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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Progressive Myoclonus Epilepsy, Lafora Type - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Progressive Myoclonus Epilepsy, Lafora Type">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2025/01/23">
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<meta name="citation_author" content="Berge Minassian">
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<meta name="citation_pmid" content="20301563">
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<meta name="citation_keywords" content="Lafora Body Disease">
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<meta name="citation_keywords" content="Lafora Disease">
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<meta name="citation_keywords" content="Progressive Myoclonic Epilepsy Type 2 (EPM2)">
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<meta name="citation_keywords" content="Lafora Body Disease">
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<meta name="citation_keywords" content="Lafora Disease">
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<meta name="citation_keywords" content="Progressive Myoclonic Epilepsy Type 2 (EPM2)">
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<meta name="citation_keywords" content="E3 ubiquitin-protein ligase NHLRC1">
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<meta name="citation_keywords" content="Laforin">
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<meta name="citation_keywords" content="EPM2A">
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<meta name="citation_keywords" content="NHLRC1">
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<meta name="citation_keywords" content="Progressive Myoclonus Epilepsy, Lafora Type">
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<meta name="DC.Title" content="Progressive Myoclonus Epilepsy, Lafora Type">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Berge Minassian">
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<meta name="DC.Date" content="2025/01/23">
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<meta name="description" content="Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus occurring in previously healthy individuals. Typical age of onset is eight to 19 years (peak: age14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may also occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbances and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic degeneration.">
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<meta name="og:description" content="Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus occurring in previously healthy individuals. Typical age of onset is eight to 19 years (peak: age14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may also occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbances and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic degeneration.">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1389_"><span class="title" itemprop="name">Progressive Myoclonus Epilepsy, Lafora Type</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Lafora Body Disease, Lafora Disease, Progressive Myoclonic Epilepsy Type 2 (EPM2)</div><p class="contribs">Minassian B.</p><p class="fm-aai"><a href="#_NBK1389_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 33 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="lafora.Summary" itemprop="description"><h2 id="_lafora_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus occurring in previously healthy individuals. Typical age of onset is eight to 19 years (peak: age14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may also occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbances and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic degeneration.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Lafora disease is established in a proband with characteristic neurologic findings and/or biallelic pathogenic variants in one of the two known causative genes, <i>EPM2A</i> or <i>NHLRC1</i>, identified by molecular genetic testing. On rare occasion, a skin biopsy to detect Lafora bodies is necessary to confirm the diagnosis.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Medical treatment in combination with physical therapy and psychosocial support. Regular evaluation and readjustment are required as the disease progresses. Anti-seizure medications are effective against generalized seizures but do not alter the progression of cognitive and behavioral manifestations. Overmedication in treating drug-resistant myoclonus is a risk. Gastrostomy feedings can decrease the risk of aspiration pneumonia when the disease is advanced.</p><p><i>Surveillance:</i> Clinical and psychosocial evaluations throughout the teenage years. Monitoring of developmental progress and educational needs, in conjunction with behavioral assessments. Continuous assessment of feeding, nutritional status, and airway protection (including aspiration risk).</p><p><i>Agents/circumstances to avoid:</i> Phenytoin as maintenance therapy; possibly lamotrigine, carbamazepine, and oxcarbazepine.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Lafora disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an <i>EPM2A</i> or <i>NHLRC1</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 being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for at-risk pregnancies, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.</p></div></div><div id="lafora.Diagnosis"><h2 id="_lafora_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, have been published.</p><div id="lafora.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Lafora disease <b>should be suspected</b> in a previously healthy older child or adolescent (usually in the early teens) with the following clinical manifestations and family history:</p><p>
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<b>Clinical manifestations</b>
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</p><ul><li class="half_rhythm"><div>Focal occipital seizures presenting as transient blindness or visual hallucinations</div></li><li class="half_rhythm"><div>Fragmentary, symmetric, or generalized myoclonus</div></li><li class="half_rhythm"><div>Generalized seizures including tonic-clonic seizures, absence seizures, or drop attacks</div></li><li class="half_rhythm"><div>Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia</div></li><li class="half_rhythm"><div>Slowing of EEG background activity, loss of alpha rhythm and sleep features, posteriorly dominant irregular spike-wave discharges, and photosensitivity on early EEGs</div></li><li class="half_rhythm"><div>Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy (See <a href="#lafora.Clinical_Description">Clinical Description</a>.)</div></li><li class="half_rhythm"><div>Normal brain MRI at disease onset; progressive cortical atrophy possible later in the course of the disease</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 id="lafora.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of Lafora disease <b>is established</b> in a proband with characteristic neurologic findings and/or biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in <a href="/books/NBK1389/table/lafora.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figoblaforaTmoleculargenetictestingused">Table 1</a>.</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="bibr" href="#lafora.REF.richards.2015.405" rid="lafora.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 variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in the genes listed in <a href="/books/NBK1389/table/lafora.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figoblaforaTmoleculargenetictestingused">Table 1</a> does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#lafora.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#lafora.Option_2">Option 2</a>).</p><div id="lafora.Option_1"><h4>Option 1</h4><p>When the phenotypic findings suggest the diagnosis of Lafora disease, the molecular genetic testing approach is use of a <b>multigene panel</b>.</p><p><b>A multigene panel</b> that includes some or all of the genes listed in <a href="/books/NBK1389/table/lafora.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figoblaforaTmoleculargenetictestingused">Table 1</a> and other genes of interest (see <a href="#lafora.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.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="lafora.Option_2"><h4>Option 2</h4><p>When the diagnosis of Lafora disease has not been considered because an individual has atypical phenotypic features, <b>comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which gene(s) are likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible. To date, the majority of <i>EPM2A</i> and <i>NHLRC1</i> pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforaTmoleculargenetictestingused"><a href="/books/NBK1389/table/lafora.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figoblaforaTmoleculargenetictestingused"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.T.molecular_genetic_testing_used"><a href="/books/NBK1389/table/lafora.