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

Abstract

MethylmalonylCoA mutase (MCM) is a mitochondrial homodimer responsible for the isomerization of methylmalonylCoA to succinylCoA. Apomutase defects are traditionally divided into muto 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 muto 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 muto patients as is significant morbidity among mut- patients. Acidosis and metabolic imbalance are not necessary preconditions for significant morbidity.

High cognitive outcome in an adolescent with mut? methylmalonic acidemia

“…Crane et al [1992] reported low normal intellectual ability and learning disabilities in three patients with mut − MMAemia. Shevell et al [1993] reported only three neurologically intact patients among nine with mut − MMAemia but no documentation of cognitive outcome. A patient with "benign" MMAemia [Sewell et al, 1996] had delayed speech and attended a special education class.…”

“…The clinical phenotypes broadly correspond to these two biochemical expressions. Mut o cases have a neonatal presentation and the patients die in early infancy or have very poor neurological outcomes [Matsui et al, 1983;Shevell et al, 1993]. The clinical outcome of mut − patients is less severe but has been quite variable.…”

“…Reports and surveys of affected children have provided some information on mental and cognitive outcome of young children, but have not documented long-term neuropsychological and neurological functioning in a detailed manner [Baumgarter and Viardot, 1995;Shevell et al, 1993;Snideman et al, 1997;Treacy et al, 1993Treacy et al, , 1996. Ledley et al [1984] reported IQ scores for five affected individuals but they had a benign phenotype with no episodes of ketoacidosis.…”

Spectrum of mutations inmutmethylmalonic acidemia and identification of a common Hispanic mutation and haplotype

“…Common clinical features include lethargy, vomiting, failure to thrive, hypotonia, neurological deficit, and early death [Matsui et al, 1983;Shevell et al, 1993]. Two biochemical phenotypes have been identified in patient fibroblasts with mut MMA.…”

Molecular basis for dysfunction of some mutant forms of methylmalonyl-CoA mutase: deductions from the structure of methionine synthase.

“…In contrast, high concentrations of AdoCbl are unable to restore the activity of mut°mutant proteins. In general, mut-patients have a milder phenotype than do mut°p atients (21). Many of the mutations that cause methylmalonic aciduria in humans affect residues in the C-terminal region of the methylmalonyl-CoA mutase subunit.…”