancy_Management"><h3>Pregnancy Management</h3><p>During pregnancy, placental and fetal beta-oxidation may temporize or even improve maternal fatty acid beta-oxidation [<a class="bk_pop" href="#vlcad.REF.mendezfigueroa.2010.558">Mendez-Figueroa et al 2010</a>]. However, labor and postpartum periods are catabolic states and place the mother at higher risk for rhabdomyolysis and subsequent myoglobinuria. A management plan for labor and delivery has been proposed by <a class="bk_pop" href="#vlcad.REF.mendezfigueroa.2010.558">Mendez-Figueroa et al [2010]</a>.</p><p>Energy needs and fat intake recommendations for women who are pregnant or lactating are listed in <a href="/books/NBK6816/table/vlcad.T.baseline_1_recommended_total_lon/?report=objectonly" target="object" rid-ob="figobvlcadTbaseline1recommendedtotallon">Table 7</a>.</p><div id="vlcad.T.recommended_surveillance_for_pre" class="table"><h3><span class="label">Table 12. </span></h3><div class="caption"><p>Recommended Surveillance for Pregnant and Lactating Women with VLCAD Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.recommended_surveillance_for_pre/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.recommended_surveillance_for_pre_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation</th><th id="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency/Comment</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nutritional deficiencies</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Formal visit w/nutritionist familiar w/VLCAD deficiency</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monthly or at least in each trimester</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Abnormal biochemical laboratory parameters</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Plasma carnitine panel (total, free, esters)</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Creatine kinase level</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Plasma acylcarnitine profile</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Weekly to monthly in pregnant women</div></li><li class="half_rhythm"><div>At every clinic visit in lactating women</div></li></ul>
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</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">RBC or plasma essential fatty acids (for persons on long-chain fat restriction)</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At least once during pregnancy</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Vitamins A, <sup>1</sup> D, & E (for persons on long-chain fat restriction)</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As baseline during pregnancy or as clinically indicated</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CBC, ferritin level, comprehensive metabolic panel <sup>2</sup></td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As clinically indicated</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Cardiomyopathy</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As baseline either prior to conception or as soon as pregnancy is recognized</td></tr><tr><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment by cardiologist & maternal fetal medicine specialist</td><td headers="hd_h_vlcad.T.recommended_surveillance_for_pre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Regularly, if affected person has known cardiac issue</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#vlcad.REF.van_calcar.2020.23">Van Calcar et al [2020]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">CBC = complete blood count; RBC = red blood cell</p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.12.1"><p class="no_margin">Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended. Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity.</p></div></dd><dt>2. </dt><dd><div id="vlcad.TF.12.2"><p class="no_margin">To include electrolytes, kidney function, liver function, and glucose</p></div></dd></dl></div></div></div><p>See <a href="https://mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for further information on medication use during pregnancy.</p></div><div id="vlcad.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p><b>Bezafibrates.</b> Small clinical trials have demonstrated controversial results.</p><ul><li class="half_rhythm"><div>An open-label clinical trial showed continuously improving physical functioning as assessed through quality of life questionnaire scores in all affected individuals who participated [<a class="bk_pop" href="#vlcad.REF.shiraishi.2019.100496">Shiraishi et al 2019</a>].</div></li><li class="half_rhythm"><div>An in vitro study found that mitochondrial metabolic capacity and glutathione were affected by benzafibrate treatment [<a class="bk_pop" href="#vlcad.REF.lund.2021.166100">Lund et al 2021</a>].</div></li></ul><p><b>Dodecanedioic acid.</b> In an in vitro study, dodecanedioic acid supplementation reduced levels of toxic very long-chain acylcarnitines [<a class="bk_pop" href="#vlcad.REF.radzikh.2021.538">Radzikh et al 2021</a>].</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="vlcad.Genetic_Counseling"><h2 id="_vlcad_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="vlcad.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is inherited in an autosomal recessive manner.</p></div><div id="vlcad.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a proband</b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be heterozygous for an <i>ACADVL</i> pathogenic variant.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an <i>ACADVL</i> pathogenic variant and to allow reliable recurrence risk assessment.</div></li><li class="half_rhythm"><div>If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a <i>de novo</i> event in the proband or as a postzygotic <i>de novo</i> event in a mosaic parent [<a class="bk_pop" href="#vlcad.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a proband</b>
|
||
