Bilateral vestibulopathy in RFC1-positive CANVAS is distinctly different compared to FGF14-linked spinocerebellar ataxia 27B

Borsche, Max; Thomsen, Mirja; Szmulewicz, David J.; Lübbers, Bente; Hinrichs, Frauke; Lockhart, Paul J.; Lohmann, Katja; Helmchen, Christoph; Brüggemann, Norbert

doi:10.1007/s00415-023-12050-0

Cited by 6 publications

(6 citation statements)

References 17 publications

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“…21,22,50 While sensory neuronopathy 56 and chronic cough 58 are highly prevalent features in RFC1related disease, they are uncommon in SCA27B. 50,55 Furthermore, episodic ataxia is not a feature of RFC1-related disease, in contrast to SCA27B. The vestibular function appears to be significantly more impaired in RFC1-related disease compared to SCA27B.…”

Section: Differential Diagnosis Of Sca27bmentioning

confidence: 99%

“…The vestibular function appears to be significantly more impaired in RFC1-related disease compared to SCA27B. 55 Finally, the pattern of inheritance (autosomal recessive in RFC1-related disorder and autosomal dominant in SCA27B) may also help differentiating both conditions, although patients with SCA27B may present sporadically or with seemingly recessive inheritance. 21,50 SCA6 and EA2 have significant phenotypic overlap with SCA27B.…”

Section: Differential Diagnosis Of Sca27bmentioning

confidence: 99%

“…30,50 Bilateral vestibulopathy (BVP) is noted in 10-75% of patients with SCA27B and appears to develop later in the disease course and to remain relatively mild (not evolving into frank vestibular areflexia). 22,30,31,55 While initial series suggested that polyneuropathy is not a core feature of SCA27B, 21,22 subsequent studies have shown that some patients may develop mild axonal sensory or sensorimotor polyneuropathy. 42,50 Whether the polyneuropathy is pathophysiologically related to SCA27B or simply reflective of an age-related disease process remains to be established.…”

Section: Phenotypic Profile and Disease Progressionmentioning

confidence: 99%

“…In addition to cerebellar impairment, vestibular hypofunction and afferent sensory defect are commonly noted in SCA27B 30,50 . Bilateral vestibulopathy (BVP) is noted in 10–75% of patients with SCA27B and appears to develop later in the disease course and to remain relatively mild (not evolving into frank vestibular areflexia) 22,30,31,55 . While initial series suggested that polyneuropathy is not a core feature of SCA27B, 21,22 subsequent studies have shown that some patients may develop mild axonal sensory or sensorimotor polyneuropathy 42,50 .…”

Section: Phenotypic Profile and Disease Progressionmentioning

confidence: 99%

“…RFC1 ‐related disease and SCA27B have been shown to have partial phenotypic overlap, based on the observation that both disorders may present with cerebellar ataxia, neuropathy and BVP 21,22,50 . While sensory neuronopathy 56 and chronic cough 58 are highly prevalent features in RFC1 ‐related disease, they are uncommon in SCA27B 50,55 . Furthermore, episodic ataxia is not a feature of RFC1 ‐related disease, in contrast to SCA27B.…”

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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Section: Differential Diagnosis Of Sca27bmentioning

confidence: 99%

Section: Differential Diagnosis Of Sca27bmentioning

confidence: 99%

Section: Phenotypic Profile and Disease Progressionmentioning

confidence: 99%

Section: Phenotypic Profile and Disease Progressionmentioning

confidence: 99%

Section: Differential Diagnosis Of Sca27bmentioning

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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RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile

Pellerin,

Heindl,

Traschütz

et al. 2024

J Neurol

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Objectives The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients (“idiopathic”), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome. Methods We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN. Results Biallelic RFC1 AAGGG expansions were identified in 15/65 patients with idiopathic DBN (23%). None of the 102 GAA-FGF14-positive patients, but 2/36 (6%) of patients with presumed secondary DBN carried biallelic RFC1 expansions. The DBN syndrome in RFC1-positive patients was characterized by additional cerebellar impairment in 100% (15/15), bilateral vestibulopathy (BVP) in 100% (15/15), and polyneuropathy in 80% (12/15) of cases. Compared to GAA-FGF14-positive and genetically unexplained patients, RFC1-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in RFC1-positive patients. Discussion Biallelic RFC1 expansions are a common monogenic cause of DBN syndrome.

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