AIM OF THE STUDY: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. MATERIALS AND METHODS: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). RESULTS: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. CONCLUSIONS AND CLINICAL IMPLICATIONS: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.
AIM OF THE STUDY: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. MATERIALS AND METHODS: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). RESULTS: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. CONCLUSIONS AND CLINICAL IMPLICATIONS: The TRIOp.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.
Authors: Mercedes Prudencio; Hector Garcia-Moreno; Karen R Jansen-West; Rana Hanna Al-Shaikh; Tania F Gendron; Michael G Heckman; Matthew R Spiegel; Yari Carlomagno; Lillian M Daughrity; Yuping Song; Judith A Dunmore; Natalie Byron; Björn Oskarsson; Katharine A Nicholson; Nathan P Staff; Sorina Gorcenco; Andreas Puschmann; João Lemos; Cristina Januário; Mark S LeDoux; Joseph H Friedman; James Polke; Robin Labrum; Vikram Shakkottai; Hayley S McLoughlin; Henry L Paulson; Takuya Konno; Osamu Onodera; Takeshi Ikeuchi; Mari Tada; Akiyoshi Kakita; John D Fryer; Christin Karremo; Inês Gomes; John N Caviness; Mark R Pittelkow; Jan Aasly; Ronald F Pfeiffer; Venka Veerappan; Eric R Eggenberger; William D Freeman; Josephine F Huang; Ryan J Uitti; Klaas J Wierenga; Iris V Marin Collazo; Philip W Tipton; Jay A van Gerpen; Marka van Blitterswijk; Guojun Bu; Zbigniew K Wszolek; Paola Giunti; Leonard Petrucelli Journal: Sci Transl Med Date: 2020-10-21 Impact factor: 17.956
Authors: Yuka Koike; Karen R Jansen-West; Rana Hanna Al-Shaikh; Yari Carlomagno; Yuping Song; Judith A Dunmore; Mark S LeDoux; Joseph H Friedman; Ashley B Pena; Ryan J Uitti; Jacek Zaremba; Jay A van Gerpen; Ronald F Pfeiffer; Venka Veerappan; Ikuko Aiba; Rina Hashimoto; Samuel S Giles; Jaimin S Shah; Philip W Tipton; Josephine F Huang; Klaas J Wierenga; Jan Aasly; John D Fryer; Leonard Petrucelli; Zbigniew K Wszolek; Mercedes Prudencio Journal: Parkinsonism Relat Disord Date: 2021-07-17 Impact factor: 4.891