Rettenmaier Leigh A, Chen Jin Yun Helen, MacMore Jason, Gupta Anoopum S, Lin Chih-Chun, Stephen Christopher D, Pellerin David, Brais Bernard, Schmahmann Jeremy D
Ataxia Center, Department of Neurology, Mass General Brigham and Harvard Medical School, 101 Merrimac Street, Suite 310, Boston, MA, 02114, USA.
Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Mass General Brigham and Harvard Medical School, Boston, MA, USA.
Cerebellum. 2025 Jul 18;24(5):133. doi: 10.1007/s12311-025-01882-3.
Spinocerebellar Ataxia type 27B (SCA27B) is caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. The core clinical phenotype is a slowly progressive, adult-onset cerebellar ataxia, often with downbeat nystagmus (DBN) and episodic worsening. We tested whether clinical phenotyping could predict this genetic disorder. We screened the Massachusetts General Hospital Ataxia Center registry (n = 3,182) for patients with a) isolated DBN, b) DBN with ataxia, and c) autosomal dominant cerebellar ataxia (ADCA) that had eluded genetic diagnosis. Patient histories, examinations, and imaging were reviewed. Genetic analysis for FGF14 expansion was performed. Of 65 identified patients, 39 completed genetic testing. Among 14 with isolated DBN, 9 carried an FGF14 repeat expansion (GAA) (range, 295-461), 1 had a potentially pathogenic allele (247 repeats), and 4 had normal alleles. Among 19 with DBN plus ataxia, 12 tested positive (276-431 repeats), 1 had a suspected pathogenic allele (228 repeats), and 6 had normal alleles. All 4 ADCA patients tested positive (320-483 repeats), as did 2 presymptomatic siblings. Our cohort enriched for suspicion of SCA27B had confirmed or suspected pathogenic FGF14-GAA expansion in 74.4% (29/39). Diagnostic success rate was 90.0% (27/30) in patients with onset > 45 years: 25/30 (GAA), 2/30 (GAA). Cerebellar atrophy was seen in 97.1% (34/35), mostly in the vermis/paravermis. Clinically meaningful improvement with 4-aminopyridine occurred in 71.0% (22/31) of patients. SCA27B can be reliably recognized from its core clinical phenotype in up to 90% of cases, enabling successful pharmacotherapy in 71.0%.
27B型脊髓小脑共济失调（SCA27B）由成纤维细胞生长因子14（FGF14）基因内含子GAA重复序列扩增引起。核心临床表型为缓慢进展的成人起病的小脑共济失调，常伴有下跳性眼球震颤（DBN）和发作性加重。我们测试了临床表型分析是否可以预测这种遗传疾病。我们在马萨诸塞州总医院共济失调中心登记处（n = 3182）筛查了以下患者：a）孤立性DBN；b）伴有共济失调的DBN；c）未得到基因诊断的常染色体显性小脑共济失调（ADCA）。回顾了患者病史、检查和影像学资料。进行了FGF14扩增的基因分析。在65例确诊患者中，39例完成了基因检测。在14例孤立性DBN患者中，9例携带FGF14重复序列扩增（GAA）（范围为295 - 461），1例有潜在致病等位基因（247次重复），4例等位基因正常。在19例伴有共济失调的DBN患者中，12例检测呈阳性（276 - 431次重复），1例有疑似致病等位基因（228次重复），6例等位基因正常。所有4例ADCA患者检测均呈阳性（320 - 483次重复），2例症状前同胞也是如此。我们这个高度怀疑SCA27B的队列中，74.4%（29/39）确诊或疑似有致病性FGF14 - GAA扩增。45岁以后起病的患者诊断成功率为90.0%（27/30）：25/30（GAA），2/30（GAA）。97.1%（34/35）可见小脑萎缩，主要位于蚓部/旁蚓部。71.0%（22/31）的患者使用4 - 氨基吡啶后有具有临床意义的改善。高达90%的病例可从SCA27B的核心临床表型中可靠识别出该疾病，71.0%的病例可实现成功的药物治疗。
