Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35).
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.
Dick
Katherine J
KJ
Medical Genetics, Clinical Developmental Sciences, St George's University of London, London, UK.
Eckhardt
Matthias
M
Paisán-Ruiz
Coro
C
Alshehhi
Aisha Alkhayat
AA
Proukakis
Christos
C
Sibtain
Naomi A
NA
Maier
Helena
H
Sharifi
Reza
R
Patton
Michael A
MA
Bashir
Wafa
W
Koul
Roshan
R
Raeburn
Sandy
S
Gieselmann
Volkmar
V
Houlden
Henry
H
Crosby
Andrew H
AH
D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D002855:Chromatography, Thin Layer; D003241:Consanguinity; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D015419:Spastic Paraplegia, Hereditary / Q000201:enzymology* / Q000235:genetics*; D014162:Transfection
D006899:Mixed Function Oxygenases; C019081:fatty acid alpha-hydroxylase