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figoblaforaTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type </p></div></div><p><b>Skin biopsy.</b> Although molecular genetic analysis of <i>EPM2A</i> and <i>NHLRC1</i> represents the gold standard for confirming the diagnosis of Lafora disease, a skin biopsy remains a useful diagnostic tool in individuals with a clinical diagnosis of Lafora disease in whom no pathogenic variants can be identified. In affected individuals, a skin biopsy reveals Lafora bodies [<a class="bibr" href="#lafora.REF.carpenter.1974.531" rid="lafora.REF.carpenter.1974.531">Carpenter et al 1974</a>, <a class="bibr" href="#lafora.REF.carpenter.1981.1564" rid="lafora.REF.carpenter.1981.1564">Carpenter & Karpati 1981</a>] composed of starch-like polyglucosans, which are insufficiently branched and hence insoluble glycogen molecules. Lafora bodies are present in either eccrine duct cells or in apocrine myoepithelial cells.</p><p>Note: (1) Normal PAS-positive apical granules in secretory apocrine cells found in the axilla can be mistaken for Lafora bodies; thus, biopsy of skin outside the axilla and genital regions is favored, as eccrine duct cell Lafora bodies are unmistakable [<a class="bibr" href="#lafora.REF.andrade.2003.1611" rid="lafora.REF.andrade.2003.1611">Andrade et al 2003</a>]. (2) Interpretation of findings on skin biopsy involves a risk of false negative results [<a class="bibr" href="#lafora.REF.lesca.2010.1691" rid="lafora.REF.lesca.2010.1691">Lesca et al 2010</a>], especially in newly symptomatic individuals, and a risk of false positive results because of the difficulty in distinguishing Lafora bodies from normal PAS-positive polysaccharides in apocrine glands [<a class="bibr" href="#lafora.REF.drury.1993.102" rid="lafora.REF.drury.1993.102">Drury et al 1993</a>, <a class="bibr" href="#lafora.REF.andrade.2003.1611" rid="lafora.REF.andrade.2003.1611">Andrade et al 2003</a>].</p></div></div></div><div id="lafora.Clinical_Characteristics"><h2 id="_lafora_Clinical_Characteristics_">Clinical Characteristics</h2><div id="lafora.Clinical_Description"><h3>Clinical Description</h3><p>Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is a rare teenage-onset progressive myoclonus epilepsy. The term "myoclonus" is emphasized because this is a relatively infrequent neurologic symptom in teenagers. When seen in an otherwise healthy adolescent, it strongly suggests a common benign form of epilepsy, juvenile myoclonic epilepsy (JME). For this reason, most individuals with Lafora disease are briefly misdiagnosed with JME. However, while the EEG background in JME is normal, it is already abnormal (slow) when myoclonus appears in individuals with Lafora disease.</p><p>Lafora disease is associated with inexorable worsening of the epilepsy. Myoclonus gradually becomes near constant. Generalized tonic-clonic seizures gradually become intractable; atypical absences with or without myoclonus eventually take over. The affected individual's interactions become such that every thought, speech, feeding, etc., are interrupted, and each of these and other functions become slow and protracted. Walking ability is lost usually in most affected individuals before age 21 years. Within ten years of disease onset, most individuals are in a vegetative state and usually die in status epilepticus or complications of poor airway control.</p><p>To date, at least 300 individuals have been identified with Lafora disease [<a class="bibr" href="#lafora.REF.orooj.2021.427" rid="lafora.REF.orooj.2021.427">Orooj et al 2021</a>, <a class="bibr" href="#lafora.REF.zaganas.2021.100477" rid="lafora.REF.zaganas.2021.100477">Zaganas et al 2021</a>, <a class="bibr" href="#lafora.REF.dorsi.2022.969297" rid="lafora.REF.dorsi.2022.969297">d'Orsi et al 2022</a>, <a class="bibr" href="#lafora.REF.katz.2022.404" rid="lafora.REF.katz.2022.404">Katz et al 2022</a>, <a class="bibr" href="#lafora.REF.krakhmal.2022.61" rid="lafora.REF.krakhmal.2022.61">Krakhmal et al 2022</a>, <a class="bibr" href="#lafora.REF.liang.2022.3467" rid="lafora.REF.liang.2022.3467">Liang et al 2022</a>, <a class="bibr" href="#lafora.REF.nordli.2022" rid="lafora.REF.nordli.2022">Nordli et al 2022</a>, <a class="bibr" href="#lafora.REF.orsini.2022.3597" rid="lafora.REF.orsini.2022.3597">Orsini et al 2022</a>, <a class="bibr" href="#lafora.REF.tang.2022.107255" rid="lafora.REF.tang.2022.107255">Tang et al 2022</a>, <a class="bibr" href="#lafora.REF.zeka.2022.360" rid="lafora.REF.zeka.2022.360">Zeka et al 2022</a>, <a class="bibr" href="#lafora.REF.dorsi.2023.1202971" rid="lafora.REF.dorsi.2023.1202971">d'Orsi et al 2023</a>, <a class="bibr" href="#lafora.REF.ferrari_aggradi.2023.1679" rid="lafora.REF.ferrari_aggradi.2023.1679">Ferrari Aggradi et al 2023</a>, <a class="bibr" href="#lafora.REF.pondrelli.2023.263" rid="lafora.REF.pondrelli.2023.263">Pondrelli et al 2023</a>, <a class="bibr" href="#lafora.REF.duan.2024" rid="lafora.REF.duan.2024">Duan et al 2024</a>, <a class="bibr" href="#lafora.REF.zhu.2024.1713" rid="lafora.REF.zhu.2024.1713">Zhu et al 2024</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforaTclinicalfindingsofprogressiv"><a href="/books/NBK1389/table/lafora.T.clinical_findings_of_progressiv/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figoblaforaTclinicalfindingsofprogressiv"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.T.clinical_findings_of_progressiv"><a href="/books/NBK1389/table/lafora.T.clinical_findings_of_progressiv/?report=objectonly" target="object" rid-ob="figoblaforaTclinicalfindingsofprogressiv">Table 2. </a></h4><p class="float-caption no_bottom_margin">Clinical Findings of Progressive Myoclonus Epilepsy, Lafora Type </p></div></div><p><b>Age of onset.</b> Lafora disease typically starts during childhood or adolescence (range: age 8-19 years, peak: age 14-16 years), after a period of apparently normal development. Many affected individuals experience isolated febrile or nonfebrile seizures during infancy or early childhood. Intractable seizures rarely begin as early as age six years. In families with more than one affected individual, clinical manifestations such as subtle myoclonus, visual hallucinations, or headaches are noted earlier in subsequently affected children than in the proband [<a class="bibr" href="#lafora.REF.minassian.2000b.341" rid="lafora.REF.minassian.2000b.341">Minassian et al 2000b</a>, <a class="bibr" href="#lafora.REF.minassian.2002.199" rid="lafora.REF.minassian.2002.199">Minassian 2002</a>]. Intra- and interfamilial variability in age at onset is considerable [<a class="bibr" href="#lafora.REF.g_mezabad.2007.1011" rid="lafora.REF.g_mezabad.2007.1011">Gómez-Abad et al 2007</a>, <a class="bibr" href="#lafora.REF.lohi.2007.996" rid="lafora.REF.lohi.2007.996">Lohi et al 2007</a>].</p><p><b>Seizure types.</b> The main seizure types in Lafora disease include myoclonic seizures and occipital seizures, although generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may occur. Generalized seizures are rare in individuals who are treated, even years after disease onset.</p><p><b>Myoclonus</b> can be fragmentary, symmetric, or massive (generalized). It occurs at rest and is exaggerated by action, photic stimulation, or excitement. Both negative (loss of tone) and positive (jerking) myoclonus can occur. Myoclonus usually disappears with sleep. Trains of massive myoclonus with relative preservation of consciousness have been reported. Myoclonus is the primary reason for early wheelchair dependency. In the advanced stages of the disease, affected individuals often have continuous generalized myoclonus.</p><p><b>Occipital seizures</b> present as transient blindness, simple or complex visual hallucinations, photomyoclonic or photoconvulsive seizures, or migraines with scintillating scotomata [<a class="bibr" href="#lafora.REF.berkovic.1993.s19" rid="lafora.REF.berkovic.1993.s19">Berkovic et al 1993</a>, <a class="bibr" href="#lafora.REF.minassian.2000b.341" rid="lafora.REF.minassian.2000b.341">Minassian et al 2000b</a>]. Not all visual hallucinations in individuals with Lafora disease are epileptic in origin, as some respond initially to anti-psychotic, rather than anti-seizure, medications [<a class="bibr" href="#lafora.REF.andrade.2005.1311" rid="lafora.REF.andrade.2005.1311">Andrade et al 2005</a>].</p><p><b>Progression.</b> The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the previously mentioned seizure types is common. Cognitive decline becomes apparent at or soon after seizure onset. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia. See <a href="/books/NBK1389/table/lafora.T.clinical_findings_of_progressiv/?report=objectonly" target="object" rid-ob="figoblaforaTclinicalfindingsofprogressiv">Table 2</a> for a comparison of the findings at onset and later in the disease course.</p><p>By their mid-twenties, most affected individuals are in a vegetative state with continuous myoclonus and require tube feeding. Some maintain minimal interactions with the family such as a reflex-like smiling upon cajoling. Affected individuals who are not tube fed aspirate frequently because of seizures; death from aspiration pneumonia is common.