GAA- FGF14-Related Ataxia

Excerpt

Clinical characteristics: GAA-FGF14-related ataxia is a mid to late adult-onset slowly progressive cerebellar syndrome with predominant gait involvement. Median age at onset is 60 years (range: 21-87 years). Nearly 50% of individuals may first experience episodic manifestations including gait and limb ataxia, visual disturbances (diplopia, oscillopsia, and blurring), vertigo and/or dizziness, or dysarthria on average two to four years before the onset of progressive ataxia. Episodic symptoms may persist after the onset of progressive ataxia and may be triggered by alcohol intake and physical activity. Although some individuals eventually require assistance with mobility, use of a wheelchair is less necessary than in other common hereditary spinocerebellar ataxias (e.g., SCA1, SCA2, and SCA3). Dysarthria does not develop in all individuals and often remains mild to moderate. Cerebellar oculomotor signs, including downbeat nystagmus, horizontal gaze-evoked nystagmus, and impaired visual fixation suppression of the vestibuloocular reflex, are common. Unilateral or bilateral vestibular hypofunction and tremor of the upper limbs may occur. Age of onset and clinical presentation can vary within the same family.

Diagnosis/testing: The diagnosis of GAA-FGF14-related ataxia is established in a symptomatic individual with a compatible phenotype by the identification of a heterozygous (GAA)_>300 repeat expansion in intron 1 of FGF14 by molecular genetic testing. Due to reduced penetrance of FGF14 (GAA)_250-300 repeat expansions, the diagnosis of GAA-FGF14-related ataxia 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. Individuals whose phenotype differs significantly from GAA-FGF14-related ataxia should be screened for other causes of inherited ataxias.

Management: Treatment of manifestations: There is no cure for GAA-FGF14-related ataxia. The goals of treatment are to improve quality of life, maximize function, and reduce complications. This ideally involves multidisciplinary care by specialists in relevant fields, such as neurologists, ophthalmologists, orthoptists, physical therapists, occupational therapists, speech-language therapists, and psychologists. Preliminary studies have shown promising symptomatic benefits of 4-aminopyridine for ataxic symptoms and downbeat nystagmus.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, regularly scheduled follow up by the treating specialists is recommended.

Agents/circumstances to avoid: Inform affected individuals that alcohol intake and strenuous physical activity may precipitate episodes of ataxia and may exacerbate incoordination. Avoid medications with known toxicity to the cerebellum and the vestibular system.

Genetic counseling: GAA-FGF14-related ataxia is inherited in an autosomal dominant manner. Most individuals diagnosed with GAA-FGF14-related ataxia inherit an abnormal GAA repeat expansion from a parent who has a high normal-size or likely pathogenic or pathogenic GAA repeat expansion (a parent with an abnormal GAA repeat expansion may or may not have manifestations of GAA-FGF14-related ataxia). Each child of an individual with GAA-FGF14-related ataxia has a 50% chance of inheriting the GAA-FGF14-related allele. The likelihood that offspring who inherit the GAA-FGF14-related allele will have a GAA repeat size in the pathogenic, reduced penetrance, or non-pathogenic range is influenced by intergenerational instability; the size of the GAA repeat is more likely to expand upon maternal transmission and to contract upon paternal transmission. Once a GAA repeat expansion has been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for GAA-FGF14-related ataxia are possible. However, accurate prediction of future possible clinical manifestations in a fetus found to have an FGF14 GAA repeat expansion is not possible, and the current lack of knowledge regarding somatic instability of the repeat prenatally makes the interpretation of prenatal genetic test results challenging.