Varying neurological phenotypes among mut° and mut− patients with methylmalonylCoA mutase deficiency

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Abstract
MethylmalonylCoA mutase (MCM) is a mito‐chondrial homodimer responsible for the isomerization of methylmalonylCoA to succinylCoA. Apomutase defects are traditionally divided into mut° and mut− classes on the basis of residual mutase activity. Clinical findings were reviewed in 20 patients with methylmalonic aciduria secondary to MCM deficiency. All 11 mut° patients had an early neonatal presentation; 6 of these patients died in infancy and 3 of 5 survivors had a poor neurological outcome as evidenced by severe delay or spastic quadriparesis with dystonia. The 2 other survivors include a 27‐month‐old child with a mild delay in verbal and fine motor skills and an adolescent with low normal intelligence. Of the 9 mut− patients, 7 became symptomatic in late infancy or childhood and 2 were picked up on screening. Two of the 9 patients have never had an episode of metabolic decompensation yet both are neurologically compromised; one severely retarded and autistic, the other mildly delayed. Four mut− patients have had episodic acidosis and are neurologically moderately affected, while 3 have had episodic acidosis and are neurologically intact. These results confirm phenotypic pleomorphism without a consistent pattern of neurological injury and suggest some broad correlation between mutase class and phenotype. Survival with good outcome is possible among mut° patients as is significant morbidity among mut− patients. Acidosis and metabolic imbalance are not necessary preconditions for significant morbidity.