Here, we focus on spinocerebellar ataxia 27B (SCA27B) caused by a GAA repeat expansion in the first intron of FGF14. Spinocerebellar ataxia 27A (SCA27A), caused by point, frameshift, or structural variants in the coding regions of FGF14, will be discussed in a separate topic.
The diagnosis of SCA27B is established in a patient with a compatible phenotype by the identification of a heterozygous (GAA)>300 repeat expansion in intron 1 of FGF14. Due to incomplete penetrance of FGF14 (GAA)250-300 repeat expansions, the diagnosis of SCA27B can also be established in symptomatic individuals with a (GAA)250-300 repeat expansion if their phenotype is compatible, other inherited causes of ataxia have been excluded, and, if possible, familial segregation with the disease is confirmed.
SCA27B is a mid- to late adult-onset slowly progressive cerebellar syndrome with predominant gait impairment. Episodic symptoms are present at disease onset in approximately half of patients and may include gait or appendicular ataxia, dysarthria, diplopia, oscillopsia, vertigo and/or dizziness. Episodic manifestations may be triggered by alcohol intake or physically demanding activities. When present, episodic symptoms usually precede the onset of progressive ataxia by two to four years and may persist after the onset of progressive ataxia. Cerebellar ocular motor signs (including downbeat nystagmus, horizontal gaze-evoked nystagmus, dysmetric saccades, and impaired visual fixation suppression of the vestibulo-ocular reflex) are present in almost all patients. Vestibular hypofunction and tremor of the upper limbs may occur. Conversely, spasticity, chronic cough, and severe polyneuropathy are not common features of SCA27B.
SCA27B is an autosomal dominant condition. Each child of an affected individual has a 50% risk of inheriting the FGF14 expansion. Intergenerational instability of the expansion is common and the of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission. The intergenerational instability may explain the high rate of sporadic cases.
Although further research is needed, studies in the European population suggest that SCA27B may be at least as common as other autosomal dominant SCAs, such as SCA3 and SCA6.
Management of SCA27B is mainly based on a multidisciplinary approach involving specialists such as neurologists, physiotherapists, and occupational therapists. Patients should avoid agents and conditions that may trigger or exacerbate ataxia-related symptoms. Preliminary observations suggest that 4-aminopyridine may improve the frequency and severity of ataxic symptoms in SCA27B.
FGF14