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VPS13D-based disease: Expansion of the clinical phenotype in two brothers and mutation diversity in the Turkish population - 23/09/22

Doi : 10.1016/j.neurol.2022.05.005 
Ö. Öztop-Çakmak a, G. Şimşir b, Ş. Tekgül b, M.S. Aygün c, O. Gökler d, B. Kahyaoğlu e, Z.E. Kaya f, R. Palvadeau b, A.N. Başak b, , S. Ertan a
a Department of Neurology, School of Medicine, Koç University, Davutpaşa Cd. No.: 4, 34010 Topkapı, Istanbul, Turkey 
b Neurodegeneration Research Laboratory, Suna and Inan Kıraç Foundation, KUTTAM, School of Medicine, Koç University, Davutpaşa Cd. No.: 4, 34010 Topkapı, Istanbul, Turkey 
c Department of Radiology, School of Medicine, Koç University, Davutpaşa Cd. No.: 4, 34010 Topkapı, Istanbul, Turkey 
d Department of Otolaryngology, Head and Neck Surgery, Koç University, Davutpaşa Cd. No.: 4, 34010 Topkapı, Istanbul, Turkey 
e Department of Neurology, American Hospital, Güzelbahçe Sk. No.: 20, 34365 Nişantaşı, Istanbul, Turkey 
f Department of Neurology, Cerrahpaşa School of Medicine, Kocamustafapaşa Cd. No.: 53 Cerrahpaşa, 34098 Fatih, Istanbul, Turkey 

Corresponding author.
Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Friday 23 September 2022

Highlights

VPS13D-based spastic ataxia mainly gives rise to a severe childhood-onset disease.
This study reports an exception with two brothers having a late-onset milder form.
All reported VPS13D variants in the literature are family-specific.
Our WES data imply that VPS13D-based ataxia is not very uncommon in Turkey.
DTI, first applied to VPS13D patients in this study, is of additional value.

Le texte complet de cet article est disponible en PDF.

Abstract

VPS13D is a recently described gene. Worldwide, only 15 families with 23 affected individuals have been reported with a VPS13D-based disease. Mutated VPS13D causes a complex phenotype with a hyperkinetic movement disorder and ataxia, especially in childhood onset disease. The clinical phenotype of the rare adult-onset cases consists of cerebellar ataxia and/or spastic paraplegia. Here, we report the extensive clinical, laboratory and genetic findings of two offspring from consanguineous parents, with ages of disease onset at 57 and 49 with VPS13D-based ataxia. Although conventional magnetic resonance imaging showed mild cerebellar and cerebral atrophy, diffusion tensor imaging, applied for the first time for VPS13D patients, revealed prominent atrophy in U fibers and cerebellopontine tracts. Whole exome sequencing analysis revealed a biallelic Ala4210Val mutation in the VPS13D, reported only once in the literature. Complementary screening of our in-house database consisting of 295 ataxia and hereditary spastic paraplegia patients revealed two further ataxia patients with novel VPS13D variants. Screening the control cohort for VPS13D variants revealed one asymptomatic individual carrying a novel VPS13D variant. In this study, the phenotypic spectrum of VPS13D-based disease is expanded with the description of pre-senile onset predominant ataxia. Further, with the additional novel mutations described, the report is expected to contribute to the understanding of the yet elusive phenotype-genotype correlations in the rare VPS13D-based movement disorder.

Le texte complet de cet article est disponible en PDF.

Keywords : SCAR4, Late adult-onset recessive ataxia, VPS13D, DTI, WES


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