ORPHA: 675216;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
13q33.1 | Spinocerebellar ataxia 27B, late-onset | 620174 | Autosomal dominant | 3 | FGF14 | 601515 |
A number sign (#) is used with this entry because of evidence that late-onset spinocerebellar ataxia-27B (SCA27B) is caused by a heterozygous GAA(n) trinucleotide repeat expansion in the FGF14 gene (601515) on chromosome 13q33. Repeats between 250 and 300 are pathogenic, but show incomplete disease penetrance, whereas those above 300 show complete penetrance. Rare individuals may carry a repeat expansion on both alleles.
Heterozygous point mutations in the FGF14 gene cause SCA27A (193003), which shows earlier onset and can be associated with neurocognitive deficits.
Late-onset spinocerebellar ataxia-27B (SCA27B) is an autosomal dominant neurodegenerative disorder characterized by the onset of gait and appendicular ataxia in adulthood, usually around age 55 (range 30 to late eighties). About half of patients present with episodic features. The disorder is slowly progressive, and some patients may lose independent ambulation. Additional features include downbeat and horizontal nystagmus, diplopia, vertigo, and dysarthria. Brain imaging tends to show cerebellar atrophy (Pellerin et al., 2023).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Pellerin et al. (2023) reported 128 patients, mostly of European or French Canadian descent, with adult-onset cerebellar ataxia. Clinical details were available for 122 individuals. The ataxia was reported as episodic at onset in 46% of the patients. Episodes consisted of variable combinations of diplopia, vertigo, dysarthria, and appendicular and gait ataxia that lasted from minutes to days, with a daily to monthly occurrence. Alcohol intake and exercise were noted to be triggers. The mean age at onset of episodic symptoms was 55 years (range 30 to 87) and of progressive ataxia 59 years (range 30 to 88). Downbeat nystagmus was observed in 42% of patients, and gaze-evoked horizontal nystagmus in 55%. Eighteen patients had postural tremor and 33 had vertigo or dizziness. Many patients (58%) eventually required a walking aid, including 13% who became wheelchair-bound. Five patients had vestibular areflexia, 9 had spasticity, and 7 had evidence of a mild peripheral axonal neuropathy, suggesting that these are not core features of the disease. Brain imaging showed cerebellar atrophy in 74% of patients. Postmortem neuropathologic examination of 2 patients showed cerebellar atrophy with widespread loss of Purkinje cells that was more prominent in the vermis compared to the hemispheres. There was also gliosis in the molecular layer and mild cell loss in the granule cell layer.
Rafehi et al. (2023) reported 28 unrelated patients with adult-onset spinocerebellar ataxia associated with a GAA(n) repeat expansion in intron 1 of the FGF14 gene. The size of the expansion ranged from 270 to 450 repeats. Most of the patients had onset of symptoms between 50 and 77 years of age, although a few had onset in their forties. Common features included limb ataxia, gait ataxia, oculomotor abnormalities, truncal ataxia, cerebellar dysarthria, and vestibular hypofunction. Brain imaging showed cerebellar atrophy and global brain atrophy. A few patients had spasticity or hyperreflexia, some had clinical autonomic nervous system dysfunction, and several had hearing loss. There was an inverse correlation between age at symptom onset and size of the repeat expansion.
The transmission pattern of SCA27B in the families reported by Pellerin et al. (2023) was consistent with autosomal dominant inheritance. Analysis of population data suggested that 250 to 300 GAA expansions in the FGF14 gene are likely to be pathogenic, although with incomplete penetrance, and that expansions greater than 300 are fully penetrant. A study of 30 meiotic events showed that the transmission of expanded GAA alleles resulted in expansion in the female germline and contraction in the male germline. This was associated with an observed reduced paternal inheritance (30%).
