Methylmalonic Acidemia

Prevalence of methylmalonic aciduria (MMA) has been estimated as 1-9 per 100,000.

MMA is an inborn error of vitamin B12 metabolism characterized by gastrointestinal and neurometabolic manifestations. It is caused by complete or partial deficiency of methylmalonyl-CoA mutase (MUT; mut- and mut0 subtypes, respectively), a defect in transport or synthesis of its cofactor adenosyl-cobalamin (MMAA cblA type; MMAB, cblB type; MMADHC, cblD-MMA type), or deficiency of methylmalonyl-CoA epimerase (MCEE). Presentation is variable:

• Infantile completely deficient (mut0) or non-B12-responsive (clbB) is the most common phenotype and presents during infancy. Infants are normal at birth, but develop lethargy, vomiting, and dehydration within the first few months of life. They may also exhibit hepatomegaly, hypotonia, encephalopathy, metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycemia.

• Partially deficient (mut-) or B12-responsive (cblA, cblD, rarely cblB) is an intermediate phenotype that can occur in the first few months or years of life. Symptoms include feeding problems, failure to thrive, hypotonia, and developmental delay. Some have protein aversion and vomiting, and lethargy after protein intake.

• Methylmalonyl-CoA epimerase (MCEE) deficiency is a persistent, moderate phenotype where findings in infants/children range from complete absence of symptoms to severe metabolic acidosis. Symptoms include ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures.

• An atypical or benign/adult version is associated with increased, albeit mild, urinary excretion of methylmalonate. It is uncertain whether these individuals will develop symptoms.

Secondary complications can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, neurologic findings, pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, and hepatoblastoma.

Onset ranges from the neonatal period to adulthood. All phenotypes demonstrate periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. Episodes of catabolic stress are associated with rapid production and accumulation of toxic metabolites which can cause decompensation, and lead to life threatening complications. MMA is associated with substantial morbidity and mortality that correlates with the underlying defect. Individuals with the mut0 and cblB subtypes tend to be more severely affected and have a higher rate of mortality than those with the mut-, cblA, and cblD subtypes. Survival in MMA has improved over time, mainly ability of newborn screening to detect MMA before early childhood encephalopathy.

Autosomal Recessive

1-2 in 50000

>= 40 %

Unknown

1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
Yes
No
2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?
Yes
No

a. Patient Management

Yes
No

b. Surveillance or Screening

Yes
No

c. Circumstances to Avoid

Yes
No
3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
Yes
No
4. Does the disease present outside of the neonatal period?
Yes
No
5. Is this condition an important health problem?
Yes
No
6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?
Yes
No
Unknown