{
    "abstract": "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.\nThis 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.\nPatients 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 \u03bcmol/L versus 70 \u03bcmol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 \u03bcmol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 \u03bcmol/mmol of creatinine versus 34.6 \u03bcmol/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 \u03bcmol/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.\nPropionic 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.",
    "authors": [
        {
            "affiliation": "Centre de R\u00e9f\u00e9rence des Maladies H\u00e9r\u00e9ditaires du M\u00e9tabolisme, H\u00f4pital Necker-Enfants Malades, APHP, Universit\u00e9 Paris Descartes, Institut Imagine, Paris, France. pascale.delonlay@nck.aphp.fr.",
            "firstname": "Mathilde",
            "initials": "M",
            "lastname": "Nizon"
        },
        {
            "affiliation": null,
            "firstname": "Chris",
            "initials": "C",
            "lastname": "Ottolenghi"
        },
        {
            "affiliation": null,
            "firstname": "Vassili",
            "initials": "V",
            "lastname": "Valayannopoulos"
        },
        {
            "affiliation": null,
            "firstname": "Jean-Baptiste",
            "initials": "JB",
            "lastname": "Arnoux"
        },
        {
            "affiliation": null,
            "firstname": "Val\u00e9rie",
            "initials": "V",
            "lastname": "Barbier"
        },
        {
            "affiliation": null,
            "firstname": "Florence",
            "initials": "F",
            "lastname": "Habarou"
        },
        {
            "affiliation": null,
            "firstname": "Isabelle",
            "initials": "I",
            "lastname": "Desguerre"
        },
        {
            "affiliation": null,
            "firstname": "Nathalie",
            "initials": "N",
            "lastname": "Boddaert"
        },
        {
            "affiliation": null,
            "firstname": "Jean-Paul",
            "initials": "JP",
            "lastname": "Bonnefont"
        },
        {
            "affiliation": null,
            "firstname": "C\u00e9cile",
            "initials": "C",
            "lastname": "Acquaviva"
        },
        {
            "affiliation": null,
            "firstname": "Jean-Fran\u00e7ois",
            "initials": "JF",
            "lastname": "Benoist"
        },
        {
            "affiliation": null,
            "firstname": "Daniel",
            "initials": "D",
            "lastname": "Rabier"
        },
        {
            "affiliation": null,
            "firstname": "Guy",
            "initials": "G",
            "lastname": "Touati"
        },
        {
            "affiliation": null,
            "firstname": "Pascale",
            "initials": "P",
            "lastname": "de Lonlay"
        }
    ],
    "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.",
    "copyrights": null,
    "doi": "10.1186/1750-1172-8-148\n10.1002/ajmg.c.30090\n10.1186/1750-1172-7-9\n10.1016/j.ymgme.2009.03.006\n10.1007/s10545-006-0351-7\n10.1186/1750-1172-8-6\n10.1007/s10545-012-9457-2\n10.1007/s10545-005-7056-1\n10.1007/s10545-006-0278-z\n10.1007/s10545-009-1189-6\n10.1016/j.ymgme.2013.05.001\n10.1016/j.ymgme.2004.08.001\n10.1016/S1096-7192(02)00197-X\n10.1016/j.ymgme.2004.11.011\n10.1016/j.ymgme.2012.05.012\n10.1007/s10571-007-9143-3\n10.1016/j.ymgme.2011.10.003\n10.1007/s10863-011-9324-0\n10.1074/jbc.M308861200\n10.1016/j.ymgme.2008.06.007\n10.1203/PDR.0b013e3181a7c270",
    "journal": "Orphanet journal of rare diseases",
    "keywords": [],
    "methods": null,
    "publication_date": "2013-09-26",
    "pubmed_id": "24059531\n16602092\n22277694\n19375370\n16763890\n23305374\n22350545\n15868474\n16763906\n19642010\n23751327\n15464417\n12559849\n15781192\n22695176\n17394058\n22078457\n11847233\n21249436\n12972416\n18676166\n19342984",
    "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 \u03bcmol/L versus 70 \u03bcmol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 \u03bcmol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 \u03bcmol/mmol of creatinine versus 34.6 \u03bcmol/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 \u03bcmol/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.",
    "title": "Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias.",
    "xml": "<Element 'PubmedArticle' at 0x788503f320c0>"
}