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

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 1, 2024

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

Language: Английский

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Adaptive Long‐Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(3), P. 486 - 497

Published: Jan. 10, 2024

Abstract Background Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant with invariable sensory neuropathy originally described in a family Swedish ancestry residing Utah more than 25 years ago. Despite tight linkage to the 16q22 region, molecular diagnosis has since remained elusive. Objectives Inspired by pathogenic structural variation implicated other 16q‐ataxias same locus, we revisited index SCA4 cases from using novel technologies investigate within candidate region. Methods We adopted targeted long‐read sequencing approach adaptive sampling on Oxford Nanopore Technologies (ONT) platform that enables detection of segregating variants genomic region without priori assumptions about any variant features. Results Using this approach, found heterozygous (GGC) n repeat expansion last coding exon zinc finger homeobox 3 ( ZFHX3 ) gene segregates disease, ranging between 48 and 57 GGC repeats affected probands. This finding was replicated separate SCA4. Furthermore, estimation size short‐read whole genome (WGS) data 21,836 individuals recruited 100,000 Genomes Project UK our in‐house dataset 11,258 exomes did not reveal repeats, indicating ultrarare. Conclusions These findings support utility as powerful tool decipher causative unsolved inherited neurological disease. © 2024 The Authors. Movement Disorders published Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

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Frequency of GAA- FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia

Neurology Genetics, Journal Year: 2023, Volume and Issue: 9(5)

Published: Aug. 28, 2023

Intronic FGF14 GAA repeat expansions have recently been found to be a common cause of hereditary ataxia (GAA-FGF14 ataxia; SCA27B). The global epidemiology and regional prevalence this newly reported disorder remain established. In study, we investigated the frequency GAA-FGF14 in large cohort Brazilian patients with unsolved adult-onset ataxia.We recruited 93 index genetically despite extensive genetic investigation genotyped locus. Patients were across 4 different regions Brazil.Of patients, 8 (9%) carried an (GAA)≥250 expansion. expansion was also identified 1 affected relative. Seven European descent, African 1was admixed American ancestry. One patient carrying (GAA)376 developed at age 28 years, confirming that can occur before 30 years. displayed episodic symptoms, while none had downbeat nystagmus. Cerebellar atrophy observed on brain MRI 7 (87%).Our results suggest is population, although larger studies are needed fully define its epidemiology.

Language: Английский

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The FGF14GAA repeat expansion in Greek patients with late‐onset cerebellar ataxia and an overview of the SCA27B phenotype across populations

Clinical Genetics, Journal Year: 2024, Volume and Issue: 105(4), P. 446 - 452

Published: Jan. 14, 2024

Abstract A pathogenic GAA repeat expansion in the first intron of fibroblast growth factor 14 gene ( FGF14 ) has been recently identified as cause spinocerebellar ataxia 27B (SCA27B). We herein screened 160 Greek index cases with late‐onset cerebellar (LOCA) for expansions using a combination long‐range PCR and bidirectional repeat‐primed PCRs. 19 (12%) carrying expansion, diagnostic yield higher than that previously repeat‐expansion ataxias LOCA patients. The age at onset SCA27B patients was 60.5 ± 12.3 years (range, 34–80). Episodic (37%), downbeat nystagmus (32%) vertigo (26%) were significantly more frequent expansion‐positive compared to expansion‐negative cases. Beyond typical signs, often displayed hyperreflexia (47%) reduced vibration sense lower extremities (42%). frequency phenotypic profile similar most other studied populations. conclude are commonest known genetic population recommend prioritizing testing algorithm LOCA.

Language: Английский

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Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions

Current Neurology and Neuroscience Reports, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 16, 2025

Language: Английский

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Non‐GAARepeat Expansions inFGF14Are Likely Not Pathogenic—Reply to: “Shaking Up Ataxia:FGF14andRFC1Repeat Expansions in Affected and Unaffected Members of a Chilean Family”

Movement Disorders, Journal Year: 2023, Volume and Issue: 38(8), P. 1575 - 1577

Published: Aug. 1, 2023

The data that support the findings of this study are available from corresponding author upon reasonable request.

Language: Английский

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

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(6), P. 1092 - 1103

Published: Sept. 12, 2024

Objectives Spinocerebellar 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 first report this disease US population, characterizing its clinical manifestations, progression, pathological abnormalities, and response 4‐aminopyridine cohort 102 patients bearing expansions. Methods We compiled series with SCA27B, recruited from 5 academic centers across United States. Clinical manifestations patient demographics were collected retrospectively records an unblinded approach using standardized form. Post‐mortem analysis was done on 4 brains genetically confirmed SCA27B. Results In our found that SCA27B (57 ± 12.5 years) slowly progressive episodic component 51% patients. Balance gait impairment almost always at onset. The principal finding post‐mortem examination brain specimens loss Purkinje neurons most severe vermis particularly anterior vermis. Similar European populations, high percent 21/28 (75%) reported positive treatment 4‐aminopyridine. Interpretation Our study further estimates prevalence expands clinical, imaging features while looking response, survival disease. Testing for should be considered all undiagnosed patients, especially those ANN NEUROL 2024;96:1092–1103

Language: Английский

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Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia

Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 69(9), P. 433 - 440

Published: June 12, 2024

Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine prevalence of Chinese populations presenting cerebellar (LOCA) and evaluate characteristics tandem inheritance, radiological features sympathetic nerve involvement.

Language: Английский

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Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN

Neurology Genetics, Journal Year: 2024, Volume and Issue: 10(6)

Published: Nov. 20, 2024

The number of GAA repeats in the FXN gene is a major but not sole determinant clinical presentation Friedreich ataxia (FRDA). objective this study was to establish whether length repeat tract FGF14 gene, which associated with another neurodegenerative disorder (SCA27B), affects (age at onset, mFARS score) patients FRDA. and genes determined using PCR cohort 221 Next, we compared absolute lengths GAAs GAAs, followed by correlative analyses determine potential effects on age onset (mFARS) We found no significant correlation between size loci our FRDA cohort. Moreover, did affect even small cases where long allele present. Despite both molecular similarities SCA27B, including potentially pathogenic alleles, influence

Language: Английский

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New Horizons on the Diagnosis of Hereditary Ataxia

Movement Disorders Clinical Practice, Journal Year: 2023, Volume and Issue: 10(11), P. 1597 - 1598

Published: Aug. 31, 2023

Language: Английский

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