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.
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Acknowledgments
We are grateful to the family members who participated in this study. We thank Dr. G. D’Alessandro and Dr. E. Savin (S.C.d.U. Medical Genetics, “Città della Salute e della Scienza” Hospital, Torino, Italy) for suggestions with immunofluorescence analysis and Ms. G. Casale for technical help with transfection experiments. This work was funded by Associazione E. E. Rulfo, PRIN 2010_2011 (Grant 20108WT59Y) (to A. Brusco), a Research Grant from the Shenzhen Municipal Government of China (NO.CXZZ20130517144604091) to H. Jiang, funds from the University of Pittsburgh to Q. S. Padiath.
Conflicts of interest
Yulan Chen and Hao Zhang are employees of BGI-Shenzhen. No further financial disclosure.
Ethical standards
This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Written informed consent was obtained from the patients. The study is a retrospective case report that does not require ethics committee approval.
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C. Mancini, S. Nassani and Y. Guo have equally contributed.
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Mancini, C., Nassani, S., Guo, Y. et al. Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations. J Neurol 262, 173–178 (2015). https://doi.org/10.1007/s00415-014-7553-y
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DOI: https://doi.org/10.1007/s00415-014-7553-y