</p><p>Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic deterioration [<a class="bibr" href="#lafora.REF.turnbull.2016.38" rid="lafora.REF.turnbull.2016.38">Turnbull et al 2016</a>].</p></div><div id="lafora.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Most pathogenic variants in <i>NHLRC1</i> (EPM2B) and <i>EPM2A</i> (EPM2A) result in complete loss of function. Phenotypes associated with these variants are indistinguishable and represent classic Lafora disease. To date, pathogenic variants in <i>EPM2A</i> affecting splicing result in the same severe classic Lafora disease [<a class="bibr" href="#lafora.REF.duan.2024" rid="lafora.REF.duan.2024">Duan et al 2024</a>].</p><p>There are reports of mild Lafora disease with slow disease progression in association with missense variants. For example, the <i>NHLRC1</i> pathogenic variant <a href="/books/NBK1389/table/lafora.T.epm2a_and_nhlrc1_pathogenic_var/?report=objectonly" target="object" rid-ob="figoblaforaTepm2aandnhlrc1pathogenicvar">p.Asp146Asn</a> has been reported in association with an atypical milder form of Lafora disease consisting of later onset of symptoms, longer disease course, and extended preservation of daily activities [<a class="bibr" href="#lafora.REF.ferlazzo.2014.e129" rid="lafora.REF.ferlazzo.2014.e129">Ferlazzo et al 2014</a>, <a class="bibr" href="#lafora.REF.lanoisel_e.2014.19" rid="lafora.REF.lanoisel_e.2014.19">Lanoiselée et al 2014</a>].</p></div><div id="lafora.Nomenclature"><h3>Nomenclature</h3><p>Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is also referred to as myoclonic epilepsy of Lafora.</p><p>The term "progressive myoclonus epilepsy" (PME) covers a large and varied group of diseases characterized by myoclonus, generalized tonic-clonic seizures, and progressive neurologic deterioration [<a class="bibr" href="#lafora.REF.genton.2016.3" rid="lafora.REF.genton.2016.3">Genton et al 2016</a>].</p></div><div id="lafora.Prevalence"><h3>Prevalence</h3><p>Exact prevalence figures for Lafora disease are lacking. Based on all published reports of Lafora disease-causing pathogenic variants to date, the overall global frequency is estimated at 4:1,000,000 [<a class="bibr" href="#lafora.REF.turnbull.2016.38" rid="lafora.REF.turnbull.2016.38">Turnbull et al 2016</a>].</p><p>Lafora disease occurs worldwide. While relatively rare in the nonconsanguineous populations of the United States, Canada, China, and Japan, Lafora disease is relatively common in the Mediterranean basin of Spain, France, and Italy, in restricted regions of central Asia, India, Pakistan, northern Africa, and the Middle East, in ethnic isolates from the southern United States and Quebec, and in other parts of the world with a high rate of consanguinity [<a class="bibr" href="#lafora.REF.delgadoescueta.2001.129" rid="lafora.REF.delgadoescueta.2001.129">Delgado-Escueta et al 2001</a>].</p><p>Within the Italian and Japanese populations, pathogenic variants in <i>NHLRC1</i> are more common than pathogenic variants in <i>EPM2A</i>. Conversely, <i>EPM2A</i> pathogenic variants are more common in Spanish and French populations. Within the Indian and Arab populations, the distribution of pathogenic variants in the two genes is more or less even [<a class="bibr" href="#lafora.REF.singh.2009.715" rid="lafora.REF.singh.2009.715">Singh & Ganesh 2009</a>, <a class="bibr" href="#lafora.REF.lesca.2010.1691" rid="lafora.REF.lesca.2010.1691">Lesca et al 2010</a>].</p><p>Note: Lafora disease has not been reported in Finland, where founder effects for a number of genetic disorders are common, and where progressive myoclonic epilepsy type 1 (EPM1; <a href="/books/n/gene/epm1/?report=reader">Unverricht-Lundborg disease</a>) has the highest prevalence [A Lehesjoki & R Kälviäinen, personal communication].</p></div></div><div id="lafora.Genetically_Related_Allelic_Disor"><h2 id="_lafora_Genetically_Related_Allelic_Disor_">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>EPM2A</i> or <i>NHLRC1</i>.</p></div><div id="lafora.Differential_Diagnosis"><h2 id="_lafora_Differential_Diagnosis_">Differential Diagnosis</h2><p>Genes of interest in the differential diagnosis of progressive myoclonus epilepsy, Lafora type (also known as Lafora disease), are listed in <a href="/books/NBK1389/table/lafora.T.genes_of_interest_in_the_differ/?report=objectonly" target="object" rid-ob="figoblaforaTgenesofinterestinthediffer">Table 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforaTgenesofinterestinthediffer"><a href="/books/NBK1389/table/lafora.T.genes_of_interest_in_the_differ/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figoblaforaTgenesofinterestinthediffer"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.T.genes_of_interest_in_the_differ"><a href="/books/NBK1389/table/lafora.T.genes_of_interest_in_the_differ/?report=objectonly" target="object" rid-ob="figoblaforaTgenesofinterestinthediffer">Table 3. </a></h4><p class="float-caption no_bottom_margin">Genes of Interest in the Differential Diagnosis of Progressive Myoclonus Epilepsy, Lafora Type </p></div></div><p><b>Other disorders.</b> Cerebrospinal fluid concentration of lactate and titers of measles antibody can be helpful in dismissing the possibility of subacute sclerosing panencephalitis (SSPE).</p><p>Visual hallucinations, withdrawal, and cognitive decline raise concerns of schizophrenia, which becomes less likely with the onset of convulsions and the appearance of an epileptiform EEG.</p><p>Brain MRI excludes structural abnormalities.</p></div><div id="lafora.Management"><h2 id="_lafora_Management_">Management</h2><p>No clinical practice guidelines for progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.</p><div id="lafora.Evaluations_Following_Initial_Dia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Lafora disease, the evaluations summarized in <a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_eval/?report=objectonly" target="object" rid-ob="figoblaforaTlaforadiseaserecommendedeval">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforaTlaforadiseaserecommendedeval"><a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_eval/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figoblaforaTlaforadiseaserecommendedeval"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.T.lafora_disease_recommended_eval"><a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_eval/?report=objectonly" target="object" rid-ob="figoblaforaTlaforadiseaserecommendedeval">Table 4. </a></h4><p class="float-caption no_bottom_margin">Lafora Disease: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="lafora.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK1389/table/lafora.T.lafora_disease_treatment_of_man/?report=objectonly" target="object" rid-ob="figoblaforaTlaforadiseasetreatmentofman">Table 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforaTlaforadiseasetreatmentofman"><a href="/books/NBK1389/table/lafora.T.lafora_disease_treatment_of_man/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figoblaforaTlaforadiseasetreatmentofman"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.T.lafora_disease_treatment_of_man"><a href="/books/NBK1389/table/lafora.T.lafora_disease_treatment_of_man/?report=objectonly" target="object" rid-ob="figoblaforaTlaforadiseasetreatmentofman">Table 5. </a></h4><p class="float-caption no_bottom_margin">Lafora Disease: Treatment of Manifestations </p></div></div><div id="lafora.Epilepsy_Treatment"><h4>Epilepsy Treatment</h4><p>In general, treatment recommendations for Lafora disease follow those of other progressive myoclonic epilepsies (PMEs) [<a class="bibr" href="#lafora.REF.michelucci.2016.145" rid="lafora.REF.michelucci.2016.145">Michelucci et al 2016</a>, <a class="bibr" href="#lafora.REF.ferlazzo.2017.5662" rid="lafora.REF.ferlazzo.2017.5662">Ferlazzo et al 2017</a>]. Anti-seizure medications (ASMs) have a clear effect against generalized seizures, sometimes controlling seizures for many months. However, ASMs do not influence the progression of cognitive and behavioral symptoms in Lafora disease.</p><ul><li class="half_rhythm"><div><b>First-line ASMs</b> include valproic acid and benzodiazepines.</div><ul><li class="half_rhythm"><div>Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time.</div></li><li class="half_rhythm"><div>Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine.</div></li><li class="half_rhythm"><div>Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease.</div></li></ul></li><li class="half_rhythm"><div><b>Second-line ASMs</b> include levetiracetam, zonisamide, topiramate, and perampanel, although evidence is limited.</div><ul><li class="half_rhythm"><div>Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine.</div></li><li class="half_rhythm"><div>An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see <a href="#lafora.Therapies_Under_Investigation">Therapies Under Investigation</a>).</div></li></ul></li><li class="half_rhythm"><div><b>Third-line strategies</b> include primidone, phenobarbital, piracetam, and ethosuximide. There are two anecdotal reports on the use of vagal nerve stimulation in Lafora disease [<a class="bibr" href="#lafora.REF.hajnsek.2013.150" rid="lafora.REF.hajnsek.2013.150">Hajnsek et al 2013</a>, <a class="bibr" href="#lafora.REF.mikati.2017.82" rid="lafora.REF.mikati.2017.82">Mikati & Tabbara 2017</a>].</div></li><li class="half_rhythm"><div><b>Emergency treatment</b> for severe aggravation with recurrent seizures or status epilepticus consists of intravenous benzodiazepines or loading with phenytoin. Phenytoin should not be kept as maintenance therapy after arrest of the status epilepticus.</div></li></ul></div><div id="lafora.Developmental_Delay__Intellectual"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="lafora.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
