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Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35) |
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| Authors: | Katherine J. Dick Matthias Eckhardt Coro Paisán‐Ruiz Aisha Alkhayat Alshehhi Christos Proukakis Naomi A. Sibtain Helena Maier Reza Sharifi Michael A. Patton Wafa Bashir Roshan Koul Sandy Raeburn Volkmar Gieselmann Henry Houlden Andrew H. Crosby |
| Affiliation: | 1. Medical Genetics, Clinical Developmental Sciences, St George's University of London, London, UK;2. Joint first authors;3. Institute of Biochemistry and Molecular Biology, University of Bonn, 53115 Bonn, Germany;4. Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Queen Square House, Queen Square, WC1N 3BG, London, United Kingdom;5. Department of Biology, College of Science, Sultan Quaboos University, P.C 123‐Muscat, Oman;6. Department of Clinical Neurosciences, Institute of Neurology, University College London, London, NW3 2PF;7. Department of Neuroradiology, Kings College Hospital, Denmark Hill, London, UK;8. Department of medicine and Health Sciences, Sultan Quaboos University, P.C 123‐Muscat, Oman |
| 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. © 2010 Wiley‐Liss, Inc. |
| Keywords: | FA2H hereditary spastic paraplegia mutation SPG35 leukodystrophy |