Ottolenghi C.,University of Paris Descartes |
Hubert L.,University of Paris Descartes |
Hubert L.,French Institute of Health and Medical Research |
Allanore Y.,French Institute of Health and Medical Research |
And 22 more authors.
Human Mutation | Year: 2011
Fumarase deficiency (FD), caused by biallelic alteration of the Fumarase Hydratase gene (FH), and a rare metabolic disorder that affects the Krebs cycle, causes severe neurological impairment and fumaric aciduria. Less than 30 unrelated cases are known to date. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). We report three additional patients with dramatically different clinical presentations of FD and novel missense mutations in the FH gene. One patient had severe neonatal encephalopathy, polymicrogyria, <1% enzyme activity, and mildly increased levels of urinary fumarate. The second patient had microcephaly, mental retardation, 20% of fumarase activity, and intermediate levels of urinary fumarate. The third patient had mild mental retardation, polymicrogyria, 42-61% enzyme activity in different cell types and massive amounts of urinary fumarate. In silico analysis predicted minor yet significant structural changes in the encoded proteins. The nuclear translocation of hypoxia-inducible factor (HIF)-1alpha (HIF1A) in cultured fibroblasts was similar to controls. These results extend the range of clinical and biochemical variation associated with FD, supporting the notion that patients with moderate increases in fumarate excretion should be investigated for this disease. The tumoral risk in the patients and their relatives requires adequate screening protocols. © 2011 Wiley-Liss, Inc.
Capo-Chichi J.-M.,Sainte Justine Research Center |
Mehawej C.,Saint - Joseph University |
Mehawej C.,Harvard University |
Delague V.,French Institute of Health and Medical Research |
And 9 more authors.
European Journal of Medical Genetics | Year: 2015
Background: Recently, biallelic mutations in the Neuroblastoma Amplified Sequence NBAS gene have been identified in ten patients that present recurrent acute liver failure (RALF) in early infancy. In addition to severe liver dysfunction, some of these individuals also suffered from other comorbidities including cardiomyopathy, neurologic phenotypes and gastrointestinal immune defects. Here we report on a consanguineous Lebanese family with three siblings affected by RALF. Of note, neonatal spontaneous fractures, developmental delay, prominent eyes, generalized hirsutism, gum hypertrophy, and hepato-splenomegaly were also present. Methods: Whole-genome SNP genotyping in all the patients, followed by exome sequencing was performed in one of the affected siblings. Results: A homozygous c.409C > T (p.Arg137Trp) missense mutation in NBAS was identified in all patients. Conclusion: Overall, our findings confirm the involvement of NBAS in the pathogenesis of this condition characterized by severe liver dysfunction and help expand its phenotypical spectrum. © 2015 Elsevier Masson SAS.
Nicolas T.,Service de Biochimie Medicale |
Cabrolier N.,Service de Biochimie Medicale |
Bardonnet K.,Service de Biochimie Medicale |
Davani S.,Service de Biochimie Medicale
Annales de Biologie Clinique | Year: 2013
We present here evaluation of a new blood gas analysis system, RapidPoint 500® (Siemens Healthcare Diagnostics). The aim of this research was to compare the ergonomics and analytical performances of this analyser with those of the RapidLab 1265 for the following parameters: pH, partial oxygen pressure, partial carbon dioxide pressure, sodium, potassium, ionized calcium, lactate and the CO-oximetry parameters: hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin, reduced hemoglobin, neonatal bilirubin; as well as with the Dimension Vista 500 results for chloride and glucose. The Valtec protocol, recommended by the French Society of Clinical Biology (SFBC), was used to analyze the study results. The experiment was carried out over a period of one month in the Department of medical biochemistry. One hundred sixty five samples from adult patients admitted to the ER or hospitalized in intensive care were tested. The RapidPoint 500® was highly satisfactory from an ergonomic point of view. Intra-and inter- assay coefficients of variation (CV) with the three control levels were below those recommended by the SFBC for all parameters, and the comparative study gave coefficients of determination higher than 0.91. Taken together, the RapidPoint 500® appears fully satisfactory in terms of ergonomics and analytical performance.