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Background Deficiency of mitochondrial trifunctional protein (MTP) is caused by mutations in the HADHA and HADHB genes, which have been mostly delineated at the genomic DNA level and have not been always elucidated. Aim To identify mutations in a French cohort of 52 MTP deficient patients and the susceptibility of mutations generating premature termination codons (PTCs) to the nonsense mRNA mediated decay (NMD). Methods Mutation screening in fibroblasts was performed at the cDNA level and real-time RT-PCR was used to compare the levels of the different PTC-bearing mRNAs before and after a treatment of fibroblasts by emetine, a translation inhibitor. Results A mutation detection rate of 100% was achieved. A total of 22 novel mutations were identified, including a large-sized genomic deletion in HADHB gene. A high proportion of all identified mutations were non-sense, frameshift and splicing mutations, generating (PTCs), distributed essentially on HADHA coding regions. We could demonstrate that the majority of mutations resulting in PTCs conform to the established rules governing the susceptibility to NMD. Conclusion Our results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects.

Very Long-Chain Acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of mitochondrial long-chain fatty acid oxidation (FAO) most often occurring in childhood with cardiac or liver involvement, but rhabdomyolysis attacks have also been reported in adults. We report in this study the clinical, biochemical and molecular studies in 13 adult patients from 10 different families with VLCAD deficiency. The enzyme defect was demonstrated in cultured skin fibroblasts or lymphocytes. All patients exhibited exercise intolerance and recurrent rhabdomyolysis episodes, which were generally triggered by strenuous exercise, fasting, cold or fever (mean age at onset: 10 years). Inaugural life-threatening general manifestations also occurred before the age of 3 years in four patients. Increased levels of long-chain acylcarnitines with tetradecenoylcarnitine (C14:1) as the most prominent species were observed in all patients. Muscle biopsies showed a mild lipidosis in four patients. For all patients but two, molecular analysis showed homozygous (4 patients) or compound heterozygous genotype (7 patients). For the two remaining patients, only one mutation in a heterozygous state was detected. This study confirms that VLCAD deficiency, although being less frequent than CPT II deficiency, should be systematically considered in the differential diagnosis of exercise-induced rhabdomyolysis. Measurement of fasting blood acylcarnitines by tandem mass spectrometry allows accurate biochemical diagnosis and should therefore be performed in all patients presenting with unexplained muscle exercise intolerance or rhabdomyolysis.

We report a family with an X-linked recessive muscular dystrophy characterised by exercise-induced myalgia, recurrent pigmenturia and mild proximal muscle involvement. Immunocytochemical and immunoblotting analysis in muscle, using the antibody directed against the rod domain of dystrophin, revealed a loss of immunoreactivity, but the immunolabelling using the antibodies directed against the COOH and NH2 domains of dystrophin were almost normal. The immunoreactions for alpha-sarcoglycan, gamma-sarcoglycan and beta-dystroglycan were normal. In the five male patients of this family with increased serum creatine kinase levels (from x8 to x50), mass spectrometry screening of the urine revealed a large increase in glycerol elimination which was quantified by enzymatic assay (from x14 to x39). An in-frame deletion of the dystrophin gene (exons 13-29) was found in the same five males and in three carrier females. All the deleted chromosomes also carried a missense mutation at nucleotide 947 of the Xp glycerol kinase (GK) gene resulting in a Thr to Met substitution at codon 278. These findings indicate that the two mutations cosegregate on the same chromosome in this family. This is the first reported case of two physically independent mutations, within the DMD and GK genes, which are contiguous but several hundred kilobases apart.

Objectifs Nous presentons 4 observations d’insuffisance hepatocellulaire aigue du nourrisson qui ont revele un deficit du cycle de l’uree. Resultats L’âge moyen est de 15 mois. Les 4 enfants presentent une symptomatologie digestive. Ils sont admis pour vomissements et troubles du comportement et /ou somnolence. La biologie montre une elevation moyenne des ASAT a 2946UI/L, et ALAT 3870UI/L, sans cholestase, une insuffisance hepatocellulaire (TP 23 %, facteur V 27 %). Les valeurs d’ammoniemie sont tres variables. Le diagnostic a ete evoque sur une chromatographie plasmatique des acides amines et le dosage de l’acide orotique. Ils revelent un deficit en Ornithine transcarbamylase (3 cas) et une citrullinemie type 1. Un regime controle en proteines et un traitement medical ont permis une normalisation rapide de la fonction hepatique sans transplantation hepatique. Conclusion Une forme infantile de deficit du cycle de l’uree peut se reveler par une insuffisance hepatocellulaire aigue qui peut faire discuter une transplantation hepatique. Bien qu’une hyperammoniemie soit difficile a interpreter en raison de l’atteinte hepatique, il est indispensable d’evoquer le diagnostic de deficit primitif du cycle de l’uree et de mener l’exploration diagnostique a son terme