title: Clinical and biochemical heterogeneity associated with fumarase deficiency.
abstract: 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.
authors.affiliation: Service de Biochimie Métabolique, Hôpital Necker-Enfants Malades, Université Paris Descartes et Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Anais
authors.initials: A
authors.lastname: Brassier
authors.forename: Cécilia
authors.initials: C
authors.lastname: Altuzarra
authors.forename: Caroline
authors.initials: C
authors.lastname: Mellot-Draznieks
authors.forename: Soumeya
authors.initials: S
authors.lastname: Bekri
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Severine
authors.initials: S
authors.lastname: Veyrieres
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Valérie
authors.initials: V
authors.lastname: Barbier
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Slama
authors.forename: Dominique
authors.initials: D
authors.lastname: Chrétien
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricquier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Marret
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.forename: Daniel
authors.initials: D
authors.lastname: Rabier
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Yves
authors.initials: Y
authors.lastname: de Keyzer
authors.forename: Hervé
authors.initials: H
authors.lastname: Toulhoat
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
mesh_terms: D015687:Cell Hypoxia; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D005260:Female; D005649:Fumarate Hydratase / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism*; D005650:Fumarates / Q000652:urine; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D054220:Malformations of Cortical Development / Q000201:enzymology* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction
chemical_list: D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C032005:fumaric acid; D005649:Fumarate Hydratase