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A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23

From the Department of Medical Genetics (K.J.D., M.A.S., M.A.P., A.H.C.), St George’s University of London, UK; and Sultan Qaboos University Hospital (R.A.-M., W.B., R.K., S.R.), Muscat, Oman.

Address correspondence and reprint requests to Dr. Andrew H. Crosby, Department of Medical Genetics, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK acrosby{at}sgul.ac.uk

Background: The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous neurodegenerative disorders in which the cardinal pathologic feature is upper motor neuron degeneration leading to progressive spasticity and weakness of the lower limbs. To date, 14 autosomal recessive HSP loci have been mapped.

Methods: We have identified a large consanguineous Omani family in which an autosomal recessive form of HSP is segregating. The age at onset varied from 6 to 11 years and the course of the disease is progressive with intellectual disability and is associated with seizures in two individuals. To map the chromosomal location of the causative gene we undertook 250K gene chip SNP analyses of all affected individuals assuming that a founder mutation was responsible.

Results: All affected individuals shared a 20.4 Mb (3.25 cM) region of homozygosity located on chromosome 16q21-q23.1, defined by SNP markers rs149428 and rs9929635 (peak multipoint lod score of 4.86). Two candidate genes, dynein, cytoplasmic 1, light intermediate chain 2 (DYNC1LI2) and vacuolar protein sorting 4 homolog A (VPS4A), were sequenced but no disease causing mutations were identified.

Conclusion: We have mapped the chromosomal location of a novel gene responsible for a form of hereditary spastic paraplegia (HSP) (SPG35) and defined its clinical presentation.

Abbreviations: HSP = hereditary spastic paraplegia.

Editorial, page 236

e-Pub ahead of print on May 7, 2008, at www.neurology.org.

This work is funded by H.M. Sultan Qaboos, Strategic Research Funding, in the ‘FamGUARD’ project and the Birth Defects Foundation Newlife.

Disclosure: The authors report no disclosures.

Received May 11, 2007. Accepted in final form November 27, 2007.

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