EFFICACITE D'UN VERROU LOCAL D'ANTIBIOTIQUE POUR LE TRAITEMENT DES INFECTIONS LIEES AUX CATHETERS CENTRAUX EN NUTRITION PARENTERALE CHEZ L'ENFANT

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Epilepsie réfractaire et hyperlactacidémie chez un nourrisson : la maladie de Menkès, un diagnostic à envisager. A propos d’un cas

International audienceMenkes disease is an X-linked recessive disorder affecting copper metabolism due to an inactivating mutation of ATP7A gene. This result in loss of copper intestinal absorption, tissue deficiency and failure in multiple essential copper-enzyme systems such as the cytochrome c oxidase. Symptoms usually occur during the first months of life with neurological signs such as epilepsy associated to other signs among them typical hair appearance. We report the case of a 3 month-old infant hospitalized due to partial tonic-clonic seizures. Laboratory findings showed increased of lactates in blood and in cerebrospinal fluid. First screenings for infectious, metabolic and genetic causes were negative. After recurrence of multifocal seizures further investigations are made according to the presence of thick and tortuous hair. Low levels of ceruloplasmin and copper in plasma are in agreement with the suspected diagnosis of Menkes disease. Molecular analysis of the ATP7A gene confirmed the diagnosis with a non-sens mutation.La maladie de Menkès est une maladie génétique rare du métabolisme du cuivre causée par une mutation inactivatrice du gène ATP7A. Il en résulte un défaut d’absorption intestinale du cuivre, une carence tissulaire et un dysfonctionnement des cupro-enzymes dont la cytochrome c oxydase. Il s’agit d’une maladie multi-systémique dont les signes cliniques apparaissent dès les premiers mois de vie incluant notamment une épilepsie sévère et un aspect caractéristique des cheveux. Nous rapportons l’observation d’un cas chez un nourrisson de 3 mois hospitalisé suite à une crise tonico-clonique partielle. Le bilan biologique révèle une hyperlactacidémie et une hyperlactatorachie. Les premières explorations infectieuses, métaboliques et génétiques sont négatives. Suite à la récidive de crises multifocales de nouvelles investigations sont réalisées avec un point d’appel sur la répartition et l’aspect anormal des cheveux. Les taux de céruloplasmine et cuivre plasmatiques effondrés sont compatibles avec une maladie de Menkès. L’analyse moléculaire du gène ATP7A a permis de confirmer le diagnostic par la mise en évidence d’une mutation non-sens

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC 16A2 mutations

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Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias

International audienceNext-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data

High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

International audiencePurpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation