@article{5090d0aa635e482ca9bf339a200781e4,
title = "Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects",
abstract = "Objective: To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias, and spastic paraplegia. Methods: In an international collaboration, we independently performed exome sequencing in 7 families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knockout model and investigated mitochondrial function in patient-derived fibroblast cultures. Results: Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all 7 families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4 (SCAR4). Linkage to chromosome 1p36 was found in this family with a logarithm of odds score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but 2 patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knockdown or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production. Interpretation: Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia–spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. Ann Neurol 2018.",
author = "Eunju Seong and Ryan Insolera and Marija Dulovic and Kamsteeg, {Erik Jan} and Joanne Trinh and Norbert Br{\"u}ggemann and Erin Sandford and Sheng Li and Ozel, {Ayse Bilge} and Li, {Jun Z.} and Tamison Jewett and Kievit, {Anneke J.A.} and Alexander M{\"u}nchau and Vikram Shakkottai and Christine Klein and Collins, {Catherine A.} and Katja Lohmann and {van de Warrenburg}, {Bart P.} and Margit Burmeister",
note = "Funding Information: This work was supported by the NIH-NINDS (NS078560, M.B.; NS069844, C.C.; F32NS098611, RI), the National Ataxia Foundation (M.B.), the European Union{\textquoteright}s Horizon 2020 research innovation program under ERA-NET Cofund action 643578, ZonMW (9003037604; B.P.v.d.W.) under the framework of the E-Rare-3 network PREPARE, the Hersenstichting (B.P.v.d.W.), Radboud University Medical Center (B.P.v.d.W.), Bioblast Pharma (B.P.v.d.W.), the Foundation of the University Hospital Schleswig-Holstein (“Gutes Tun!”; A.M. and K.L.), and a career development award from the Hermann and Lilly Schilling Foundation (C.K.). Funding Information: This work was supported by the NIH-NINDS (NS078560, M.B.; NS069844, C.C.; F32NS098611, RI), the National Ataxia Foundation (M.B.), the European Union's Horizon 2020 research innovation program under ERA-NET Cofund action 643578, ZonMW (9003037604; B.P.v.d.W.) under the framework of the E-Rare-3 network PREPARE, the Hersenstichting (B.P.v.d.W.), Radboud University Medical Center (B.P.v.d.W.), Bioblast Pharma (B.P.v.d.W.), the Foundation of the University Hospital Schleswig-Holstein (“Gutes Tun!”; A.M. and K.L.), and a career development award from the Hermann and Lilly Schilling Foundation (C.K.). We thank the patients for their willingness to participate and their patience during our research; Dr P. Capetian for clinical evaluation of Family LUB1 and for referring to the study; L. Gates, T. Kubisiak, and F. Hinrichs for excellent technical assistance; Dr J. Gudjonsson for fibroblast biopsies; S. Cho for useful discussion on VPS13 evolution; and Drs B. Post, J. Schieving, M. Jongen, and A. Shaikh for providing important clinical data. Publisher Copyright: {\textcopyright} 2018 American Neurological Association",
year = "2018",
month = jun,
doi = "10.1002/ana.25220",
language = "English (US)",
volume = "83",
pages = "1075--1088",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "6",
}