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<b>Gross motor dysfunction</b>
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</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li><li class="half_rhythm"><div>For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox<sup>®</sup>, anti-parkinsonian medications, or orthopedic procedures.</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction</b> should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.</p></div><div id="lafora.NeurobehavioralPsychiatric_Concer"><h4>Neurobehavioral/Psychiatric Concerns</h4><p>Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.</p><p>Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.</p><p>Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.</p></div></div><div id="lafora.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_surv/?report=objectonly" target="object" rid-ob="figoblaforaTlaforadiseaserecommendedsurv">Table 6</a> are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforaTlaforadiseaserecommendedsurv"><a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_surv/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figoblaforaTlaforadiseaserecommendedsurv"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.T.lafora_disease_recommended_surv"><a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_surv/?report=objectonly" target="object" rid-ob="figoblaforaTlaforadiseaserecommendedsurv">Table 6. </a></h4><p class="float-caption no_bottom_margin">Lafora Disease: Recommended Surveillance </p></div></div></div><div id="lafora.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>As in other forms of progressive myoclonic epilepsies, the use of phenytoin as maintenance therapy should be avoided.</p><p>Anecdotal reports describe possible exacerbation of myoclonus with the following:</p><ul><li class="half_rhythm"><div>Lamotrigine [<a class="bibr" href="#lafora.REF.cerminara.2004.373" rid="lafora.REF.cerminara.2004.373">Cerminara et al 2004</a>, <a class="bibr" href="#lafora.REF.crespel.2005.762" rid="lafora.REF.crespel.2005.762">Crespel et al 2005</a>]</div></li><li class="half_rhythm"><div>Carbamazepine [<a class="bibr" href="#lafora.REF.nanba.1999.664" rid="lafora.REF.nanba.1999.664">Nanba & Maegaki 1999</a>]</div></li><li class="half_rhythm"><div>Oxcarbazepine [<a class="bibr" href="#lafora.REF.kaddurah.2006.289" rid="lafora.REF.kaddurah.2006.289">Kaddurah & Holmes 2006</a>]</div></li></ul></div><div id="lafora.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#lafora.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to evaluation of at-risk relatives for genetic counseling purposes.</p></div><div id="lafora.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Due to the severity of the disorder, individuals with Lafora disease typically do not have children. However, in cases of mild Lafora disease with slow disease progression (as reported with the <a href="/books/NBK1389/table/lafora.T.epm2a_and_nhlrc1_pathogenic_var/?report=objectonly" target="object" rid-ob="figoblaforaTepm2aandnhlrc1pathogenicvar">p.Asp146Asn</a> variant in <i>NHLRC1</i>), pregnancies could occur [<a class="bibr" href="#lafora.REF.ferlazzo.2014.e129" rid="lafora.REF.ferlazzo.2014.e129">Ferlazzo et al 2014</a>]. The universal use of anti-seizure medications in individuals with Lafora disease, even when mild, warrant counseling regarding the potential consequences of fetal exposure to maternal anti-convulsant therapy.</p><p>See <a href="https://www.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="lafora.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures greater than 74% from baseline in four individuals. Seven had major improvement in myoclonus. Three withdrew due to inefficacy or side effects. There was no improvement in disability or cognition [<a class="bibr" href="#lafora.REF.goldsmith.2016.132" rid="lafora.REF.goldsmith.2016.132">Goldsmith & Minassian 2016</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="lafora.Genetic_Counseling"><h2 id="_lafora_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="lafora.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease), is inherited in an autosomal recessive manner.</p></div><div id="lafora.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be heterozygous for an <i>EPM2A</i> or <i>NHLRC1</i> pathogenic variant.</div></li><li class="half_rhythm"><div>If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an <i>EPM2A</i> or <i>NHLRC1</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="bibr" href="#lafora.REF.j_nsson.2017.519" rid="lafora.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>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>If both parents are known to be heterozygous for an <i>EPM2A</i> or <i>NHLRC1</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 being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Variability in age at onset among affected family members is considerable (see <a href="#lafora.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>The offspring of an individual with Lafora disease would be obligate heterozygotes (carriers) for a pathogenic variant in <i>EPM2A</i> or <i>NHLRC1</i>.</div></li><li class="half_rhythm"><div>Because of the early onset and rapid deterioration, individuals with Lafora disease typically do not reproduce.</div></li></ul><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>EPM2A</i> or <i>NHLRC1</i> pathogenic variant.</p></div><div id="lafora.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>EPM2A</i> or <i>NHLRC1</i> pathogenic variants in the family.</p></div><div id="lafora.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Family planning</b>
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</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><li class="half_rhythm"><div>It is appropriate to offer <i>EPM2A</i> and <i>NHLRC1</i> molecular genetic testing for reproductive partners of individuals known to be heterozygous for a Lafora disease-related pathogenic variant, particularly if consanguinity is likely.</div></li></ul></div><div id="lafora.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>EPM2A</i> or <i>NHLRC1</i> pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="lafora.Resources"><h2 id="_lafora_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>Chelsea’s Hope Lafora Children Research Fund</b>
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</div><div>
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<a href="https://chelseashope.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">chelseashope.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>American Epilepsy Society</b>
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</div><div>
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<a href="https://www.aesnet.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aesnet.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Epilepsy Foundation</b>
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</div><div><b>Phone:</b> 800-332-1000; 866-748-8008</div><div>
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<a href="https://www.epilepsy.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">epilepsy.com</a>
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</div></li></ul>
