Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

Abstract

Background and ObjectivesThe GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late‐onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan.MethodsWe collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat‐primed PCR, and long‐read sequencing.ResultsPathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270–316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow‐up study conducted after a mean period of 6 years did not reveal any significant progression.DiscussionThis study highlights the importance of FGF14 GAA repeat analysis in patients with late‐onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA‐FGF14‐related diseases.

Advancing molecular, phenotypic and mechanistic insights ofFGF14pathogenic expansions (SCA27B)

“…The frequency of pathogenic expansions found in our ataxia cohort, considering the previously established threshold of 250 repeats, was remarkably high (23%), equivalent to or even higher than previous reports 6,7,19–21,25,34–36 . The difference in incidence is possibly linked to the population studied but it could also result from the sensitivity of the genetic test used.…”

“…Of note, the patient with later onset of Parkinsonism and dementia previously had tentative clinical diagnosis of multiple system atrophy, cerebellar subtype (MSA-C). This would be the third patient with this diagnosis in whom a FGF14 pathogenic expansion is identified 19,21 . However, in the context of our patient, a careful retrospective examination ruled out the MSA-C diagnosis and revealed that this patient in fact had a typical SCA27B phenotype with later onset of second diagnoses that are frequent in elderly people.…”

“…We performed a meta-analysis of the correlation between the AAO and expansion size by pooling data of patients with FGF14 expansions from our study and from four previous studies 7,19–21 . We also included data of patients with truncating variants 4,5,22,23 or the F150S (F145S in MANE isoform 1) missense variant in FGF14 3,24 in the comparison (information on age at onset on request).…”

Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia

“…Future studies are needed to define the regional prevalence of SCA27B, although ongoing screening efforts suggest that SCA27B is also a relatively common cause of late‐onset ataxia in South Asia (10%) 21 and Brazil (9%) 43 . However, SCA27B may not be as common in East Asian populations, as it was not identified in 312 patients with suspected spinocerebellar degeneration of unknown cause from the Hokkaido island in northern Japan in one study 44 and was identified in only 11 of 940 individuals (1.2%) from Japan with chronic progressive cerebellar ataxia in another study 45 …”

“…43 However, SCA27B may not be as common in East Asian populations, as it was not identified in 312 patients with suspected spinocerebellar degeneration of unknown cause from the Hokkaido island in northern Japan in one study 44 and was identified in only 11 of 940 individuals (1.2%) from Japan with chronic progressive cerebellar ataxia in another study. 45 In Quebec, a frequency of SCA27B as high as 60% has been reported among French-Canadian patients with previously unexplained adult-onset ataxia, making it the most common genetic cause of adult-onset ataxia in this population. 21,46 The observation of a common disease haplotype shared by some French-Canadian patients suggest that the high proportion of SCA27B in this population may correspond to a founder effect in this population known to be enriched for such effects.…”