Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias

Mathilde Nizon,Daniel Rabier,Vassili Valayannopoulos,Valérie Barbier,Florence Habarou,Nathalie Boddaert,Chris Ottolenghi,Jean-François Benoist,Isabelle Desguerre,Guy Touati,Jean-Paul Bonnefont,Pascale De Lonlay,Jean-Baptiste Arnoux,Cécile Acquaviva

doi:10.1186/1750-1172-8-148

Abstract

BackgroundClassical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications.MethodsThis study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data.ResultsPatients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 μmol/L versus 70 μmol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 μmol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 μmol/mmol of creatinine versus 34.6 μmol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 μmol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene.ConclusionPropionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients.

Highlights

Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications
Metabolic dysfunction led to liver transplantation for one PA patient and kidney transplantation for two MMA patients
One patient with PA died at 19 years old of an accidental fall, one with MMA died at 17 years old of a gastrointestinal bleeding after hernia surgery, and two patients with MMA died following an acute metabolic episode at 11 and 7 years old respectively

Summary

Introduction

Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. The classical organic acidurias are branched-chain amino acids disorders involving intermediate metabolism. MCM converts methylmalonyl-CoA into succinyl-CoA, an intermediate of the tricarboxylic acid cycle, the major source of NADH used by the mitochondrial respiratory chain. Two of these diseases, PA and MMA, affect the pathway common to valine, isoleucine, methionine and threonine metabolism. Reports are increasing of long-term complications, such as neurological disorders by degeneration of the basal ganglia, progressive renal failure in MMA, cardiomyopathy in PA and acute pancreatitis in all [3,4,5]

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