General description

Methylmalonic acidemia (MMA) is the most common type of congenital organic acidemia and represents a significant metabolic disorder with multisystem complications. Methylmalonic acidemia is primarily caused by defects in the metabolism of methylmalonyl-coenzyme A (methylmalonyl-CoA) to succinyl-CoA. Under normal circumstances, methylmalonyl-CoA generates succinyl-CoA under the action of methylmalonyl-CoA mutase (MCM) and adenosylcobalamin, subsequently participating in the tricarboxylic acid cycle. When this conversion is blocked, it results in the abnormal accumulation of intermediate metabolites, including methylmalonic acids, methylmalonyl-CoA, methylmalonyl carnitine, propanoic acid, methylcitric acid, and β-hydroxybutyric acid.

MMA can be classified into two main categories based on the type of enzyme deficiency:

1. MCM deficiency (mutant type): Caused by mutations in the MCM gene that alter enzyme activity.
2. Cobalamin metabolism disorder (cobalamin type): Results from defects in the synthesis, activation, or transport of cobalamin, which is a necessary cofactor for MCM.

Methylmalonic acidemia (MMA) presents with a wide range of symptoms that vary by age and severity, making diagnosis challenging. In newborns and early infancy, symptoms include lethargy, apnea, feeding difficulties, hypotonia, seizures, and nystagmus, along with non-neurological issues such as blood abnormalities, hydrocephalus, and pulmonary hypertension. Acute cases may involve vomiting, weight loss, hypoglycemia, and irritability, sometimes leading to coma.

In later-onset cases, affected individuals may experience failure to thrive, neurological impairments such as developmental delays, cognitive deficits, epilepsy, and motor dysfunction, as well as cardiac and kidney complications. Neurological issues commonly include intellectual disability, ataxia, abnormal muscle tone, and various types of seizures, some progressing to recurrent status epilepticus. Visual impairments such as optic atrophy and retinal diseases are also observed.

Despite early treatment, most MMA patients suffer from some degree of neurological damage, including delays in cognitive, motor, and language development.

References

1. Chen, Tao, et al. "Methylmalonic acidemia: Neurodevelopment and neuroimaging." Frontiers in Neuroscience 17 (2023): 1110942.
2. Bindu, Parayil Sankaran, J. M. Kovoor, and Rita Christopher. "Teaching NeuroImages: MRI in methylmalonic acidemia." Neurology 74.4 (2010): e14.