New Genetic Forms of Neurodegeneration Discovered

The number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia (HSP) has been doubled.

HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.


Scientists at the University of California (San Diego, CA; USA) recruited a cohort of more than 50 families displaying autosomal recessive HSP, the largest such cohort assembled to date. They analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome.

Whole exome sequencing was performed using the SureSelect Human All Exome Kit (Agilent Technologies, Santa Clara, CA, USA) with 100-bp paired-end read sequences generated on a HiSeq 2000 (Illumina, San Diego, CA, USA). The investigators identified a genetic mutation in almost 75% of the cases, half of which were in genes never before linked with human disease, and greatly increasing the number of mutated genes in HSP.

Joseph G. Gleeson, MD, the senior author of the study said, “After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an 'HSP-ome,' a map that included all of the new and previously described causes.”

This ‘HSP-ome’ helped the scientists locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. They were also interested in understanding how HSP relates to other groups of disorders and they found that the ‘HSP-ome’ links HSP to other more common neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis.

The authors concluded that the principle that integrating family-based gene discovery together with prior knowledge can facilitate the identification of biological pathways and processes disrupted in disease. Furthermore, this mode of analysis should be highly useful in the future to aid in the validation of private mutations in genes found in single families, to identify novel candidate genes and pathways, and for the discovery of potential therapeutic targets. The study was published on January 31, 2014, in the journal Science.

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