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

Orphanet Journal of Rare Diseases

Pascale de Lonlay⁶  Guy Touati⁶  Daniel Rabier⁶  Jean-François Benoist²  Cécile Acquaviva⁷  Jean-Paul Bonnefont³  Nathalie Boddaert⁴  Isabelle Desguerre¹  Florence Habarou⁵  Valérie Barbier⁶  Jean-Baptiste Arnoux⁶  Vassili Valayannopoulos⁶  Chris Ottolenghi⁵  Mathilde Nizon⁶ 

[1] Service de Neurologie, Hôpital Necker-Enfants Malades, APHP, Université Paris Descartes, Paris, France;Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Biochimie, Hôpital Robert-Debré, APHP, Paris, France;Service de Génétique Médicale, Hôpital Necker-Enfants Malades, APHP, Université Paris Descartes, Institut Imagine, Paris, France;Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, APHP, Université Paris Descartes, Institut Imagine, Paris, France;Service de Biochimie métabolique, Hôpital Necker-Enfants Malades, U747, Inserm - Université Paris Descartes, Paris, France;Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, APHP, Université Paris Descartes, Institut Imagine, Paris, France;Service de Maladies Héréditaires du Métabolisme, Centre de Biologie et Pathologie Est, Bron, France

关键词: Mitochondrial dysfunction;    Long-term prognosis;    Neurological evolution;    Isovaleric aciduria;    Methylmalonic aciduria;    Propionic aciduria;    Organic aciduria;   

Others  :  863518
DOI  :  10.1186/1750-1172-8-148

 received in 2013-05-13, accepted in 2013-09-10,  发布年份 2013

【 摘 要 】

Background

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.

Methods

This 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.

Results

Patients 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.

Conclusion

Propionic 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.

【 授权许可】

   
2013 Nizon et al.; licensee BioMed Central Ltd.

【 图 表 】

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