title: Pure Cerebellar Ataxia with Homozygous Mutations in the PNPLA6 Gene.
abstract: Autosomal-recessive cerebellar ataxias (ARCA) are clinically and genetically heterogeneous conditions primarily affecting the cerebellum. Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations in a field where the genotype-phenotype correlations are rapidly expanding. We identified two cousins from a consanguineous family belonging to a large Zoroastrian (Parsi) family residing in Mumbai, India, who presented with pure cerebellar ataxia without chorioretinal dystrophy or hypogonadotropic hypogonadism. We used a combined approach of clinical characterisation, homozygosity mapping, whole-exome and Sanger sequencing to identify the genetic defect in this family. The phenotype in the family was pure cerebellar ataxia. Homozygosity mapping revealed one large region of shared homozygosity at chromosome 19p13 between affected individuals. Within this region, whole-exome sequencing of the index case identified two novel homozygous missense variants in the PNPLA6 gene at c.3847G>A (p.V1283M) and c.3929A>T (p.D1310V) in exon 32. Both segregated perfectly with the disease in this large family, with only the two affected cousins being homozygous. We identified for the first time PNPLA6 mutations associated with pure cerebellar ataxia in a large autosomal-recessive Parsi kindred. Previous mutations in this gene have been associated with a more complex phenotype but the results here suggest an extension of the associated disease spectrum.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. s.wiethoff.12@ucl.ac.uk.|Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany. s.wiethoff.12@ucl.ac.uk.|National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. s.wiethoff.12@ucl.ac.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
authors.forename: Conceição
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Reema
authors.initials: R
authors.lastname: Paudel
authors.affiliation: Department of Assisted Reproduction and Genetics, Jaslok Hospital and Research Centre, Mumbai, 400026, India.
authors.forename: Prochi
authors.initials: P
authors.lastname: Madon
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Section of Epilepsy, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.|National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hersheson
authors.affiliation: Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India.
authors.forename: Noshir
authors.initials: N
authors.lastname: Wadia
authors.affiliation: Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India.
authors.forename: Joy
authors.initials: J
authors.lastname: Desai
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000368:Aged; D002524:Cerebellar Ataxia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D003241:Consanguinity; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010740:Phospholipases / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D000217:Acyltransferases
chemical_list: D010740:Phospholipases; C586915:PNPLA6 protein, human; D000217:Acyltransferases
keywords: Cerebellar ataxia; Gene; Mutations; PNPLA6