Clinical characteristics: For this GeneReview, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid. Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut⁰ enzymatic subtype or mut^– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Prior to the advent of newborn screening, common phenotypes included:

1. Infantile/non-B₁₂-responsive form (mut⁰ enzymatic subtype, cblB), the most common phenotype, associated with infantile-onset lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds. Without appropriate treatment, the infantile/non-B₁₂-responsive phenotype could rapidly progress to coma due to hyperammonemic encephalopathy.

2. Partially deficient or B₁₂-responsive phenotypes (mut^– enzymatic subtype, cblA, cblB [rare], cblD-MMA), in which symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation

3. Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures.

In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer.

Diagnosis/testing: The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in MCEE, MMAA, MMAB, MMADHC, or MMUT or (in some instances) by significantly reduced activity of one of the following enzymes: methylmalonyl-CoA mutase, methylmalonyl-CoA mutase enzyme cofactor 5'-deoxyadenosylcobalamin, or methylmalonyl-CoA epimerase. Because of its relatively high sensitivity, easier accessibility, and noninvasive nature, molecular genetic testing can obviate the need for enzymatic testing in most instances.

Management: Treatment of manifestations / Prevention of primary manifestations: When isolated MMA is suspected during the diagnostic evaluation due to elevated propionylcarnitine (C3) on a newborn blood spot, metabolic treatment should be initiated immediately, while the suspected diagnosis is being confirmed. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach by experienced subspecialists from a specialized metabolic center. The main principles of treatment are to provide supplemental vitamin B₁₂ to those who are known to be vitamin B₁₂ responsive; restrict natural protein, particularly of propiogenic amino acid precursors, while maintaining a high-calorie diet; address feeding difficulties, recurrent vomiting, and growth failure; provide supplemental carnitine to those with carnitine deficiency; reduce propionate production from gut flora; and provide emergency treatment during episodes of acute decompensation with the goal of averting catabolism and minimizing central nervous system injury. In those with significant metabolic instability and/or renal failure, liver and/or renal transplantation may be considered.

Prevention of secondary complications: MedicAlert^® bracelets and up-to-date, easily accessed, detailed emergency treatment and presurgical protocols to facilitate care.

Surveillance: Regular evaluations by a metabolic specialist and metabolic dietician; screening laboratory testing, including plasma amino acids, plasma and urine MMA levels, serum acylcarnitine profile and free and total carnitine levels, blood chemistries, and complete blood count at least every six months to one year, or more frequently in infants or in those who are unstable or require frequent changes in dietary management; measurement of renal function at least annually or as clinically indicated; assessment for liver disease at least annually or as clinically indicated; assessment of developmental progress and for signs of movement disorder at each visit; ophthalmology evaluation to monitor for optic atrophy at least annually or as clinically indicated; audiology evaluation at least annually in childhood and adolescence or as clinically indicated.

Agents/circumstances to avoid: Fasting, stress, increased dietary protein, supplementation with the individual propiogenic amino acids valine and isoleucine, nephrotoxic medications or agents, and agents that prolong QTc in the EKG.

Evaluation of relatives at risk: For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, measure serum methylmalonic acid, urine organic acids, plasma acylcarnitine profile, plasma amino acids, and serum B₁₂; test for the familial isolated methylmalonic acidemia-causing pathogenic variants if biochemistry is abnormal.

Pregnancy management for an affected mother: Monitor for complications including acute decompensation or hyperammonemia, deterioration of renal function, and obstetric complications including preeclampsia and preterm delivery.

Pregnancy management for an unaffected mother with an affected fetus: Oral and intramuscular vitamin B₁₂ has been administered to women pregnant with a fetus with vitamin B₁₂-responsive MMA, resulting in decreased maternal MMA urine output; however, further study of this treatment is needed.

Genetic counseling: All forms of isolated MMA are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an isolated MMA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the isolated MMA-causing pathogenic variants have been identified in an affected family member, molecular genetic carrier testing and prenatal/preimplantation genetic testing are possible.