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


CONCLUSIONS
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.
Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, APHP, Université Paris Descartes, Institut Imagine, Paris, France. pascale.delonlay@nck.aphp.fr.
Mathilde
M
Nizon
Chris
C
Ottolenghi
Vassili
V
Valayannopoulos
Jean-Baptiste
JB
Arnoux
Valérie
V
Barbier
Florence
F
Habarou
Isabelle
I
Desguerre
Nathalie
N
Boddaert
Jean-Paul
JP
Bonnefont
Cécile
C
Acquaviva
Jean-François
JF
Benoist
Daniel
D
Rabier
Guy
G
Touati
Pascale
P
de Lonlay
D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000652:urine; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000031:analogs & derivatives / Q000652:urine; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood; D056693:Propionic Acidemia / Q000097:blood / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000652:urine; D011859:Radiography; D055815:Young Adult
D019344:Lactic Acid; D008764:Methylmalonic Acid; C031601:hydracrylic acid