</p><ul><li class="half_rhythm"><div>If both parents are known to be heterozygous for an <i>ACADVL</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> Unless an affected individual's reproductive partner also has VLCAD deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in <i>ACADVL</i>.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of an <i>ACADVL</i> pathogenic variant.</p></div><div id="vlcad.Carrier_Detection"><h3>Carrier Detection</h3><p><b>Molecular genetic carrier testing</b> for at-risk relatives requires prior identification of the <i>ACADVL</i> pathogenic variants in the family.</p><p><b>Biochemical genetic testing.</b> Measurement of acylcarnitines (an acylcarnitine profile), particularly in an unstressed individual, is not reliable for identifying heterozygotes. Functional testing of fibroblasts, using the various protocols of palmitate oxidation and incorporation into small acylcarnitine species, also does not typically identify carriers. A direct VLCAD enzyme assay may provide better evidence of a carrier state than the options described previously, but in most cases molecular genetic testing is preferred. In addition, the clinical availability of the VLCAD enzyme assay has varied with time.</p></div><div id="vlcad.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>The genetic status of full sibs should be determined since many individuals with VLCAD deficiency are not symptomatic during early childhood. See Management, <a href="#vlcad.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis, treatment, and preventive measures.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#vlcad.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="vlcad.Prenatal_Testing_and_Preimplantati"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>ACADVL</i> pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p><b>Biochemical genetic testing.</b> Prenatal diagnosis of VLCAD deficiency based on the pattern of incorporation of labeled carbons (ranging from palmitate into shorter-chain acylcarnitines) by cultured amniocytes (similar to the fibroblast in vitro acylcarnitine profile) has been described. Assay of VLCAD enzyme activity can distinguish between affected and unaffected cells. Absence of immunoreactive VLCAD on western blot analysis in those with severe VLCAD deficiency should provide additional information. As experience with and clinical availability of these assays is limited in the United States, molecular genetic testing is preferred for prenatal testing.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="vlcad.Resources"><h2 id="_vlcad_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Medical Home Portal</b>
|
||
</div><div>
|
||
<a href="https://www.medicalhomeportal.org/diagnoses-and-conditions/vlcadd" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VLCADD</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="https://medlineplus.gov/genetics/condition/very-long-chain-acyl-coa-dehydrogenase-deficiency/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Very long-chain acyl-coenzyme A dehydrogenase deficiency</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>STAR-G (Screening, Technology and Research in Genetics)</b>
|
||
</div><div><b>Email:</b> info@newbornscreening.info</div><div>
|
||
<a href="http://www.newbornscreening.info/Parents/fattyaciddisorders/VLCADD.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Very long chain acyl-coenzyme A dehydrogenase</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>FOD Family Support Group (Fatty Oxidation Disorder)</b>
|
||
</div><div><b>Phone:</b> 517-381-1940</div><div><b>Email:</b> deb@fodsupport.org; fodgroup@gmail.com</div><div>
|
||
<a href="http://www.fodsupport.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">fodsupport.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Newborn Screening in Your State</b>
|
||
</div><div>Health Resources & Services Administration</div><div>
|
||
<a href="https://newbornscreening.hrsa.gov/your-state" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">newbornscreening.hrsa.gov/your-state</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>United Mitochondrial Disease Foundation</b>
|
||
</div><div><b>Phone:</b> 888-317-UMDF (8633)</div><div><b>Email:</b> info@umdf.org</div><div>
|
||
<a href="https://www.umdf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.umdf.org</a>
|
||
</div></li></ul>
|
||
</div><div id="vlcad.Molecular_Genetics"><h2 id="_vlcad_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="vlcad.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_vlcad.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_vlcad.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_vlcad.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_vlcad.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_vlcad.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_vlcad.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_vlcad.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/37" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>ACADVL</i>
|
||
</a>
|
||
</td><td headers="hd_b_vlcad.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=37" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17p13<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_b_vlcad.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/P49748" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Very long-chain specific acyl-CoA dehydrogenase, mitochondrial</a>
|
||
</td><td headers="hd_b_vlcad.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://research.cchmc.org/LOVD2/home.php?select_db=ACADVL" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CCHMC - Human Genetics Mutation Database (ACADVL)</a>
|
||
</td><td headers="hd_b_vlcad.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ACADVL" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ACADVL</a>
|
||
</td><td headers="hd_b_vlcad.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=ACADVL[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ACADVL</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="vlcad.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
