Kumar KR, Blair NF, Vandebona H, et al., J Neurol 2013;260:2516-2522.
Submitted by Andrew Tarulli, MD, NSE Board
Mutations in the SPAST (SPG4) gene are the most common cause of autosomal dominant forms of hereditary spastic paraplegia (HSP). Kumar and colleagues performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample for further molecular characterization. Of a cohort of 44 patients with HSP, 17 with SPAST (SPG4) mutations were excluded. The remaining 27 patients underwent study with a PCR-based library and NGS to screen for 10 autosomal dominant and 9 autosomal recessive HSP-causing genes. A genetic cause for HSP was identified in 7 of these 27 (26%) patients. Mutations were identified in 6 of 15 autosomal recessive or sporadic patients, but only 1 of 12 autosomal dominant patients. Of the patients who were not diagnosed, 7 had pure and 13 had complex HSP phenotypes.
Confirmation of the diagnosis of HSP can be vexing for a clinician, as more than 50 individual causative genes have been identified. When testing for the most common SPAST mutation is negative, the physician is left with a dizzying array of other potentially causative mutations. Unfortunately, there is little to guide directed testing, because the correlation between HSP phenotype and genotype is poor. Commercially available panels can help to identify some of the more common causes of HSP, but a specific gene mutation remains unidentified in a large majority of patients. While this study was able to identify causative mutations in only 26% of the SPAST-negative patients, NGS of a more comprehensive set of known mutations appears to be a promising and powerful technique to identify the cause of HSP.
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