A NGS-based analysis on a large cohort of ataxic patients refines the clinical spectrum associated with SCA21.

Introduction Spinocerebellar Ataxia 21 is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here we describe clinical and molecular findings in 5 additional SCA21 patients from 4 unrelated families, diagnosed through a multicentre Next-Generation Sequencing (NGS)-based molecular screening project on a large cohort of patients with degenerative and congenital ataxias. Methods A cohort of 393 patients with ataxia of unknown aetiology was selected. Following the identification of heterozygous pathogenic TMEM240 variants using a target resequencing panel, we carried out an in-depth phenotyping of the novel SCA21 patients. Results Five patients from 4 unrelated families, three of Italian and one of Libyan origin were identified. These patients were carriers of previously reported TMEM240 mutations. Clinically, our SCA21 cohort includes both adult-onset, slowly progressive cerebellar ataxias associated with cognitive impairment resembling Cerebellar Cognitive Affective Syndrome (CCAS) and early-onset forms associated with cognitive delay, neuropsychiatric features or evidence of hypomielination at the brain MRI. None of our patients exhibited signs of extrapyramidal involvement. The so called "recurrent" c.509C>T (p.Pro170Leu) mutation was detected in two out of four families, corroborating its role as hot-spot. Conclusion Our results confirm that SCA21 is present also in Italy, suggesting that it might be not as rare as previously thought. The phenotype of these novel SCA21 variants indicates that slowly progressive cerebellar ataxia, cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene.