Raneem H. Alghamdi
King Faisal Specialist Hospital and Research Center, Saudi Arabia
Title: Natural history of HSP56 informed by a common ancient CYP2U1 founder mutation
Biography
Biography: Raneem H. Alghamdi
Abstract
Biallelic mutations of CYP2U1 are known to cause a complicated form of hereditary Spastic Paraplegia (SPG56). Only 26 families with SPG56 have been reported to date with 29 variants in CYP2U1. Here, we report 18 additional families (25 patients) all but two are homozygous for a founder Arab variant c.947A>T:p.Asp316Val. This largest cohort to date on SPG56 demonstrates a remarkably consistent phenotypic expression of the founder variant with predictable and universal loss of ambulation but variable degree of loss of speech, intellectual disability and white matter changes. Two families had novel variants in CYP2U1 (c.890T>C:p.Phe297Ser and c.967 997del) and the phenotype was compatible with that seen in the rest of the cohort. Haplotype analysis allowed us to estimate the age of the founder mutation at 1040 years, which makes this as one of the most ancient intellectual disability mutations in Arabia and explains its high carrier frequency and wide geographic distribution.