Late-onset cerebellar ataxias (LOCA), with symptom onset after 30 years of age, are a diagnostic challenge. Despite expanding knowledge regarding this heterogeneous group of neurodegenerative disorders, molecular diagnosis is often elusive and almost 75% of patients remain undiagnosed.
In a recently published study, Pellerin et al. (2023) used bioinformatics tools and long-read sequencing to search for novel pathogenic repeat expansions in patients with LOCA. After initial screening with genome sequencing of six patients from three French Canadian families a candidate pathogenic GAA expansion in FGF14 was found.
FGF14 is expressed more abundantly in the cerebellar granule and Purkinje cells, regulating, and promoting localization of voltage-gated sodium channels. It was already known that mutations in FGF14 cause a slowly progressive, autosomal dominant cerebellar ataxia, classified as SCA27.
The association between the GAA-FGF14expansion and disease was assessed in a French Canadian (66 patients and 209 controls), a German (228 patients and 199 controls), an Australian (20 patients) and an Indian (31 patients) cohorts.
Clinically, GAA-FGF14–related ataxia was characterized by a late-onset ataxia (in the sixth decade of life). Isolated downbeat nystagmus early in the disease course, an episodic onset of symptoms and cerebellar atrophy on MRI were frequent findings. Unlike SCA27, postural tremor and neuropsychiatric manifestations were not frequent. The results supported incomplete penetrance of (GAA)250–300 expansions and full penetrance of (GAA)>300 expansions. In total, 128 (37%) patients with LOCA who carried an FGF14 (GAA)≥250 expansion were found.
The authors performed neuropathological and mechanistic studies, who suggest that the intronic GAA expansion leads to loss of function by interfering with FGF14 transcription and that GAA-FGF14–related ataxia may be a type of channelopathy.
A causative role for the GAA-FGF14 expansion in late-onset ataxia was further supported in a recent similar study by Rafehi et al. (2023) in an Australian (95 patients and 311 controls) and a German (104 patients and 190 controls) cohorts. In total, 28 patients (14%) with LOCA who carried an FGF14 (GAA)≥250 expansion were found. Clinically, mean age at symptom onset was 61 years and the more common features were bilateral vestibular hypofunction (the most frequent), hyperreflexia and autonomic dysfunction.
Both studies strongly support that an intronic FGF14 GAA repeat expansion is a frequent cause of autosomal-dominant LOCA and highlight the importance of genome sequencing and bioinformatics to identify noncoding repeat expansions, probably an underrecognized cause of neurodegenerative disorders.
Key points:
- GAA-FGF14–related ataxia appears to be an important and frequent cause of autosomal dominant late-onset cerebellar ataxia.
- An early episodic presentation, isolated downbeat nystagmus, vestibular hypofunction and cerebellar atrophy were common features.
- Further studies are needed to generate more specific pathogenic expansion ranges and for better phenotyping.
References:
Pellerin D, Danzi MC, Wilke C, et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388(2):128-141. doi:10.1056/NEJMoa2207406 pubmed.ncbi.nlm.nih.gov/36516086/ Rafehi H, Read J, Szmulewicz DJ, et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am J Hum Genet. 2023;110(1):105-119. doi:10.1016/j.ajhg.2022.11.015 https://pubmed.ncbi.nlm.nih.gov/36493768/
Author:
João Durães, Centro Hospitalar e Universitário de Coimbra
Co-author:
Michelangelo Mancuso, Neurological Institute, University of Pisa
Kailash Bhatia, UCL Queen Square Institute of Neurology, University College London
Publish on behalf of the Coordinating Panel on Rare Neurological Disease