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</div><div id="lafora.Molecular_Genetics"><h2 id="_lafora_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 class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforamolgenTA"><a href="/books/NBK1389/table/lafora.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figoblaforamolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.molgen.TA"><a href="/books/NBK1389/table/lafora.molgen.TA/?report=objectonly" target="object" rid-ob="figoblaforamolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Progressive Myoclonus Epilepsy, Lafora Type: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforamolgenTB"><a href="/books/NBK1389/table/lafora.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figoblaforamolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.molgen.TB"><a href="/books/NBK1389/table/lafora.molgen.TB/?report=objectonly" target="object" rid-ob="figoblaforamolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Progressive Myoclonus Epilepsy, Lafora Type (View All in OMIM) </p></div></div><div id="lafora.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><b><i>EPM2A.</i></b> This gene encodes a dual-specificity phosphatase called laforin and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. There are two isoforms of the laforin protein that have unique C termini [<a class="bibr" href="#lafora.REF.ganesh.2002b.1134" rid="lafora.REF.ganesh.2002b.1134">Ganesh et al 2002b</a>, <a class="bibr" href="#lafora.REF.ianzano.2004.170" rid="lafora.REF.ianzano.2004.170">Ianzano et al 2004</a>]. The carboxyl terminal of isoform B targets laforin to the nucleus, a feature that is not shared by the longer laforin isoform A. <a class="bibr" href="#lafora.REF.ianzano.2004.170" rid="lafora.REF.ianzano.2004.170">Ianzano et al [2004]</a> demonstrated that disturbances in the physiologic functions of laforin isoform A underlie the pathogenesis of Lafora disease, and isoform B cannot functionally substitute for laforin isoform A. Remarkably, more recent data indicates that laforin's phosphatase function is dispensable insofar as Lafora bodies, the neurotoxic accumulations that characterize the disease, are concerned. Several experiments showed that inactivating laforin's phosphatase domain while keeping the rest of the protein intact does not lead to Lafora body formation [<a class="bibr" href="#lafora.REF.nitschke.2017.906" rid="lafora.REF.nitschke.2017.906">Nitschke et al 2017</a>, <a class="bibr" href="#lafora.REF.skurat.2024.107271" rid="lafora.REF.skurat.2024.107271">Skurat et al 2024</a>]. All indications at present are that malin, encoded by <i>NHLRC1</i>, the second gene associated with Lafora disease, is key [<a class="bibr" href="#lafora.REF.sullivan.2019.1334" rid="lafora.REF.sullivan.2019.1334">Sullivan et al 2019</a>].</p><p><b><i>NHLRC1</i>.</b>
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<i>NHLRC1</i> encodes E3 ubiquitin-protein ligase NHLRC1 (also known as malin), a 395-amino acid protein. Malin contains a zinc finger of the RING type and six NHL-repeat protein-protein interaction domains [<a class="bibr" href="#lafora.REF.chan.2003b.125" rid="lafora.REF.chan.2003b.125">Chan et al 2003b</a>]. The pathology underlying Lafora disease consists of progressive formation of polyglucosans (insoluble glucose polysaccharides that precipitate and aggregate into concretized masses called Lafora bodies), resulting in neurodegeneration. Lafora bodies form in neuronal perikarya and in neuronal short processes (mostly dendrites). Lafora bodies in the neuronal processes are much smaller, but they massively outnumber Lafora bodies in the perikarya. Extraneurally, Lafora bodies also form in heart, liver, and skeletal muscle, but cause no symptoms in these organs [<a class="bibr" href="#lafora.REF.turnbull.2011.e1002037" rid="lafora.REF.turnbull.2011.e1002037">Turnbull et al 2011</a>]. The current view on Lafora disease pathogenesis suggests that Lafora disease is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. The principal function of laforin (the gene product of <i>EPM2A</i>) relevant to Lafora disease is mediated through malin (the gene product of <i>NHLRC1</i>) and directed to preventing glycogen molecules with hyperextended chains. In the absence of either protein, some glycogen molecules precipitate and gradually over time aggregate and amass into Lafora bodies, which, reaching a certain threshold profusion (at age ~14 years in humans), initiate and then drive the progressive myoclonus epilepsy [<a class="bibr" href="#lafora.REF.nitschke.2017.906" rid="lafora.REF.nitschke.2017.906">Nitschke et al 2017</a>, <a class="bibr" href="#lafora.REF.sullivan.2017.e1743" rid="lafora.REF.sullivan.2017.e1743">Sullivan et al 2017</a>]. Laforin's key function appears to be the targeting of malin to glycogen for malin's E3 ubiquitin ligase to regulate certain yet unconfirmed proteins [<a class="bibr" href="#lafora.REF.mitra.2023.dmm049802" rid="lafora.REF.mitra.2023.dmm049802">Mitra et al 2023</a>]. Suspected malin substrates are glycogen metabolism proteins [<a class="bibr" href="#lafora.REF.skurat.2024.107271" rid="lafora.REF.skurat.2024.107271">Skurat et al 2024</a>].</p><p>
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<b>Mechanism of disease causation</b>
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</p><ul><li class="half_rhythm"><div><i>EPM2A</i>-related Lafora disease: loss of function</div></li><li class="half_rhythm"><div><i>NHLRC1-</i>related Lafora disease: loss of function</div></li></ul><p><b><i>EPM2A-</i> and <i>NHLRC1</i>-specific laboratory technical considerations.</b>
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<i>NHLRC1</i> is a single-exon gene spanning 1,188 base pairs that has all of the proposed features of the consensus sequence of an eukaryotic translational initiation site at its 5' end and two putative polyadenylation signals at its 3' end.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figlaforaTepm2aandnhlrc1pathogenicvar"><a href="/books/NBK1389/table/lafora.T.epm2a_and_nhlrc1_pathogenic_var/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figoblaforaTepm2aandnhlrc1pathogenicvar"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="lafora.T.epm2a_and_nhlrc1_pathogenic_var"><a href="/books/NBK1389/table/lafora.T.epm2a_and_nhlrc1_pathogenic_var/?report=objectonly" target="object" rid-ob="figoblaforaTepm2aandnhlrc1pathogenicvar">Table 7. </a></h4><p class="float-caption no_bottom_margin"><i>EPM2A</i> and <i>NHLRC1</i> Pathogenic Variants Referenced in This <i>GeneReview</i> </p></div></div></div></div><div id="lafora.Chapter_Notes"><h2 id="_lafora_Chapter_Notes_">Chapter Notes</h2><div id="lafora.Author_Notes"><h3>Author Notes</h3><p><b>Berge A Minassian, MD,</b> directs the Child Neurology program at University of Texas Southwestern and co-directs the university's Gene Therapy Program. The two are intimately linked because most of Child Neurology is neurogenetic diseases. In addition to his work on developing gene therapies for childhood neurologic diseases, he has had an abiding interest in understanding the pathogenesis of Lafora disease, to which he has been committed for more than 30 years.</p></div><div id="lafora.Author_History"><h3>Author History</h3><p>Eva Andermann, MD, PhD, FCCMG; McGill University (2007-2025)<br />Anna C Jansen, MD, PhD; Vrije Universiteit Brussel (2007-2025)<br />Berge Minassian, MD (2025-present)</p></div><div id="lafora.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>23 January 2025 (gm) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 February 2019 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 January 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>3 November 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 December 2007 (me) Review posted live</div></li><li class="half_rhythm"><div>2 January 2007 (ea) Original submission</div></li></ul></div></div><div id="lafora.References"><h2 id="_lafora_References_">References</h2><div id="lafora.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="lafora.REF.altindag.2009.359">Altindag
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[<a href="https://pubmed.ncbi.nlm.nih.gov/38407811" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38407811</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1389_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Berge Minassian</span>, MD<div class="affiliation small">University of Texas Southwestern<br />Dallas, Texas<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.nretsewhtuostu@naissanim.egreb" class="oemail">ude.nretsewhtuostu@naissanim.egreb</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">December 28, 2007</span>; Last Update: <span itemprop="dateModified">January 23, 2025</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Minassian B. Progressive Myoclonus Epilepsy, Lafora Type. 2007 Dec 28 [Updated 2025 Jan 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/epm1/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/ppr-dysp/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figoblaforaTmoleculargenetictestingused"><div id="lafora.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of LD Attributed to Pathogenic Variants in Gene</th><th id="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>3</sup> Identified by Method</th></tr><tr><th headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_lafora.T.molecular_genetic_testing_used_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></th><th headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_lafora.T.molecular_genetic_testing_used_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EPM2A</i>
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</td><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50% <sup>6</sup></td><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_3 hd_h_lafora.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85%-90% <sup>6</sup></td><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_3 hd_h_lafora.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-15% <sup>6</sup></td></tr><tr><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NHLRC1</i>
