TY - JOUR
T1 - A next generation sequencing-based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21
AU - Riso, Vittorio
AU - Galatolo, Daniele
AU - Barghigiani, Melissa
AU - Galosi, Serena
AU - Tessa, Alessandra
AU - Ricca, Ivana
AU - Rossi, Salvatore
AU - Caputi, Caterina
AU - Cioffi, Ettore
AU - Leuzzi, Vincenzo
AU - Casali, Carlo
AU - Santorelli, Filippo M.
AU - Silvestri, Gabriella
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - CCAS
KW - NGS
KW - SCA21
KW - TMEM240
KW - spinocerebellar ataxia
KW - CCAS
KW - NGS
KW - SCA21
KW - TMEM240
KW - spinocerebellar ataxia
UR - http://hdl.handle.net/10807/182928
U2 - 10.1111/ene.14868
DO - 10.1111/ene.14868
M3 - Article
SN - 1351-5101
VL - 28
SP - 2784
EP - 2788
JO - European Journal of Neurology
JF - European Journal of Neurology
ER -