A next generation sequencing‐based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21. (27th May 2021)

• Record Type: Journal Article
• Authors: Riso, Vittorio; Galatolo, Daniele; Barghigiani, Melissa; Galosi, Serena; Tessa, Alessandra; Ricca, Ivana; Rossi, Salvatore; Caputi, Caterina; Cioffi, Ettore; Leuzzi, Vincenzo; Casali, Carlo; Santorelli, Filippo M.; Silvestri, Gabriella
• Is Part Of: European journal of neurology. Volume 28:Number 8(2021)
• Page Start: 2784
• Page End: 2788
• Publication Date: 2021-05-27
• Subjects: CCAS -- NGS -- SCA21 -- spinocerebellar ataxia -- TMEM240; Neurology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/ene.14868
• Languages: English
• ISSNs: 1351-5101

Abstract

Abstract: Background and purpose: Spinocerebellar ataxia 21 (SCA21) 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 five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing‐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 four 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 and early onset forms associated with cognitive delay, neuropsychiatric features, or evidence of hypomyelination on brain magnetic resonance imaging. None of our patients exhibited signs of extrapyramidal involvement. The so‐called "recurrent" c.509C>T (p.Pro170Leu) mutation was detected in two of four families, corroborating its role as a hot spot. Conclusions: Our results confirm that SCA21 is present also in Italy, suggesting that it might not be as rare as previously thought. The phenotype of these novel SCA21 patients indicates that slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms are the most typical clinical features associated with mutations in the TMEM240 gene. Abstract : Spinocerebellar ataxia 21 (SCA21), caused by heterozygous TMEM240 mutations, so far has been rarely reported. By screening a cohort of 393, mostly Italian, ataxic patients with ataxia of unknown aetiology using a next generation sequencing‐based targeted resequencing approach, we identified five novel SCA21 patients from four unrelated families. In all of them, we detected previously described TMEM240 mutations, with the c.509C>T (p.Pro170Leu) mutation confirmed as a mutational hot spot. Thus, SCA21 might not be as rare as previously thought; slowly progressive cerebellar ataxia, and cognitive and psychiatric symptoms appear to be the most typically associated clinical features. ​