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</td><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50% <sup>6</sup></td><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_3 hd_h_lafora.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>90% <sup>6</sup></td><td headers="hd_h_lafora.T.molecular_genetic_testing_used_1_1_1_3 hd_h_lafora.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><10% <sup>6, 7</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">LD = Lafora disease</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="lafora.TF.1.1"><p class="no_margin">Genes are listed alphabetically.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="lafora.TF.1.2"><p class="no_margin">See <a href="/books/NBK1389/?report=reader#lafora.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="lafora.TF.1.3"><p class="no_margin">See <a href="#lafora.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="lafora.TF.1.4"><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/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="lafora.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. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="lafora.TF.1.6"><p class="no_margin"><a class="bibr" href="#lafora.REF.turnbull.2016.38" rid="lafora.REF.turnbull.2016.38">Turnbull et al [2016]</a>; data also derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#lafora.REF.stenson.2020.1197" rid="lafora.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="lafora.TF.1.7"><p class="no_margin">Heterozygous deletions of the entire <i>NHLRC1</i> gene have been reported in an Italian and a Serbian family [<a class="bibr" href="#lafora.REF.lohi.2007.996" rid="lafora.REF.lohi.2007.996">Lohi et al 2007</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblaforaTclinicalfindingsofprogressiv"><div id="lafora.T.clinical_findings_of_progressiv" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Clinical Findings of Progressive Myoclonus Epilepsy, Lafora Type</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.T.clinical_findings_of_progressiv/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.T.clinical_findings_of_progressiv_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation Type</th><th id="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At Onset</th><th id="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Later in Disease Course</th></tr></thead><tbody><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>General physical exam, incl liver & spleen size</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic exam, incl fundi & reflexes</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysarthria, ataxia, spasticity; fundi remain normal</td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Mental state exam</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Visual hallucinations, cognitive deficits, depressed mood, headaches</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↑ hallucinations, agitation, & dementia w/predominantly frontal cognitive impairment affecting mainly performance ability & executive function</td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>EEG</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or slow background, occipital discharges</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Slow background, paroxysms of generalized irregular spike-wave discharges w/occipital predominance, & focal (esp occipital) abnormalities; loss of sleep features; marked photosensitivity</td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Visual, somatosensory, & auditory brain stem evoked potentials</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">High-voltage visual & somatosensory evoked potentials</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Amplitudes may return to normal size; prolongation of brain stem & central latencies</td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Nerve conduction studies</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>MRI of brain</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal or atrophy</td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Proton MR spectroscopy of brain</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Data not available</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">↓ NAA-to-creatine ratio in frontal & occipital cortex, basal ganglia, & cerebellum; ↓ NAA-to-myoinositol ratio in frontal gray & white matter; ↓ NAA-to-choline ratio in cerebellum; ↓ GABA; ↑ glutamate/glutamine; ↑ UDPG; ↑ G6P <sup>1</sup></td></tr><tr><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Transcranial magnetic stimulation</b>
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</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Not applicable</td><td headers="hd_h_lafora.T.clinical_findings_of_progressiv_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Defective short-interval intracortical inhibition: inhibition at ISI 6 ms & ISI 10 ms; defective long-interval cortical inhibition</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Based on <a class="bibr" href="#lafora.REF.altindag.2009.359" rid="lafora.REF.altindag.2009.359">Altindag et al [2009]</a>, <a class="bibr" href="#lafora.REF.canafoglia.2010.232" rid="lafora.REF.canafoglia.2010.232">Canafoglia et al [2010]</a>, <a class="bibr" href="#lafora.REF.turnbull.2016.38" rid="lafora.REF.turnbull.2016.38">Turnbull et al [2016]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">G6P = glucose-6-phosphate; GABA = gamma-aminobutyric acid; ISI = interstimulus intervals; NAA = N-acetylaspartate; UDPG = uridine diphosphate glucose</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="lafora.TF.2.1"><p class="no_margin">At least two years after onset of symptoms</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblaforaTgenesofinterestinthediffer"><div id="lafora.T.genes_of_interest_in_the_differ" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of Progressive Myoclonus Epilepsy, Lafora Type</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.T.genes_of_interest_in_the_differ/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.T.genes_of_interest_in_the_differ_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Disorder</th></tr><tr><th headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4" id="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/Lafora disease</th><th headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4" id="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from Lafora disease</th></tr></thead><tbody><tr><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CSTB</i>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/epm1/?report=reader">Progressive myoclonic epilepsy type 1</a> (EPM1; Unverricht-Lundborg disease)</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PME; focal occipital seizures & fragmentary, symmetric, or generalized myoclonus beginning in previously healthy persons</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Earlier age at onset, slower rate of disease progression, & absence of Lafora bodies on skin biopsy</td></tr><tr><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EFHC1</i>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Juvenile myoclonic epilepsy (OMIM <a href="https://omim.org/entry/254770" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">254770</a>)</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Myoclonus & generalized tonic-clonic seizures in adolescence</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Normal neurologic exam & undisturbed background of EEG</td></tr><tr><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>KCNC1</i>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive myoclonic epilepsy type 7 (EPM7) (OMIM <a href="https://omim.org/entry/616187" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616187</a>)</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PME</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Slower progression, non-fatal, & no Lafora bodies</td></tr><tr><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TF</i>
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<br />
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<i>MT-TH</i>
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<br />
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<i>MT-TI</i>
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<br />
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<i>MT-TK</i>
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<br />
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<i>MT-TL1</i>
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<br />
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<i>MT-TP</i>
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<br />
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<i>MT-TS1</i>
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<br />
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<i>MT-TS2</i>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/merrf/?report=reader">MERRF</a> (myoclonic epilepsy w/ragged red fibers)</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mat</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PME; onset usually in childhood after normal early development</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Brain MRI often shows brain atrophy & basal ganglia lesions.</div></li><li class="half_rhythm"><div>Muscle biopsy typically shows ragged red fibers.</div></li></ul>