In 128 patients with SCA27B, Pellerin et al. (2023) identified a heterozygous trinucleotide (GAA)n repeat expansion (equal to or greater than 250 repeats) in intron 1 of the FGF14 gene, which is included in pre-mRNA transcript 2 and not in pre-mRNA transcript 1 (601515.0006). The GAA repeat was initially found in 21 affected individuals from 3 large multigenerational French Canadian families who underwent genome sequencing specifically looking for pathogenic repeat expansions. The number of repeat units was greater than 300 in all but 1, who had 250 repeat units. One of the patients carried expansions on both alleles (300/716). Eight (0.98%) of 816 control chromosomes carried an expansion of at least 250 triplet repeats, and none had a GAA expansion over 300 repeats. Subsequently, 4 independent cohorts of patients from different populations with unsolved late-onset cerebellar ataxia were screened for this FGF14 repeat expansion. GAA expansions equal to or greater than 250 repeats were found in 40 (61%) of 66 French Canadian patients, compared to 1% of controls; in 42 (18%) of 228 German patients, compared to 3% of controls; in 3 (15%) of 20 Australian patients, and in 3 (10%) of 31 East Asian Indian patients. The expansion was also present in affected relatives of some of the families. The repeat expansions were detected by long-range PCR, gel electrophoresis, and targeted long-range nanopore sequencing. Haplotype analysis of 5 French Canadian families was consistent with a founder effect in this population, but the authors noted that there were 2 Turkish and 3 Indian patients, suggesting that this repeat expansion may arise on multiple haplotype backgrounds. The findings also demonstrated that there is a high degree of polymorphism of this repeat locus in the general population. The data suggested that 250-300 GAA expansions are likely to be pathogenic, although with incomplete penetrance, and that expansions greater than 300 are fully penetrant. Postmortem cerebellar tissue derived from 2 patients and motor neurons derived from induced pluripotent stem cells (iPSCs) from 2 other patients showed decreased expression of total FGF14 and FGF14 transcript 2 and decreased levels of the protein, suggesting that the intronic GAA expansion interferes with FGF14 transcription. The findings were consistent with haploinsufficiency as the pathogenetic mechanism. The authors postulated that this disorder may be a type of channelopathy, which may explain the episodic nature of some of the features.
Rafehi et al. (2023) identified a GAA(n) repeat expansion in intron 1 of the FGF14 gene in patients with autosomal dominant adult-onset ataxia. Among a cohort of 95 affected Australian individuals, 13 carried an allele greater than GAA(250), 4 of whom had more than 335 GAA repeats. Only 2 controls (0.6%) had a pure GAA expanded allele greater than GAA(250), with the maximum size being GAA(300). These data suggested that heterozygous expansion of a pure GAA repeat in FGF14 (over 250 repeats) represents a common cause of ataxia (OR = 24.3). A replication cohort of 104 German individuals with ataxia identified 9 (8.7%) patients with more than 335 GAA repeats and 6 (5.8%) with between 250 and 335 repeats, whereas 10 (5.3%) controls had more than 250 GAA repeats, but none had more than 335 GAA repeats. These data strongly supported a fully penetrant threshold of GAA(335) or greater and suggested that repeats between GAA(250) and GAA(335) is likely pathogenic, although with incomplete penetrance. The primary site of expression of the long isoform of FGF14 (1b) is in the brain. The GAA(n) repeat expansion is located within intron 1 of isoform 1b, suggesting that it may interfere with gene transcription. Functional studies of patient fibroblasts were inconclusive because FGF14 is not strongly expressed in those cells. The authors hypothesized that the pathogenic mechanism is reduced functional protein due to decreased expression of the allele with the expanded repeat.
Pellerin, D., Danzi, M. C., Wilke, C., Renaud, M., Fazal, S., Dicaire, M.-J., Scriba, C. K., Ashton, C., Yanick, C., Beijer, D., Rebelo, A., Rocca, C., and 40 others. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. New Eng. J. Med. 388: 128-141, 2023. [PubMed: 36516086] [Full Text: https://doi.org/10.1056/NEJMoa2207406]
Rafehi, H., Read, J., Szmulewicz, D. J., Davies, K. C., Snell, P., Fearnley, L. G., Scott, L., Thomsen, M., Gillies, G., Pope, K., Bennett, M. F., Munro, J. E., and 19 others. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am. J. Hum. Genet. 110: 105-119, 2023. Note: Erratum: Am. J. Hum. Genet. 110: 1018 only, 2023. [PubMed: 36493768] [Full Text: https://doi.org/10.1016/j.ajhg.2022.11.015]