Document Detail

Clinical and biochemical heterogeneity associated with fumarase deficiency.
MedLine Citation:
PMID:  21560188     Owner:  NLM     Status:  Publisher    
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.
Chris Ottolenghi; Laurence Hubert; Yannick Allanore; Anais Brassier; Cécilia Altuzarra; Caroline Mellot-Draznieks; Soumeya Bekri; Alice Goldenberg; Severine Veyrieres; Nathalie Boddaert; Valérie Barbier; Vassili Valayannopoulos; Abdelhamid Slama; Dominique Chrétien; Daniel Ricquier; Stéphane Marret; Thierry Frebourg; Daniel Rabier; Arnold Munnich; Yves de Keyzer; Hervé Toulhoat; Pascale de Lonlay
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-10
Journal Detail:
Title:  Human mutation     Volume:  -     ISSN:  1098-1004     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2011 Wiley-Liss, Inc.
Service de Biochimie Métabolique, Hôpital Necker-Enfants Malades, Université Paris Descartes et Assistance Publique Hôpitaux de Paris, Paris, France; Unité INSERM UMR-747 et Université Paris Descartes, Centre Universitaire des Saints Pères, Paris, France.
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