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Clinical and biochemical heterogeneity associated with fumarase deficiency
Author(s) -
Ottolenghi Chris,
Hubert Laurence,
Allanore Yannick,
Brassier Anais,
Altuzarra Cécilia,
MellotDraznieks Caroline,
Bekri Soumeya,
Goldenberg Alice,
Veyrieres Severine,
Boddaert Nathalie,
Barbier Valérie,
Valayannopoulos Vassili,
Slama Abdelhamid,
Chrétien Dominique,
Ricquier Daniel,
Marret Stéphane,
Frebourg Thierry,
Rabier Daniel,
Munnich Arnold,
de Keyzer Yves,
Toulhoat Hervé,
de Lonlay Pascale
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21534
Subject(s) - fumarase , biology , polymicrogyria , medicine , urinary system , endocrinology , missense mutation , mutation , cancer research , genetics , epilepsy , gene , neuroscience
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. Hum Mutat 32:1–7, 2011. © 2011 Wiley‐Liss, Inc.