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</td></tr><tr><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NEU1</i>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sialidosis types I & II (OMIM <a href="https://omim.org/entry/256550" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">256550</a>)</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Careful ophthalmologic exam, incl electroretinography, is useful in addressing possibilities of neuronal ceroid-lipofuscinoses.</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PRDM8</i>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PRDM8</i>-related early-onset Lafora body disease (OMIM <a href="https://omim.org/entry/616640" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616640</a>)</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PME & Lafora bodies in muscle (but not in sweat glands)</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Presents at age ~5 years; disease course is much more protracted than either typical LD or the phenotypically similar infantile neuronal ceroid lipofuscinosis.</div></li><li class="half_rhythm"><div>Note: Early-onset LD has been reported in 2 families to date. <sup>1</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SCARB2</i>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/amrf/?report=reader"><i>SCARB2</i>-related action myoclonus – renal failure syndrome</a>
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</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PME</td><td headers="hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_1_4 hd_h_lafora.T.genes_of_interest_in_the_differ_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult onset, prominent action myoclonus, & renal failure</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; LD = Lafora disease; Mat = maternal; PME = progressive myoclonic epilepsy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="lafora.TF.3.1"><p class="no_margin"><a class="bibr" href="#lafora.REF.turnbull.2012.2684" rid="lafora.REF.turnbull.2012.2684">Turnbull et al [2012]</a>, <a class="bibr" href="#lafora.REF.davarzani.2022.3847" rid="lafora.REF.davarzani.2022.3847">Davarzani et al [2022]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblaforaTlaforadiseaserecommendedeval"><div id="lafora.T.lafora_disease_recommended_eval" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Lafora Disease: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_eval/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.T.lafora_disease_recommended_eval_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl brain MRI & EEG</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech-language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
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|
</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurobehavioral/</b>
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<br />
|
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<b>Psychiatric</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For persons age >12 mos: screening for concerns incl sleep disturbances, ADHD, anxiety, &/or findings suggestive of ASD</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of LD to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family support</b>
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<br />
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<b>& resources</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By clinicians, wider care team, & family support organizations</td><td headers="hd_h_lafora.T.lafora_disease_recommended_eval_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of family & social structure to determine need for:
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<ul><li class="half_rhythm"><div>Community or <a href="#lafora.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a></div></li><li class="half_rhythm"><div>Social work involvement for parental support</div></li><li class="half_rhythm"><div>Home nursing referral</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; LD = Lafora disease; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="lafora.TF.4.1"><p class="no_margin">Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblaforaTlaforadiseasetreatmentofman"><div id="lafora.T.lafora_disease_treatment_of_man" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Lafora Disease: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.T.lafora_disease_treatment_of_man/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.T.lafora_disease_treatment_of_man_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_lafora.T.lafora_disease_treatment_of_man_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_lafora.T.lafora_disease_treatment_of_man_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Developmental delay / Intellectual disability / Neurobehavioral issues</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#lafora.Developmental_Delay__Intellectual">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Epilepsy</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Many ASMs may be effective (see <a href="#lafora.Epilepsy_Treatment">Epilepsy Treatment</a>).</div></li><li class="half_rhythm"><div>As the disease progresses, generalized seizures become more frequent & myoclonus more disabling, requiring more intensive support in the home environment or through institutionalization, depending on availability of care & family preferences.</div></li><li class="half_rhythm"><div>Serial seizures &/or status epilepticus may require admission to critical care.</div></li><li class="half_rhythm"><div>Education of parents/caregivers <sup>1</sup></div></li></ul>
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</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Tone abnormalities</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider need for positioning & mobility devices, disability parking placard.</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Pulmonary issues</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess airway control & protection.</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Placement by percutaneous endoscopy of a gastrostomy tube for feeding can be helpful in ↓ risk of aspiration pneumonia in persons w/advanced disease.</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Transition to adult care</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Develop realistic plans for adult life (see <a href="https://www.aesnet.org/docs/default-source/pdfs-clinical/aestransitionspracticetool-devdelayedfinalapproved4-21-132.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care</a>).</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Starting by age ~10 yrs</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family/Community</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
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</td><td headers="hd_h_lafora.T.lafora_disease_treatment_of_man_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ongoing assessment of need for palliative care involvement &/or home nursing</div></li><li class="half_rhythm"><div>Consider involvement in adaptive sports or <a href="https://www.specialolympics.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Special Olympics</a>.</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="lafora.TF.5.1"><p class="no_margin">Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblaforaTlaforadiseaserecommendedsurv"><div id="lafora.T.lafora_disease_recommended_surv" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Lafora Disease: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.T.lafora_disease_recommended_surv/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.T.lafora_disease_recommended_surv_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Neurologic</b>
|
|
</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor seizures as clinically indicated.</div></li><li class="half_rhythm"><div>Assess for new manifestations such as seizures, changes in tone & ataxia.</div></li></ul>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_3" rowspan="7" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
|
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurobehavioral/Psychiatric</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral assessment for anxiety, ADHD, ASD, aggression, & self-injury</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical medicine, OT/PT assessment of mobility, self-help skills</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Feeding</b>
|
|
</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Measurement of growth parameters</div></li><li class="half_rhythm"><div>Eval of nutritional status & safety of oral intake</div></li></ul>
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</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Respiratory</b>
