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 ERlysosome 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.

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies

“…Since then, at least 36 potentially causal CLN5 sequence variants have been found in human NCL patients (http://www.ucl.ac.uk/ncl/cln5.shtml). For most CLN5 patients, the onset of clinical signs occurred between 4 and 7 years of age, but some presumably hypomorphic mutations have produced much later disease onsets . Although CLN5 mutations have been recognized as causes of NCL for over 16 years, the biological functions of the gene product and the mechanisms leading to neurodegeneration remain unknown .…”

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

“…As with the dogs, these patients exhibited an initial mild loss of coordination. This was followed by increasingly severe mental and motor deterioration, visual impairment, and seizures and culminated with premature death [47][48][49][50][51]. Atypical human CLN5 disease variants with delayed onset and a slower progression of clinical signs have been described [48][49][50][51].…”

Phenotype and natural history of variant late infantile ceroid‐lipofuscinosis 5

“…A recent survey found that patients with CLN5 represent about 6% of all those molecularly diagnosed in Italy . CLN5 disease is considered as a variant late infantile onset NCL, but cases with adolescent and even adult onset have been described . A unique case of congenital CLN5 disease was reported in an infant carrying compound heterozygous CLN5 mutations associated with a variant in POLG1 .…”