chromosome locus from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="vlcad.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (<a href="/omim/201475,609575" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/201475" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">201475</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN, DEFICIENCY OF; ACADVLD</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/609575" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">609575</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN; ACADVL</td></tr></tbody></table></div></div><div id="vlcad.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The fatty acid oxidation (FAO) spiral is a series of four reactions occurring in the mitochondrial matrix. Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation (β-oxidation) of long-chain fatty acids with a chain length of 14 to 20 carbons. There are a total of four highly homologous, straight-chain acyl-coenzyme A (CoA) dehydrogenases with differing, but overlapping, substrate specificities:</p><ul><li class="half_rhythm"><div>Short (SCAD; uses C4-C6 fatty acyl-CoAs)</div></li><li class="half_rhythm"><div>Medium (MCAD; C6-C10 fatty acyl-CoAs)</div></li><li class="half_rhythm"><div>Long (LCAD; C10-C14 fatty acyl-CoAs)</div></li><li class="half_rhythm"><div>Very long (VLCAD; C14-C20 fatty acyl-CoAs)</div></li></ul><p>SCAD, MCAD, and LCAD are homotetramers localized to the mitochondrial matrix; VLCAD is a homodimer associated with the inner mitochondrial membrane. These four homologs share about 40% amino acid identity or similarity within the catalytic domain; all use flavin adenine dinucleotide as the electron-accepting cofactor. Electrons are fed into the electron transport chain via ETF and ETF dehydrogenase.</p><p>With every turn of the β-oxidation spiral, the chain length is shortened by two carbon atoms. Reactions distal to the long-chain acyl-CoA dehydrogenase (LCAD) include those catalyzed by the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) / trifunctional protein, including a hydratase step, dehydrogenase step, and thiolase step.</p><p>As one of the first enzymes in the FAO spiral, the enzyme VLCAD controls a critical point in the supply of electrons to the respiratory chain, and also provides a pathway permissive to the production of ketones. It would be expected that significant reduction at this step of fatty acid oxidation would impair the ability to transition successfully from fetal to neonatal life, maintain cardiac output, adapt to long fasting, and generate energy for exercise.</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div id="vlcad.T.notable_acadvl_pathogenic_varian" class="table"><h3><span class="label">Table 13. </span></h3><div class="caption"><p>Notable <i>ACADVL</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK6816/table/vlcad.T.notable_acadvl_pathogenic_varian/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vlcad.T.notable_acadvl_pathogenic_varian_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000018.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000018<wbr style="display:inline-block"></wbr>.4</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000009.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000009<wbr style="display:inline-block"></wbr>.1</a>
|
||
</td><td headers="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.709T>C</td><td headers="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys237Arg<br />(Cys215Arg)</td><td headers="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assoc w/cardiac disease [<a class="bk_pop" href="#vlcad.REF.diekman.2015.989">Diekman et al 2015</a>]</td></tr><tr><td headers="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.848T>C</td><td headers="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val283Ala<br />(Val243Ala)</td><td headers="hd_h_vlcad.T.notable_acadvl_pathogenic_varian_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The most common pathogenic variant; accounts for ~10%-29% of all pathogenic alleles [<a class="bk_pop" href="#vlcad.REF.miller.2015.139">Miller et al 2015</a>, <a class="bk_pop" href="#vlcad.REF.pena.2016.272">Pena et al 2016</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="vlcad.TF.13.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></div></div></div></div></div><div id="vlcad.Chapter_Notes"><h2 id="_vlcad_Chapter_Notes_">Chapter Notes</h2><div id="vlcad.Author_History"><h3>Author History</h3><p>Jessica A Connor, MS; Counsyl, Inc (2014-2017)<br />Nancy D Leslie, MD (2009-present)<br />Sofia Saenz-Ayala, MD (2022-present)<br />Kerry Shooner, MS, CGC; Cincinnati Children's Hospital Medical Center (2009-2014)<br />Arnold W Strauss, MD; Cincinnati Children's Hospital Medical Center (2009-2022)<br />Brad T Tinkle, MD, PhD; Cincinnati Children's Hospital Medical Center (2009-2014)<br />C Alexander Valencia, PhD; Cincinnati Children's Hospital Medical Center (2014-2022)<br />Kejian Zhang, MD, MBA; Cincinnati Children's Hospital Medical Center (2009-2022)</p></div><div id="vlcad.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>13 July 2023 (nl) Revision: C14:1 level unit of measurement corrected to µmol/L in <a href="#vlcad.Suggestive_Findings">Suggestive Findings</a></div></li><li class="half_rhythm"><div>16 June 2022 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>4 January 2018 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>11 September 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 September 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 May 2009 (me) Review posted live</div></li><li class="half_rhythm"><div>29 December 2008 (ks) Original submission</div></li></ul></div></div><div id="vlcad.References"><h2 id="_vlcad_References_">References</h2><div id="vlcad.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="vlcad.REF.andresen.1999.479">Andresen
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D. Long-term experience with triheptanoin in 12 Austrian patients with long-chain fatty acid oxidation disorders.
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Orphanet J Rare Dis.
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2021;16:28.
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[<a href="/pmc/articles/PMC7807521/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7807521</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33446227" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33446227</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="vlcad.REF.zweers.2012.127">Zweers
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[<a href="/pmc/articles/PMC3565639/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3565639</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23430950" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23430950</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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