|
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</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor for evidence of aspiration, respiratory insufficiency.</td></tr><tr><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family/Community</b>
|
|
</td><td headers="hd_h_lafora.T.lafora_disease_recommended_surv_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblaforamolgenTA"><div id="lafora.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Progressive Myoclonus Epilepsy, Lafora Type: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_lafora.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_lafora.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_lafora.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_lafora.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_lafora.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_lafora.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_lafora.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/7957" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>EPM2A</i>
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</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=7957" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">6q24<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/O95278" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Laforin</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://databases.lovd.nl/shared/genes/EPM2A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EPM2A database</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=EPM2A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EPM2A</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=EPM2A[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EPM2A</a>
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</td></tr><tr><td headers="hd_b_lafora.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/378884" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>NHLRC1</i>
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</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=378884" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">6p22<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q6VVB1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">E3 ubiquitin-protein ligase NHLRC1</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://databases.lovd.nl/shared/genes/NHLRC1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NHLRC1 database</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NHLRC1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NHLRC1</a>
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</td><td headers="hd_b_lafora.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=NHLRC1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NHLRC1</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="lafora.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figoblaforamolgenTB"><div id="lafora.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Progressive Myoclonus Epilepsy, Lafora Type (<a href="/omim/254780,607566,608072,620681" 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/NBK1389/table/lafora.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/254780" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">254780</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MYOCLONIC EPILEPSY OF LAFORA 1; MELF1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/607566" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607566</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EPM2A GLUCAN PHOSPHATASE, LAFORIN; EPM2A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/608072" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608072</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NHL REPEAT-CONTAINING PROTEIN 1; NHLRC1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/620681" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">620681</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MYOCLONIC EPILEPSY OF LAFORA 2; MELF2</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figoblaforaTepm2aandnhlrc1pathogenicvar"><div id="lafora.T.epm2a_and_nhlrc1_pathogenic_var" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p><i>EPM2A</i> and <i>NHLRC1</i> Pathogenic Variants Referenced in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1389/table/lafora.T.epm2a_and_nhlrc1_pathogenic_var/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__lafora.T.epm2a_and_nhlrc1_pathogenic_var_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EPM2A</i>
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</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_005670.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_005670<wbr style="display:inline-block"></wbr>​.4</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_005661.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_005661<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.721C>T</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg241Ter</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The so-called "Spanish" pathogenic variant, which accounts for approximately 17% of <i>EPM2A</i>-related LD. Its high prevalence is the result of both a founder effect & recurrent event [<a class="bibr" href="#lafora.REF.g_mezgarre.2000.946" rid="lafora.REF.g_mezgarre.2000.946">Gómez-Garre et al 2000</a>, <a class="bibr" href="#lafora.REF.ganesh.2002a.1263" rid="lafora.REF.ganesh.2002a.1263">Ganesh et al 2002a</a>].</td></tr><tr><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NHLRC1</i>
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</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_2" rowspan="4" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_198586.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_198586<wbr style="display:inline-block"></wbr>​.3</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_940988.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_940988<wbr style="display:inline-block"></wbr>​.2</a>
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</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.436G>A</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp146Asn</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A common variant assoc w/atypical milder form of LD consisting of a later onset of symptoms, longer disease course, & extended preservation of daily activities in all persons reported to date. It has not been reported in persons w/typical LD [<a class="bibr" href="#lafora.REF.ferlazzo.2014.e129" rid="lafora.REF.ferlazzo.2014.e129">Ferlazzo et al 2014</a>, <a class="bibr" href="#lafora.REF.lanoisel_e.2014.19" rid="lafora.REF.lanoisel_e.2014.19">Lanoiselée et al 2014</a>].</td></tr><tr><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.205C>G</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro69Ala</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The most common variant in <i>NHLRC1</i>, accounting for approximately 15% of <i>NHLRC1</i> pathogenic variants. It is present in all affected persons of Portuguese origin & has been reported repeatedly in affected persons of Italian, French, & Spanish ancestry, suggesting a founder effect [<a class="bibr" href="#lafora.REF.chan.2003a.671" rid="lafora.REF.chan.2003a.671">Chan et al 2003a</a>, <a class="bibr" href="#lafora.REF.g_mezabad.2005.982" rid="lafora.REF.g_mezabad.2005.982">Gómez-Abad et al 2005</a>, <a class="bibr" href="#lafora.REF.franceschetti.2006.640" rid="lafora.REF.franceschetti.2006.640">Franceschetti et al 2006</a>].</td></tr><tr><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.468_469delAG</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly158ArgfsTer17</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Accounts for approximately 8% of <i>NHLRC1</i> pathogenic variants; 1 of the most common deletions. It is identified in many persons belonging to the same genetic isolate of tribal Oman, suggesting a founder effect [<a class="bibr" href="#lafora.REF.turnbull.2008.240" rid="lafora.REF.turnbull.2008.240">Turnbull et al 2008</a>].</td></tr><tr><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.76T>A</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys26Ser</td><td headers="hd_h_lafora.T.epm2a_and_nhlrc1_pathogenic_var_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">A prevalent variant in French-Canadian ethnic isolates [<a class="bibr" href="#lafora.REF.chan.2003a.671" rid="lafora.REF.chan.2003a.671">Chan et al 2003a</a>, <a class="bibr" href="#lafora.REF.singh.2006.e48" rid="lafora.REF.singh.2006.e48">Singh et al 2006</a>]. The shared chromosome 6p22 haplotype of these pedigrees suggests a founder effect [<a class="bibr" href="#lafora.REF.chan.2003a.671" rid="lafora.REF.chan.2003a.671">Chan et al 2003a</a>].</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">LD = Lafora disease</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the author. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><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/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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