Methylmalonic acidemia (MMA) is a heterogeneous disorder, with onset from infancy to adulthood and varying degrees of organ involvement and severity. Cardiac disease is a known lethal complication of other organic acidemias, but has not been associated with MMA. We identified 3 patients with MMA and cardiac disease.
"This patient had the most severe phenotype among the cblB patients. So far, only 3 patients with isolated MMA, 2 with mut 0 and 1 with cblB, have been reported to have cardiomyopathy . This indicates that cardiomyopathy is a complication which could occur in MMA patients, especially those with severe subtypes, and that the cardiac sequelae should be monitored as it is in cases of propionic acidemia . "
[Show abstract][Hide abstract] ABSTRACT: Isolated methylmalonic acidemia (MMA) is a genetically heterogeneous organic acid disorder caused by either deficiency of the enzyme methylmalonyl-CoA mutase (MCM), or a defect in the biosynthesis of its cofactor, adenosyl-cobalamin (AdoCbl). Herein, we report and review the genotypes and phenotypes of 14 Thai patients with isolated MMA. Between 1997 and 2011, we identified 6 mut patients, 2 cblA patients, and 6 cblB patients. The mut and cblB patients had relatively severe phenotypes compared to relatively mild phenotypes of the cblA patients. The MUT and MMAB genotypes were also correlated to the severity of the phenotypes. Three mutations in the MUT gene: c.788G>T (p.G263V), c.809_812dupGGGC (p.D272Gfs*2), and c.1426C>T (p.Q476*); one mutation in the MMAA gene: c.292A>G (p.R98G); and three mutations in the MMAB gene: c.682delG (p.A228Pfs*2), c.435delC (p.F145Lfs*69), and c.585-1G>A, have not been previously reported. RT-PCR analysis of a common intron 6 polymorphism (c.520-159C>T) of the MMAB gene revealed that it correlates to deep intronic exonization leading to premature termination of the open reading frame. This could decrease the ATP:cobalamin adenosyltransferase (ATR) activity resulting in abnormal phenotypes if found in a compound heterozygous state with a null mutation. We confirm the genotype-phenotype correlation of isolated MMA in the study population, and identified a new molecular basis of the cblB disorder.
[Show abstract][Hide abstract] ABSTRACT: This review focuses on the pathophysiology of organic acidurias (OADs), in particular, OADs caused by deficient amino acid metabolism. OADs are termed classical if patients present with acute metabolic decompensation and multiorgan dysfunction or cerebral if patients predominantly present with neurological symptoms but without metabolic crises. In both groups, however, the brain is the major target. The high energy demand of the brain, the gate-keeping function of the blood-brain barrier, a high lipid content, vulnerable neuronal subpopulations, and glutamatergic neurotransmission all make the brain particularly vulnerable against mitochondrial dysfunction, oxidative stress, and excitotoxicity. In fact, toxic metabolites in OADs are thought to cause secondary impairment of energy metabolism; some of these toxic metabolites are trapped in the brain. In contrast to cerebral OADs, patients with classical OADs have an increased risk of multiorgan dysfunction. The lack of the anaplerotic propionate pathway, synergistic inhibition of energy metabolism by toxic metabolites, and multiple oxidative phosphorylation (OXPHOS) deficiency may best explain the involvement of organs with a high energy demand. Intriguingly, late-onset organ dysfunction may manifest even under metabolically stable conditions. This might be explained by chronic mitochondrial DNA depletion, increased production of reactive oxygen species, and altered gene expression due to histone modification. In conclusion, pathomechanisms underlying the acute disease manifestation in OADs, with a particular focus on the brain, are partially understood. More work is required to predict the risk and to elucidate the mechanism of late-onset organ dysfunction, extracerebral disease manifestation, and tumorigenesis.
[Show abstract][Hide abstract] ABSTRACT: Effects of circulatory arrest upon an inborn error of metabolism patient are unknown.
A retrospective chart review was performed of outcome and biochemical parameters obtained during palliative cardiac surgery for a mutase-deficient methylmalonic aciduria patient with Ebstein's cardiac anomaly was performed.
The levels of ammonia, methylmalonic acid, free carnitine, and propionylcarnitine of the patient were improved. The patient survived surgery following institution of four metabolic treatment principles: 1) restriction of toxic substrate; 2) promotion of anabolism via administration of carbohydrate and lipid calories; 3) administration of detoxifying levocarnitine and sodium benzoate; and 4) cobalamin enzymatic co-factor administration. The patient died from post-operative dysrhythmia and was posthumously determined to have compound heterozygosity for mutations predicting severe, cobalamin non-responsive disease: c.322C>T/c.1233del3 (p.R108C/p.ΔI412).
Metabolic decompensation is preventable during cardiopulmonary bypass and cardioplegia using four principles of metabolic treatment.
World Journal of Pediatrics 02/2014; 10(1):83-5. DOI:10.1007/s12519-014-0458-0 · 1.05 Impact Factor
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