Objective: To characterize the genetic and phenotypic characteristics of patients from five unrelated families with adult-onset  ataxia

Background: Biallelic variants of the CLN5 gene were first identified in relation to childhood-onset Neuronal ceroid lipofuscinosis (NCL). In 2015, a new form of autosomal recessive spinocerebellar ataxia was identified in an Italian family, linked to  the CLN5 gene, characterized by gait instability, dysarthria, and modest cognitive impairment. 

Method: Examination of clinical and genetic data regarding the c.562T>C variant in the CLN5 gene in Kuwait and the Kingdom of Saudi Arabia, as well as the potential founder mutation as a cause of adult-onset spinocerebellar ataxia.

Results: In the first case (A), a 52-year-old male exhibited a decade-long history of progressively unsteady gait, accompanied by positive cerebellar findings upon examination. The MRI of the brain revealed cerebellar atrophy, predominantly affecting the vermis. Whole exome sequencing (WES) identified a new homozygous missense mutation in CLN5 (c.562T>C; p. Phe188Leu, NM_006493.2).  

A greater number of families exhibited identical phenotypes and genotypes in the second family (B), originating from Kuwait, which had a familial history of a comparable disease in the elder brother and asymptomatic relatives. The index case is a 54-year-old female exhibiting symptoms that commenced in her 40s, characterized by dysarthria and gait instability, cerebellar atrophy seen on brain imaging, and the presence of an identical mutation in the CLN5 gene. An unrelated example from Kuwait emerged in her forties, with gait ataxia accompanied by cerebellar atrophy. The fourth (D) and fifth (E) unrelated families from Saudi Arabia, aged between 36 and 62 years, exhibited adult-onset ataxia mostly affecting gait and speech, both displaying the identical mutation in the CLN5 gene.Subsequently, an unrelated case from Kuwait emerged involving a 45-year-old individual exhibiting gait instability and cerebellar atrophy as evidenced by MRI. 

Conclusion: CLN5 may manifest as a  gait ataxia and verbal impairment. It should be regarded as a factor contributing to adult-onset autosomal recessive spinocerebellar ataxia in the Arab region

References: Mancini, C., S. Nassani, Y. Guo, Y. Chen, E. Giorgio, A. Brussino, E. Di Gregorio, S. Cavalieri, N. Lo Buono, A. Funaro, N. R. Pizio, B. Nmezi, A. Kyttala, F. M. Santorelli, Q. S. Padiath, H. Hakonarson, H. Zhang and A. Brusco (2015). “Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations.” J Neurol 262(1): 173-178.
Sulaiman, R. A., S. M. Wakil and S. Boholega (2020). “Late-onset cerebellar ataxia in an adult with a novel mutation in the CLN5 gene.” Discoveries Reports 3.
Sun, Y., R. Almomani, G. J. Breedveld, G. W. Santen, E. Aten, D. J. Lefeber, J. I. Hoff, E. Brusse, F. W. Verheijen, R. M. Verdijk, M. Kriek, B. Oostra, M. H. Breuning, M. Losekoot, J. T. den Dunnen, B. P. van de Warrenburg and A. J. Maat-Kievit (2013). “Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).” Hum Mutat 34(5): 706-713.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-analysis-of-kuwaiti-and-saudi-families-exhibiting-cln5-adult-onset-autosomal-recessive-spinocerebellar-ataxia-a-potential-founder-mutation/