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

Nizon M, Ottolenghi C, Valayannopoulos V, Arnoux JB, Barbier V, Habarou F, Desguerre I, Boddaert N, Bonnefont JP, Acquaviva C, Benoist JF, Rabier D, Touati G, de Lonlay P - Orphanet J Rare Dis (2013)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

ABSTRACT

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.

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Brain MRI data for 16 PA patients, 28 MMA patients and 6 IVA patients; median 13.1 years. Secondary brain MRI normalization performed in 5 patients with a follow-up of 5 years.
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Figure 6: Brain MRI data for 16 PA patients, 28 MMA patients and 6 IVA patients; median 13.1 years. Secondary brain MRI normalization performed in 5 patients with a follow-up of 5 years.

Mentions: Imaging was available for 50/80 patients including 16/24 PA, 28/38 MMA and 6/18 IVA. Brain MRI was normal for 19% of PA, 46% of MMA and 33% of IVA when available (see Figure 6). Abnormalities included basal ganglia lesions for 56% of PA, 36% of MMA and 17% of IVA, notably involving the striatum and the globus pallidum, white matter anomalies for 38 to 50% and cerebellar anomalies for three MMA and one IVA. For five patients, normalization of basal ganglia lesions and white matter anomalies were observed at a distance from the acute episode. Furthermore, two patients PA and three patients MMA had increased lactate concentration in basal ganglia. Magnetic resonance spectroscopy was not performed for the other patients.


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

Nizon M, Ottolenghi C, Valayannopoulos V, Arnoux JB, Barbier V, Habarou F, Desguerre I, Boddaert N, Bonnefont JP, Acquaviva C, Benoist JF, Rabier D, Touati G, de Lonlay P - Orphanet J Rare Dis (2013)

Brain MRI data for 16 PA patients, 28 MMA patients and 6 IVA patients; median 13.1 years. Secondary brain MRI normalization performed in 5 patients with a follow-up of 5 years.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016503&req=5

Figure 6: Brain MRI data for 16 PA patients, 28 MMA patients and 6 IVA patients; median 13.1 years. Secondary brain MRI normalization performed in 5 patients with a follow-up of 5 years.
Mentions: Imaging was available for 50/80 patients including 16/24 PA, 28/38 MMA and 6/18 IVA. Brain MRI was normal for 19% of PA, 46% of MMA and 33% of IVA when available (see Figure 6). Abnormalities included basal ganglia lesions for 56% of PA, 36% of MMA and 17% of IVA, notably involving the striatum and the globus pallidum, white matter anomalies for 38 to 50% and cerebellar anomalies for three MMA and one IVA. For five patients, normalization of basal ganglia lesions and white matter anomalies were observed at a distance from the acute episode. Furthermore, two patients PA and three patients MMA had increased lactate concentration in basal ganglia. Magnetic resonance spectroscopy was not performed for the other patients.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus