Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35)

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

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127 Citations (Scopus)

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.

Original languageEnglish
JournalHuman Mutation
Volume31
Issue number4
DOIs
Publication statusPublished - Apr 2010

Keywords

  • FA2H
  • Hereditary spastic paraplegia
  • Leukodystrophy
  • Mutation
  • SPG35

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Dick, K. J., Eckhardt, M., Paisán-Ruiz, C., Alshehhi, A. A., Proukakis, C., Sibtain, N. A., Maier, H., Sharifi, R., Patton, M. A., Bashir, W., Koul, R., Raeburn, S., Gieselmann, V., Houlden, H., & Crosby, A. H. (2010). Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Human Mutation, 31(4). https://doi.org/10.1002/humu.21205