title: Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations.
abstract: Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.
authors.affiliation: Department of Medical Sciences, University of Torino, Via Santena 19, 10126, Turin, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mancini
authors.forename: Stefano
authors.initials: S
authors.lastname: Nassani
authors.forename: Yiran
authors.initials: Y
authors.lastname: Guo
authors.forename: Yulan
authors.initials: Y
authors.lastname: Chen
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brussino
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Gregorio
authors.forename: Simona
authors.initials: S
authors.lastname: Cavalieri
authors.forename: Nicola
authors.initials: N
authors.lastname: Lo Buono
authors.forename: Ada
authors.initials: A
authors.lastname: Funaro
authors.forename: Nicola Renato
authors.initials: NR
authors.lastname: Pizio
authors.forename: Bruce
authors.initials: B
authors.lastname: Nmezi
authors.forename: Aija
authors.initials: A
authors.lastname: Kyttala
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Quasar Salem
authors.initials: QS
authors.lastname: Padiath
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
mesh_terms: D017668:Age of Onset; D002524:Cerebellar Ataxia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003241:Consanguinity; D005260:Female; D006801:Humans; D007558:Italy; D051907:Lysosomal Membrane Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D035781:Siblings
chemical_list: C113332:CLN5 protein, human; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins