An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14

Rafehi, Haloom; Read, Justin; Szmulewicz, David J.; Davies, Kayli C.; Snell, Penny; Fearnley, Liam G.; Scott, Liam; Thomsen, Mirja; Gillies, Greta; Pope, Kate; Bennett, Mark F; Munro, Jacob E.; Ngo, Kathie J.; Chen, Liming; Wallis, Mathew; Butler, Ernest; Kumar, Kishore R.; Wu, Kathy H C; Tomlinson, Susan; Tisch, Stephen; Malhotra, Abhishek; Lee‐Archer, Matthew; Dolzhenko, Egor; Eberle, Michael A.; Roberts, Leslie; Fogel, Brent L.; Brüggemann, Norbert; Lohmann, Katja; Delatycki, Martin B.; Bahlo, Melanie; Lockhart, Paul J.

doi:10.1016/j.ajhg.2023.05.005

Cited by 36 publications

(50 citation statements)

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“…21 The two publications found that expansions above 300 GAA repeat units appear fully penetrant based on the largest GAA-pure alleles observed in 408 and 311 controls, respectively. 21,22 Biallelic expansions have also been identified in a few patients. 21,[28][29][30] It is likely that the incomplete and fully penetrant thresholds will need to be refined as more patient and control screening is completed.…”

Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

“…23 This observation is in line with other studies that have shown SCA27B to have a frequency of approximately 15−30% in European cohorts of patients with unsolved adult-onset ataxia. 21,22,30,35,41,42 Such high prevalence may be reflective of a population structure in individuals of European descent who appear to more commonly carry larger FGF14 GAA alleles compared to other populations. 21,22 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%).…”

Section: Epidemiology and Regional Distributionmentioning

confidence: 99%

“…21,22,30,35,41,42 Such high prevalence may be reflective of a population structure in individuals of European descent who appear to more commonly carry larger FGF14 GAA alleles compared to other populations. 21,22 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.…”

Section: Epidemiology and Regional Distributionmentioning

confidence: 99%

“…The diagnosis of SCA27B is established in a symptomatic individual with characteristic clinical findings by the identification of a heterozygous GAA repeat expansion in the first intron of FGF14. 21,22 Affected individuals usually carry 250 or more GAA repeats, although recent data have raised the possibility of a lower pathogenic threshold (Figure 1A). 23,31 Ongoing multicentre screening efforts are currently exploring the lower boundaries of the pathogenic threshold and the incompletely penetrant range.…”

Section: Molecular Diagnosismentioning

confidence: 99%

“…Since a substantial percentage of cases are sporadic (15-50%), 21,30,41,50 patients with a compatible phenotype should be screened for SCA27B regardless of family history. As of today, since short-read sequencing cannot accurately size FGF14 GAA expansions, 22 molecular testing for SCA27B relies on a bespoke targeted PCRbased gene analysis to determine the length and purity of FGF14 GAA repeats. 41 With accumulating evidence suggesting that non-GAA-pure repeat expansions are likely non-pathogenic for ataxia, 21,23,34 it becomes imperative to adopt standardised diagnostic strategies to diagnose SCA27B.…”

Section: Molecular Diagnosismentioning

confidence: 99%

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

Pellerin,

Danzi,

Renaud

et al. 2024

Clinical & Translational Med

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Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up to 75% of such patients remain without a genetic diagnosis. In an era of emerging disease‐modifying gene‐stratified therapies, the identification of causative alleles has become increasingly important. Over the past few years, the implementation of advanced bioinformatics tools and long‐read sequencing has allowed the identification of a number of novel repeat expansion disorders, such as the recently described spinocerebellar ataxia 27B (SCA27B) caused by a (GAA)•(TTC) repeat expansion in intron 1 of the fibroblast growth factor 14 (FGF14) gene. SCA27B is rapidly gaining recognition as one of the most common forms of adult‐onset hereditary ataxia, with several studies showing that it accounts for a substantial number (9–61%) of previously undiagnosed cases from different cohorts. First natural history studies and multiple reports have already outlined the progression and core phenotype of this novel disease, which consists of a late‐onset slowly progressive pan‐cerebellar syndrome that is frequently associated with cerebellar oculomotor signs, such as downbeat nystagmus, and episodic symptoms. Furthermore, preliminary studies in patients with SCA27B have shown promising symptomatic benefits of 4‐aminopyridine, an already marketed drug. This review describes the current knowledge of the genetic and molecular basis, epidemiology, clinical features and prospective treatment strategies in SCA27B.

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Section: Genetic Basis Of Sca27bmentioning

confidence: 99%

Section: Epidemiology and Regional Distributionmentioning

confidence: 99%

Section: Epidemiology and Regional Distributionmentioning

confidence: 99%

Section: Molecular Diagnosismentioning

confidence: 99%

Section: Molecular Diagnosismentioning

confidence: 99%

See 3 more Smart Citations

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

Pellerin,

Danzi,

Renaud

et al. 2024

Clinical & Translational Med

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Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B)

Abou Chaar,

Eranki,

Stevens

et al. 2024

Annals of Neurology

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ObjectivesSpinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late‐onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4‐aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.MethodsWe compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post‐mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B.ResultsIn our cohort of 102 patients with SCA27B, we found that SCA27B was a late‐onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post‐mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4‐aminopyridine.InterpretationOur study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024

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