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P.071 Novel mutations in SPG7 identified from patients with late-onset spasticity

  • MM Almomen (a1), KA Martens (a1), A Hanson (a1), L Korngut (a1) and G pfeffer (a1)...

Abstract

Background: Hereditary spastic paraplegia (HSP) is a group of genetic diseases that cause progressive degeneration of the corticospinal tract. Historically, this disease was divided into two types:the classic subtype, with leg weakness and hypertonic bladder, and the complicated subtype, with features such as cerebellar ataxia or optic atrophy.Mutations in SPG7 (encoding paraplegin) leads to complicated HSP causing cerebellar ataxia, progressive external ophthalmoplegia in addition to the classical symptoms. AFG3L2 is a binding partner of paraplegin and mutations in AFG3L2 cause a similar syndrome Methods: From a neurogenetic clinic , we identified 11 patients with late-onset HSP. Sequencing of SPG7 and AFG3L2 was performed using a customised assay, and/or clinical diagnostic sequencing panels.SPG7 transcript level quantification was performed from whole blood RNA on a digital droplet qPCR system. Results: We identified 4 patients with pathogenic variants or variants of unknown significance in SPG7. No AFG3L2 mutations were identified. We provide evidence for pathogenicity for three mutations that were not previously associated with SPG7-related disease, based on their occurrence in context of the correct phenotype, and the reduction of transcript levels measured with RT-qPCR.A curious association of the heterozygous p.Gly349Ser mutation in association with an ALS-like syndrome is reported. Conclusions:SPG7 mutations sequencing has high diagnostic yield in late onset paraparesis

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