Koutsis Georgios, Kartanou Chrisoula, Kontogeorgiou Zoi, Koniari Chrysoula, Mitrousias Alexandros, Pellerin David, Dicaire Marie-Jose, Iruzubieta Pablo, Danzi Matt C, Athanassopoulos Konstantinos, Ragazos Nikolaos, Stamelou Maria, Rentzos Michail, Anagnostou Evangelos, Zuchner Stephan, Brais Bernard, Houlden Henry, Panas Marios, Stefanis Leonidas, Karadima Georgia
Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginitio Hospital, Athens, Greece.
Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginitio Hospital, Athens, Greece.
J Neurol Sci. 2024 Dec 15;467:123309. doi: 10.1016/j.jns.2024.123309. Epub 2024 Nov 15.
Late-onset cerebellar ataxia (LOCA) is a slowly progressive cerebellar disorder with symptom onset ≥30years of age. Intronic tandem repeat expansions (TREs) in RFC1 and FGF14 have recently emerged as common causes of LOCA. The relative contribution of classic vs. newly discovered TREs has not been systematically investigated in LOCA cohorts.
Over 28 years, 206 consecutive Greek LOCA index patients were referred for genetic testing and, based on clinical data and inheritance pattern, screened for FRDA, SCA1,2,3,6,7, FXTAS, CANVAS and SCA27B.
A genetic diagnosis was reached in 62 of 206 cases (30.1 %). Mean age was 60.1 ± 11.2 (35-87) years and mean age at onset (AAO) 52.5 ± 11.4 (30-80) years. SCA27B accounted for 9.7 % of LOCA cases, CANVAS for 7.8 % and FRDA for 4.4 %. The overall frequency of SCA1, SCA2 and SCA7 was 6.8 %. No cases of SCA3 and SCA6 were identified. FXTAS contributed 1.5 % of cases. In sporadic cases, the diagnostic yield was 22.8 % (34 of 149; SCA27B: 8.7 %, CANVAS: 8.1 %, FRDA: 2.7 %, SCA2: 1.3 %, FXTAS: 1.3 % and SCA7: 0.7 %). In familial cases, the diagnostic yield was 49.1 % (28 of 57). Two cases with CANVAS had pseudodominant inheritance. Patients with SCA27B, CANVAS and FXTAS had mean AAO > 50 years, whereas patients with FRDA, SCA1, SCA2 and SCA7 had mean AAO < 50 years.
Recently-discovered TREs causing SCA27B and CANVAS represent the commonest known genetic causes of LOCA. Prioritizing testing for FGF14 and RFC1 expansions in the diagnostic algorithm of LOCA is recommended.
迟发性小脑共济失调（LOCA）是一种症状出现于30岁及以上的缓慢进展性小脑疾病。RFC1和FGF14基因内含子串联重复扩增（TREs）最近已成为LOCA的常见病因。在LOCA队列中，经典TREs与新发现的TREs的相对贡献尚未得到系统研究。
在28年期间，连续206例希腊LOCA索引患者接受了基因检测，并根据临床数据和遗传模式，对其进行了Friedreich共济失调（FRDA）、脊髓小脑共济失调1型（SCA1）、2型、3型、6型、7型、脆性X震颤共济失调综合征（FXTAS）、小脑脑桥角血管病（CANVAS）和脊髓小脑共济失调27B型（SCA27B）的筛查。
206例患者中有62例（30.1%）获得了基因诊断。平均年龄为60.1±11.2（35 - 87）岁，平均发病年龄（AAO）为52.5±11.4（30 - 80）岁。SCA27B占LOCA病例的9.7%，CANVAS占7.8%，FRDA占4.4%。SCA1、SCA2和SCA7的总体发生率为6.8%。未发现SCA3和SCA6病例。FXTAS占病例的1.5%。在散发病例中，诊断率为22.8%（149例中的34例；SCA27B：8.7%，CANVAS：8.1%，FRDA：2.7%，SCA2：1.3%，FXTAS：1.3%，SCA7：0.7%）。在家族病例中，诊断率为49.1%（57例中的28例）。2例CANVAS患者具有假显性遗传。SCA27B、CANVAS和FXTAS患者的平均AAO>50岁，而FRDA、SCA1、SCA2和SCA7患者的平均AAO<50岁。
导致SCA27B和CANVAS的新发现的TREs是LOCA最常见的已知遗传病因。建议在LOCA诊断算法中优先检测FGF14和RFC1扩增。
