++
Heterogeneous inborn error of metabolism affecting
amino acid metabolism, leading to metabolic acidosis and accumulation of
methylmalonic acid (MMA) and its by-products.
++
Methylmalonic Aciduria, Methylmalonic-Coenzyme A Mutase
Deficiency; MMA.
++
First reported in 1967 by Oberholzer and Stokke.
++
Approximately 1:25,000-50,000 (all types of MMA
included). Consanguinity is a risk factor. No gender predilection has been
reported.
++
Autosomal recessive (for all types). The gene
encoding the enzyme methylmalonyl-CoA mutase has been mapped to 6p12-21.1.
Two forms of this mutase deficiency exist: the mut0 form with complete
absence of mutase activity, and the mut- form with reduced
mutase activity. The mutase defect accounts for approximately 50% of
patients with MMA. The defect in adenosylcobalamin synthesis has been mapped
to chromosome 4q31.1-2.
++
Methylmalonic-coenzyme A mutase is a vitamin
B12-dependent enzyme involved in the catabolism of leucine, isoleucine,
and valine; its deficiency leads to increased amounts of MMA in plasma and
urine. Because of secondary inhibition of propionyl-CoA carboxylase,
propionic acid also accumulates, as do other organic acids. Accumulation of
propionyl-CoA results in inhibitory effects on various pathways of
intermediary mitochondrial metabolism and secondary carnitine deficiency,
thus explaining hypoglycemia, hyperammonemia, and hyperlactacidemia and the
synthesis of odd-numbered abnormal fatty acids. Moreover, gut bacteria
produce approximately 25% of the propionate to be metabolized.
++
Neonatal screening for inborn errors of metabolism should
detect all genetic variants of MMA. Large amounts of MMA, methylcitrate,
propionic acid, and 3-hydroxy propionic acid can be detected in the urine by
gas chromatography-mass spectrometry. However, once other causes for
neonatal or infantile ketoacidosis have been ruled out, simple colorimetric
assays for urinary MMA for suspected MMA are also available. Enzyme analysis
in fibroblasts is used to detect the specific enzyme abnormality and
finalize the diagnosis. Cultured amniotic cells are used for prenatal
diagnosis.
++
The clinical picture has a high variability, and
asymptomatic children with mutase apoenzyme deficiency have been identified
through newborn screening. Although the signs in symptomatic children are
basically similar to those of Propionic Acidemia, complications and
prognosis are worse in MAA. In 80%, manifestation of mut0 patients
occurs in the first week of life and the remainder by 6 months of life. In
contrast, mut- and cobalamin disorder patients most often
present after the first month of life. The most common signs and symptoms at
onset after a period of normal feeding are lethargy or coma, poor feeding
with failure to thrive, recurrent vomiting with dehydration,
hepatosplenomegaly, respiratory distress, and muscular hypotonia. MMA caused
by a cobalamin-related defect usually has onset later in childhood or
adolescence, starting with decreased lower leg sensitivity, thrombosis
secondary to persistent homocystinuria, and progressive myopathy leading to
chronic gait disturbances, which may not be irreversible. The majority of
patients present with metabolic acidosis with a blood pH less than 6.9 and
bicarbonate concentrations as low as 5 mmol/l. Ketonemia and ketonuria,
hyperammonemia, ...