Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype

Abstract

Background: Spinocerebellar ataxia (SCA) is an uncommon form of progressive cerebellar ataxia with multiple genetic causes and marked variability in phenotypic expression even across patients with identical genetic abnormalities. SCA27 is a recently identified SCA caused by mutations in the Fibroblast Growth Factor 14 gene, with a phenotypic expression that is only beginning to be fully appreciated. We report here a case of a 70-year-old male who presented with slowly worsening tremor and gait instability that began in his early adulthood along with additional features of parkinsonism on examination. Work-up revealed a novel pathogenic mutation in the Fibroblast Growth Factor 14 gene, and symptoms improved with amantadine and levodopa. We also provide a review of the literature in order to better characterize the phenotypic expression of this uncommon condition. Methods: Case report and review of the literature. Results: Review of the literature revealed a total of 32 previously reported clinical cases of SCA27. Including our case, we found that early-onset tremor (12.1 ¡ 10.5 years) was present in 95.8%, while gait ataxia tended to present later in life (23.7 ¡ 16.7 years) and was accompanied by limb ataxia, dysarthria, and nystagmus. Other features of SCA27 that may distinguish it from other SCAs include the potential for episodic ataxia, accompanying psychiatric symptoms, and cognitive impairment. Discussion: Testing for SCA27 should be considered in individuals with ataxia who report tremor as an initial or early symptom, as well as those with additional findings of episodic ataxia, neuropsychiatric symptoms, or parkinsonism.

FGF14‐related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9

“…Other symptoms, including orofacial dyskinesias, psychiatric manifestations, cognitive delay, or parkinsonism are common. Symptom onset occurs early in life nevertheless the disease course is usually very slow and motor function is maintained through life in most of the patients 1 . More recently, animal model studies and genome‐wide association studies suggested that FGF14 may be a risk factor for various neuropsychiatric diseases including depression addiction and schizophrenia, as well as neurodegenerative diseases, 2,3 FGF14 encodes fibroblast growth factor 14 highly expressed in the brain and especially in Purkinje cells, where it interacts with voltage‐gated Na+ channels to regulate neuronal excitability.…”

Sex-Specific Proteomics Changes Induced by Genetic Deletion of the Fibroblast Growth Factor 14 (FGF14) Regulator of Neuronal Ion Channels

“…Originally identified as the genetic locus of missense mutations leading to spinocerebellar ataxia type 27 [1][2][3][4][5][6][7], FGF14 is an emerging risk factor for neuropsychiatric disorders [8]. Unlike canonical secreted FGFs, which act through activation of FGF receptor signaling, FGF14 is retained intracellularly where it has been shown to regulate ion channel function [9][10][11][12][13].…”

Genome-Wide Association Study Points New Direction for Downbeat Nystagmus Research

“…The common association of FGF14 with DBN and SCA27 poses a key question: what is the phenotypic similarity between isolated DBN and those with spinocerebellar ataxia type 27? The latter, a typical childhood onset disorder, presents with tremor, robust gait ataxia, depression, and anger outbursts [10][11][12][13][14]. Nystagmus is reported in about 84% of spinocerebellar ataxia patients, but DBN is extremely rare and was reported only twice in the literature [12].…”

“…The latter, a typical childhood onset disorder, presents with tremor, robust gait ataxia, depression, and anger outbursts [10][11][12][13][14]. Nystagmus is reported in about 84% of spinocerebellar ataxia patients, but DBN is extremely rare and was reported only twice in the literature [12]. Parkinsonism is another feature of spinocerebellar ataxia type 27 [12].…”

“…Nystagmus is reported in about 84% of spinocerebellar ataxia patients, but DBN is extremely rare and was reported only twice in the literature [12]. Parkinsonism is another feature of spinocerebellar ataxia type 27 [12].…”