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Schiff M.,French Institute of Health and Medical Research | Schiff M.,University Paris Diderot | Schiff M.,Reference Center for Inherited Metabolic Disease | Schiff M.,University of Pittsburgh | And 6 more authors.
Trends in Endocrinology and Metabolism

Mitochondrial diseases encompass a wide range of presentations and mechanisms, dictating a need to consider both broad-based and disease-specific therapies. The manifestations of mitochondrial dysfunction and the response to therapy vary between individuals. This probably reflects the genetic complexity of mitochondrial biology, which requires an excess of 2000 genes for proper function, with numerous interfering epigenetic and environmental factors. Accordingly, we are increasingly aware of the complexity of these diseases which involve far more than merely decreased ATP supply. Indeed, recent therapeutic progress has addressed only specific disease entities. In this review present and prospective therapeutic approaches will be discussed on the basis of targets and mechanism of action, but with a broad outlook on their potential applications. © 2012 Elsevier Ltd. Source

Ogier de Baulny H.,Reference Center for Inherited Metabolic Disease | Ogier de Baulny H.,University Paris Diderot | Schiff M.,Reference Center for Inherited Metabolic Disease | Schiff M.,French Institute of Health and Medical Research | And 2 more authors.
Molecular Genetics and Metabolism

Lysinuric protein intolerance (LPI) is an inherited defect of cationic amino acid (lysine, arginine and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells caused by mutations in SLC7A7 encoding the y+LAT1 protein. LPI has long been considered a relatively benign urea cycle disease, when appropriately treated with low-protein diet and l-citrulline supplementation. However, the severe clinical course of this disorder suggests that LPI should be regarded as a severe multisystem disease with uncertain outcome. Specifically, immune dysfunction potentially attributable to nitric oxide (NO) overproduction secondary to arginine intracellular trapping (due to defective efflux from the cell) might be a crucial pathophysiological route explaining many of LPI complications. The latter comprise severe lung disease with pulmonary alveolar proteinosis, renal disease, hemophagocytic lymphohistiocytosis with subsequent activation of macrophages, various auto-immune disorders and an incompletely characterized immune deficiency. These results have several therapeutic implications, among which lowering the l-citrulline dosage may be crucial, as excessive citrulline may worsen intracellular arginine accumulation. © 2012 Elsevier Inc. Source

Schiff M.,Reference Center for Inherited Metabolic Disease | Schiff M.,French Institute of Health and Medical Research | Schiff M.,University Paris Diderot | Ogier de Baulny H.,Reference Center for Inherited Metabolic Disease | And 4 more authors.
Seminars in Fetal and Neonatal Medicine

Neonatal cardiomyopathies due to mitochondrial oxidative phosphorylation (OXPHOS) defects are extremely severe conditions which can be either isolated or included in a multi-organ disease, with or without metabolic crises, of which profound lactic acidosis is the prominent feature. Cardiomyopathy is more often hypertrophic than dilated. Antenatal manifestations such as fetal cardiomyopathy, arrhythmia and/or hydrops have been reported. Pathophysiological mechanisms are complex, going beyond ATP deficiency of the high-energy-consuming neonatal myocardium. Birth is a key metabolic period when the myocardium switches ATP production from anaerobic glycolysis to mitochondrial fatty acid oxidation and OXPHOS. Heart-specificity of the defect may be related to the specific localization of the defect, to the high myocardium dependency on OXPHOS, and/or to interaction between the primary genetic alteration and other factors such as modifier genes. Therapeutic options are limited but standardized diagnostic procedures are mandatory to confirm the OXPHOS defect and to identify its causal mutation, allowing genetic counseling and potential prenatal diagnosis. © 2011. Source

Mercimek-Mahmutoglu S.,University of Toronto | Mercimek-Mahmutoglu S.,VU University Amsterdam | Ndika J.,VU University Amsterdam | Kanhai W.,VU University Amsterdam | And 17 more authors.
Human Mutation

Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene. © 2014 WILEY PERIODICALS, INC. Source

Schiff M.,Reference Center for Inherited Metabolic Disease | Schiff M.,French Institute of Health and Medical Research | Schiff M.,University Paris Diderot | Broue P.,Competence Center for Inherited Metabolic Disease and Pediatric Hepatology | And 10 more authors.
Journal of Inherited Metabolic Disease

The 1991 introduction of 2-(2-nitro-4-trifluoromethylbenzyol)-1, 3 cyclohexanedione (NTBC) as a treatment for hereditary tyrosinemia type 1 (HT-1), a disorder of tyrosine catabolism, has radically modified the natural history of this disorder. Despite the dramatic improvements in survival, outcomes and quality of life seen with NTBC treatment, HT-1 remains a chronic disorder with several long-term complications, including, a persistent (albeit low) risk of hepatocellular carcinoma and suboptimal neuropsychological outcomes. There remain unsolved keyquestions concerning the long-term outcomes of patients with HT-1, which closely depend on the quality of followup in these patients. In the absence of published guidelines, we investigated the follow-up methods used for French and Belgian patients with HT-1. A simple questionnaire providing a rapid overview of follow-up procedures was sent to the 19 physicians in charge of HT-1 patients treated with NTBC and low-tyrosine diet in France and Belgium. Several areas of heterogeneity (especially liver imaging, slit lamp examination, neuropsychological evaluation and maximal plasma tyrosine level accepted) were observed. In an attempt to improve long-term management and outcome of patients with HT-1, we proposed follow-up recommendations. © SSIEM and Springer 2011. Source

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