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.
| Original language | English |
|---|---|
| Pages (from-to) | 173-178 |
| Number of pages | 6 |
| Journal | Journal of Neurology |
| Volume | 262 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 1 2015 |
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Keywords
- Ceroid lipofuscinosis
- CLN5
- Hereditary ataxias
- SCAR
ASJC Scopus subject areas
- Clinical Neurology
- Neurology
Cite this
Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations. / Mancini, Cecilia; Nassani, Stefano; Guo, Yiran; Chen, Yulan; Giorgio, Elisa; Brussino, Alessandro; Di Gregorio, Eleonora; Cavalieri, Simona; Lo Buono, Nicola; Funaro, Ada; Pizio, Nicola Renato; Nmezi, Bruce; Kyttala, Aija; Santorelli, Filippo Maria; Padiath, Quasar Salem; Hakonarson, Hakon; Zhang, Hao; Brusco, Alfredo.
In: Journal of Neurology, Vol. 262, No. 1, 01.01.2015, p. 173-178.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations
AU - Mancini, Cecilia
AU - Nassani, Stefano
AU - Guo, Yiran
AU - Chen, Yulan
AU - Giorgio, Elisa
AU - Brussino, Alessandro
AU - Di Gregorio, Eleonora
AU - Cavalieri, Simona
AU - Lo Buono, Nicola
AU - Funaro, Ada
AU - Pizio, Nicola Renato
AU - Nmezi, Bruce
AU - Kyttala, Aija
AU - Santorelli, Filippo Maria
AU - Padiath, Quasar Salem
AU - Hakonarson, Hakon
AU - Zhang, Hao
AU - Brusco, Alfredo
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - Ceroid lipofuscinosis
KW - CLN5
KW - Hereditary ataxias
KW - SCAR
UR - http://www.scopus.com/inward/record.url?scp=84930178220&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930178220&partnerID=8YFLogxK
U2 - 10.1007/s00415-014-7553-y
DO - 10.1007/s00415-014-7553-y
M3 - Article
VL - 262
SP - 173
EP - 178
JO - Journal of Neurology
JF - Journal of Neurology
SN - 0340-5354
IS - 1
ER -