Long-Term Outcome in Methylmalonic Acidurias Is Influenced by the Underlying Defect (mut0, mut−, cblA, cblB)

Abstract

Isolated methylmalonic acidurias comprise a heterogeneous group of inborn errors of metabolism caused by defects of methylmalonyl-CoA mutase (MCM) (mut0, mut-) or deficient synthesis of its cofactor 5'-deoxyadenosylcobalamin (AdoCbl) (cblA, cblB). The aim of this study was to compare the long-term outcome in patients from these four enzymatic subgroups. Eighty-three patients with isolated methylmalonic acidurias (age 7-33 y) born between 1971 and 1997 were enzymatically characterized and prospectively followed to evaluate the long-term outcome (median follow-up period, 18 y). Patients with mut0 (n = 42), mut- (n = 10), cblA (n = 20), and cblB (n = 11) defects were included into the study. Thirty patients (37%) died, and 26 patients survived with a severe or moderate neurologic handicap (31%), whereas 27 patients (32%) remained neurologically uncompromised. Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF. Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects. In addition, long-term outcome was dependent on the age cohort and cobalamin responsiveness.

MRI Characteristics of Globus Pallidus Infarcts in Isolated Methylmalonic Acidemia

“…The relatively lower prevalence of both GP and SNr infarcts in patients with mutcompared with other variants suggests that partial activity of the MUT enzyme has a protective effect, likely because patients with mut-typically have lower concentrations of abnormal metabolites and less severe mitochondrial dysfunction. 9 Although patients with cblA (and occasional patients with cblB) can be responsive to hydroxocobalamin supplementation, we found that their average stroke volume was significantly larger compared with patients with mut. The reasons for this finding are unclear, and it is possible that factors not directly related to the disease mechanism contribute.…”

“…6 MMA treatment strategies vary 4,7,8 but generally involve adherence to a low-protein diet to restrict the intake of amino acids that are oxidized to propionyl-coenzyme A (isoleucine, valine, threonine, methionine), hydroxocobalamin injections for cobalamin-responsive patients, carnitine supplementation to relieve acyl-coenzyme A accretion in the mitochondrion, and a high-energy diet to prevent catabolism. Despite vigilant dietary and metabolic management, patients with MMA experience multisystem disease, including metabolic instability, pancreatitis, 9 renal failure, 9,10 intellectual impairment, 9,11 growth retardation, 9 optic nerve atrophy, 9 and acute injury to the globus pallidus. [12][13][14][15][16][17][18][19][20][21][22] Some patients eventually require liver and/or kidney transplantation.…”

Predictors of survival in children with methymalonic acidemia with homocystinuria in Beijing, China: A prospective cohort study

“…Hörster, et al [15] reported that high concentrations of MMA in urine are a known risk factor for the development of chronic kidney disease. Moreover, homocysteine can induce myocardial injury by promotion of endothelial dysfunction, formation of thromboxane A2, enhancement of platelet aggregation, reduction in the protective effect of nitric oxide, and the procoagulant effects [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The disturbance of the tricarboxylic acid cycle and respiratory chain may also be involved in the pathogenesis [18].…”

Neurocognitive Phenotype of Isolated Methylmalonic Acidemia

“…5 The disorder is difficult to manage and has a highly variable outcome. [6][7][8][9][10][11][12] Treatment options involve injections of vitamin B 12 in responsive patients 13 ; strict adherence to a low-protein diet; carnitine supplementation; and solid organ transplantation. 14 Neurocognitive and neurologic deficits have been recognized to occur in patients with MMA, 6,8,11 including global developmental delay and hyperkinetic movement disorders secondary to basal ganglia injury.…”