ICNC Abstracts, ICNC 2018

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A founder homozygous mutation in VPS53 as the cause of Complicated Hereditary Spastic Paraparesis
Moran Hausman-Kedem, Shay Ben-Shachar, Shay Menascu, Liora Sagie, Aviva Fattal-Valevski

Last modified: 2018-09-09


Hereditary Spastic Paraparesis (HSP) is a progressive neurodegenerative disorder, mainly characterized by progressive lower limb weakness and spasticity. Multiple gene mutations are associated with HSP, both the pure and complicated type. Founder mutation in the VPS53 gene (∼1:50 carrier rate) was recently described in a cohort of 10 families of Moroccan Jewish ancestry with progressive cerebello-cerebral atrophy (PCCA) type 2. The syndrome is characterized by progressive microcephaly, spasticity, profound Intellectual disability, and generalized seizures. VPS53 gene acts as a component of the Golgi associated retrograde protein (GARP) complex that is involved in intracellular cholesterol transport and sphingolipid homeostasis. We describe the same canonical splice-site homozygous founder mutation in the VPS53 gene (c.2084A>G p.Gln695Arg), in two female siblings presented with a different phenotype of complicated HSP. The older sister presented with progressive spasticity and weakness of lower limbs, normal head circumference, normal cognitive function, and a normal brain MRI. The younger sister had similar features but with borderline cognitive function. None had the typical cerebellar atrophy, microcephaly or seizures described in PCCA type2 and both were able to walk and attend school. Both parents and a healthy sibling were heterozygous for the mutation and show normal neurological examination and cognitive function. This is the first description of VPS53 gene mutation as a plausible cause of complicated HSP. Impaired cholesterol trafficking can lead to lysosomal dysfunction, which could explain neurodegenerative processes responsible for the HSP phenotype. Other genetic or environmental modifiers could contribute to the diverse phenotype and should be further studied.



Hereditary Spastic Paraperesis;HSP;PCCA type 2; VPS53

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