eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Methylmalonic Acidemia
Updated: Jul 7, 2008
Introduction
Background
Oberholzer et al and Stokke et al reported the first patients with methylmalonic acidemia (MMA).1,2 Clinical and genetic heterogeneity became evident very early when some patients responded to pharmacological doses of cobalamin (vitamin B-12) and others did not.
MMA encompasses a heterogeneous group of disorders characterized by accumulation of methylmalonic acid and its by-products in biological fluids. These disorders are due to a deficiency of the adenosylcobalamin-dependent enzyme methylmalonyl-CoA mutase (apoenzyme deficiency), a defect in intracellular cobalamin metabolism (coenzyme deficiency), transcobalamin II deficiency, intrinsic factor deficiency, or dietary cobalamin deficiency, which is found in vegetarians. A subset of children with defects of intracellular cobalamin metabolism may also have simultaneous homocystinuria. In addition, transient MMA can be detected in otherwise healthy infants.
In the context of this review, MMA refers to disorders resulting in methylmalonyl-CoA mutase deficiency and disorders of intracellular cobalamin metabolism.
Pathophysiology
Adenosylcobalamin-dependent methylmalonyl-CoA mutase is an enzyme that catalyses the isomerization of methylmalonyl-CoA to succinyl-CoA. Succinyl-CoA subsequently enters the tricarboxylic acid cycle, where it is converted to pyruvate. Methylmalonyl-CoA is derived from propionyl-CoA by the action of propionyl-CoA carboxylase, the enzyme that is deficient in patients with propionic acidemia (see Propionic Acidemia). Propionyl-CoA is formed through the catabolism of isoleucine, valine, threonine, methionine, thymine, uracil, cholesterol, or odd-chain fatty acids. Gut bacteria may generate a significant amount of propionyl-CoA.
Methylmalonyl-CoA mutase is a dimer of identical subunits to which adenosylcobalamin is tightly bound. The complimentary deoxyribonucleic acid (cDNA) of methylmalonyl-CoA mutase has been cloned and its genomic structure delineated. The gene is mapped to 6p12. Mutations in this gene have been reported to cause MMA. Adenosylcobalamin is an essential cofactor of methylmalonyl-CoA mutase.
Complementation studies revealed the presence of at least 8 different complementation groups (mut0, mut-, cblA, cblB, cblC, cblD, cblF, cblH) that cause MMA. In the mut0 group, mutase activity in fibroblasts is undetectable, whereas fibroblasts of the mut- group show some residual mutase activity. CblA, cblB, and cblH are defects in the pathway of adenosylcobalamin synthesis. CblC and cblD are defects in the common pathway of cobalamin reduction, leading to combined MMA and homocystinuria, secondary to impaired adenosylcobalamin and methylcobalamin formation. CblF is caused by impaired lysosomal cobalamin transport.
The molecular basis for all complementation groups, except for cblF and cblH, is not presently known. The gene for cblC has been recently identified. All genetic forms of MMA are inherited as autosomal recessive traits.
Frequency
United States
Screening of infants aged 3-4 weeks in Massachusetts revealed an approximate frequency for MMA of 1 case per 48,000 infants.3
International
Newborn screening programs in Germany and Austria have identified approximately 1 newborn with MMA (mutase deficiency) per 250,000 newborns screened. MMA is more frequent in populations with increased rates of consanguinity.
Mortality/Morbidity
All children with genetic forms of MMA are at risk of metabolic decompensation with increased morbidity and mortality. The risk is greater for mut0 and mut- forms of MMA compared with cobalamin-responsive forms. Newborns and infants with mut0 or mut- forms of MMA may die early, before a diagnosis can be reached.
Race
MMA is prevalent in populations with increased rates of consanguinity but has been reported in all ethnic groups.
Sex
No sex predilection is reported.
Age
The mut0 and mut- forms of MMA typically present during the newborn period and early infancy, respectively.
CblA, cblB, cblC, and cblH forms of MMA typically present during early infancy. MMA forms CblD and cblF typically present during later infancy or childhood. The cblC form of MMA may present during childhood or adolescence.
Theoretically, neonatal screening via tandem mass spectrometry should reveal all genetic forms of MMA. Some reports have shown that this may not be true for some forms of MMA, such as cblC.4
Clinical
History
A history of poor feeding, vomiting, progressive lethargy, floppiness, and muscular hypotonia in a newborn who has been healthy for the first 1-2 weeks of life is typical for methylmalonic acidemia (MMA) mut0 or MMA mut-. These newborns typically have been fed for 1-2 weeks or less.
Older infants or children with one of the other forms of MMA or mild mut- may present for the first time during an episode of decompensation with lethargy, seizures, and hypoglycemia.
Older children or adolescents with the cblC form of MMA may present with progressive myopathy, lower leg hyposensitivity, and thrombosis due to the persistent homocystinuria in the cblC form of MMA. The myopathy may not be reversible despite treatment, leading to continued gait disturbances.
Eye findings (eg, retinopathy, nystagmus, reduced visual acuity), hydrocephalus, and microcephaly have been observed in children with the cblC form of MMA.
Renal disease with reduced glomerular filtration rate (GFR) may be observed at presentation or as a long-term complication.
Family history may be positive for siblings with MMA or siblings who died during the neonatal period for reasons that are not clear.
Physical
Symptoms include the following:
- Dehydration, failure to thrive
- Lethargy, muscular hypotonia, floppiness
- Developmental delay
- Facial dysmorphism (eg, high forehead, broad nasal bridge, epicanthal folds, long smooth philtrum, triangular mouth)
- Skin lesions (eg, moniliasis)
- Occasional hepatomegaly
- Acute onset of choreoathetosis, dystonia, dysphagia, and dysarthria (potentially signs of a stroke)
- Reduced GFR
More on Methylmalonic Acidemia |
 Overview: Methylmalonic Acidemia |
| Differential Diagnoses & Workup: Methylmalonic Acidemia |
| Treatment & Medication: Methylmalonic Acidemia |
| Follow-up: Methylmalonic Acidemia |
| References |
| Next Page » |
References
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Further Reading
Keywords
methylmalonic acidemia, MMA, methylmalonic aciduria, methylmalonic acid, propionic acidemia, lethargy, hypoglycemia, seizures, progressive myopathy, lower leg hyposensitivity, thrombosis, retinopathy, nystagmus, reduced visual acuity, hydrocephalus, microcephaly, dehydration, failure to thrive, developmental delay, choreoathetosis, dystonia, dysphagia, dysarthria
