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Mutation of FA2H Underlies a Complicated Form of Hereditary Spastic Paraplegia (SPG35)

Dick, KJ; Eckhardt, M; Paisan-Ruiz, C; Alshehhi, AA; Proukakis, C; Sibtain, NA; Maier, H; ... Crosby, AH; + view all (2010) Mutation of FA2H Underlies a Complicated Form of Hereditary Spastic Paraplegia (SPG35). HUM MUTAT , 31 (4) E1251 - E1260. 10.1002/humu.21205.

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Abstract

Hereditary spastic paraplegia (HSP) describes a heterogeneous group of inherited neurodegenerative disorders in which the cardinal pathological feature is upper motor neurone degeneration leading to progressive spasticity and weakness of the lower limbs. Using samples from a large Omani family we recently mapped a gene for a novel autosomal recessive form of HSP (SPG35) in which the spastic paraplegia was associated with intellectual disability and seizures. Magnetic resonance imaging of the brain of SPG35 patients showed white matter abnormalities suggestive of a leukodystrophy. Here we report homozygous mutations in the fatty acid 2-hydroxylase gene (FA2H) in the original family used to define the SPG35 locus (p.Arg235Cys) as well as in a previously unreported Pakistani family with a similar phenotype (p.Arg53_Ile58del). Measurement of enzyme activity in vitro revealed significantly reduced enzymatic function of FA2H associated with these mutations. These results demonstrate that mutations in FA2H are associated with SPG35, and that abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe progressive phenotype, with a clinical presentation of complicated HSP and radiological features of leukodystrophy. (C) 2010 Wiley-Liss, Inc.

Type: Article
Title: Mutation of FA2H Underlies a Complicated Form of Hereditary Spastic Paraplegia (SPG35)
DOI: 10.1002/humu.21205
Keywords: FA2H, hereditary spastic paraplegia, mutation, SPG35, leukodystrophy, PELIZAEUS-MERZBACHER-DISEASE, FATTY-ACID 2-HYDROXYLASE, CENTRAL-NERVOUS-SYSTEM, TROYER-SYNDROME, SILVER-SYNDROME, MYELIN, LOCUS, ONSET, GENE, LEUKODYSTROPHY
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/174689
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