Natural History and Phenotypic Spectrum of <scp>GAA‐<i>FGF14</i></scp> Sporadic Late‐Onset Cerebellar Ataxia (<scp>SCA27B</scp>)

Wirth, Thomas; Clément, Guillemette; Delvallée, Clarisse; Bonnet, Céline; Богдан, Т.В.; Iosif, Andra-Valentina; Schalk, Audrey; Chanson, Jean‐Baptiste; Pellerin, David; Brais, Bernard; Roth, Virginie; Wandzel, Marion; Fleury, Marie-Céline; Piton, Amélie; Calmels, Nadège; Namer, Izzie Jacques; Kremer, Stéphane; Tranchant, Christine; Renaud, Mathilde; Anheim, Mathieu

doi:10.1002/mds.29560

Cited by 27 publications

(46 citation statements)

References 16 publications

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“…1 SCA27B due to FGF14 GAA repeats has been identified in ataxia cohorts from various ethnic backgrounds, including French-Canadian, German, Australian, Indian, and French populations. 1,2,[4][5][6][7] Additionally, a family lineage with a monoallelic FGF14 GAA repeat and biallelic RFC1 AAGGG repeats was reported from Chile. 14 Taken together, these findings suggest that FGF14 is implicated in cerebellar ataxia across diverse ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

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Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

Ando,

Higuchi,

Yuan

et al. 2023

Ann Clin Transl Neurol

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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.

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Section: Discussionmentioning

confidence: 99%

“…patients with late-onset ataxia across diverse ethnic backgrounds. 1,2,[4][5][6][7] The high prevalence of this genetic abnormality highlights the need to identify potential treatment options. One study demonstrated that 4aminopyridine results in symptomatic improvement and thus has therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

Ando,

Higuchi,

Yuan

et al. 2023

Ann Clin Transl Neurol

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“…30,42 The limited multisystemic involvement in SCA27B was reflected in one study by the overall low burden of non-ataxia features measured by the Inventory of Non-Ataxia Signs scale, which increased only slowly with disease duration. 30 Disease progression in SCA27B, averaging 0.23-0.40 SARA point per year, 30,42 is considerably slower than in other common late-onset genetic ataxias, such as SCA6 (0.80 SARA point/year) 48 and RFC1-related disease (1.30 SARA points/year). 58 The slow disease progression in SCA27B is also reflected in the gradual accrual of functional disability, amounting to only 0.10 FARS stage per year of disease duration.…”

Section: Phenotypic Profile and Disease Progressionmentioning

confidence: 99%

“…[21][22][23]30,31,41,42,50 Some -but not allcases carrying biallelic FGF14 GAA repeat expansions may manifest before the age of 30 and/or have a more severe phenotype. 28,29 The GAA repeat length only appears to correlate weakly with the age at onset, 21,22,30,31,42 in contrast to polyglutamine SCAs. 49 Several factors may account for such weak correlation in SCA27B, including patients' failure to recognise early episodic symptoms, co-occurrence of 'second-hit' neurological disease and medical comorbidities, 30,31 unknown genetic modifiers and possibly brain somatic mosaicism.…”

Section: Phenotypic Profile and Disease Progressionmentioning

confidence: 99%

“…65,66 The mean age at onset of patients with SCA6 is approximately 5−10 years earlier (mean age, 49−55 years) 48,49,66 than that of patients with SCA27B (mean age, 55−67 years). [21][22][23]30,31,35,42,51 Similar to SCA27B, vertigo and visual disturbances, such as diplopia and oscillopsia, are common features of SCA6. [65][66][67] However, episodic ataxia is less frequent and cerebellar dysarthria more frequent in SCA6 compared to SCA27B, respectively occurring in less than 15% and more than 90% of patients with SCA6.…”

Section: Differential Diagnosis Of Sca27bmentioning

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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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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Natural History and Phenotypic Spectrum of GAA‐FGF14 Sporadic Late‐Onset Cerebellar Ataxia (SCA27B)

Cited by 27 publications

References 16 publications

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

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

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

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