GAA-FGF14-Related Ataxia

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.

Suggestive Findings

GAA-FGF14-related ataxia should be suspected in probands with the following clinical findings, imaging findings, and family history.

Clinical findings. Mid to late adult-onset (median age: 60 years; range: 21 to 87 years) of slowly progressive cerebellar ataxia.

Commonly associated neurologic findings include the following:

• Episodic ataxia, commonly triggered by exercise / physically demanding tasks or alcohol intake; may manifest with diplopia, vertigo, dysarthria, and ataxia
• Cerebellar oculomotor signs, such as saccadic pursuit, dysmetric saccades, rebound nystagmus, gaze-evoked nystagmus, impaired visual fixation suppression of the vestibuloocular reflex, and downbeat nystagmus. Note that early in the disease course, downbeat nystagmus may occur with other cerebellar oculomotor signs in the absence of other neurologic findings.
• Visual symptoms, such as diplopia, oscillopsia, and visual blurring
• Vertigo and/or dizziness
• Vestibular hypofunction that can present with dizziness and loss of balance
• Decreased vibration sense in distal lower extremities

Less commonly associated neurologic findings include the following:

• Mild spasticity
• Postural tremor
• Autonomic dysfunction, mostly urinary urgency
• Mild sensory or sensorimotor axonal polyneuropathy

Imaging findings. Brain MRI shows cerebellar atrophy in a substantial number of individuals, which is most pronounced in the vermis and is mostly mild to moderate [Pellerin et al 2023a, Wilke et al 2023].

Family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations) or the proband may represent a simplex case (i.e., the only family member known to be affected). Because reduced penetrance and intergenerational instability are observed in GAA-FGF14-related ataxia, absence of a known family history or seemingly autosomal recessive inheritance (e.g., affected males and females in a single generation) does not preclude the diagnosis [Pellerin et al 2023a, Wilke et al 2023].

Establishing the Diagnosis

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 (see Table 1 and Table 9).

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 has been confirmed.

Individuals whose phenotype differs significantly from GAA-FGF14-related ataxia should be screened for other causes of inherited ataxias.

Repeat sizes [Pellerin et al 2023a, Rafehi et al 2023, Méreaux et al 2024]

• Normal. Six to 249 GAA repeats
• Likely pathogenic (reduced penetrance). 250 to 300 GAA repeats
• Pathogenic. >300 GAA repeats

Note: (1) To date, pathogenic GAA repeat expansions in FGF14 cannot be reliably detected by standard sequence-based multigene panels, exome sequencing, or short-read genome sequencing. (2) Non-GAA-pure repeat expansions in FGF14 are likely not pathogenic for GAA-FGF14-related ataxia [Pellerin et al 2023b]. Therefore, the molecular diagnosis of GAA-FGF14-related ataxia relies on the accurate detection and establishment of both the size and purity of the GAA repeat expansion [Bonnet et al 2023, Hengel et al 2023, Pellerin et al 2023b] (see Tables 7 and 9).

Molecular genetic testing relies on targeted analysis to characterize the size and purity of FGF14 GAA repeats [Bonnet et al 2023] (see Table 8).

Note (1) Short-read genome sequencing (GS)-based tools for the detection of triplet repeat expansions have been developed [Dolzhenko et al 2017, Dolzhenko et al 2019, Ibañez et al 2022]. However, short-read GS cannot accurately differentiate pathogenic from non-pathogenic FGF14 alleles beyond approximately 50 triplets. As such, short-read GS must always be followed by suitable techniques such as long-range PCR and repeat-primed PCR to confirm a diagnosis of GAA-FGF14-related ataxia. (2) Long-read sequencing may be able to detect GAA repeat expansions [Pellerin et al 2023a, Rafehi et al 2023] (see Table 7).

Table 1.

Molecular Genetic Testing Used in GAA-FGF14-Related Ataxia

Clinical Description

To date, more than 400 individuals with GAA-FGF14-related ataxia have been identified [Ashton et al 2023, Bonnet et al 2023, Brais et al 2023, Hengel et al 2023, Iruzubieta et al 2023, Novis et al 2023, Pellerin et al 2023a, Rafehi et al 2023, Wilke et al 2023, Wirth et al 2023, Zeng et al 2023, Ando et al 2024, Borsche et al 2024, Méreaux et al 2024, Pellerin et al 2024b, Pellerin et al 2024c]. The following description of the phenotypic features associated with this condition is based on these reports (see Table 2).

Table 2.

GAA-FGF14-Related Ataxia: Frequency of Select Features

GAA-FGF14-related ataxia is a mid to late adult-onset slowly progressive cerebellar syndrome with predominant gait involvement. Age of onset and clinical presentation can vary within the same family.

The median age at onset is 60 years (range: 21 to 87 years) [Iruzubieta et al 2023, Pellerin et al 2023a, Rafehi et al 2023, Wilke et al 2023, Wirth et al 2023, Zeng et al 2023, Méreaux et al 2024]. While the most common manifestation at disease onset is an unsteady gait (80%), nearly 50% of individuals present initially with episodic manifestations, including ataxia, visual disturbances (diplopia, oscillopsia, visual blurring), vertigo, or dysarthria, on average two to four years before the onset of progressive ataxia [Ashton et al 2023, Bonnet et al 2023, Pellerin et al 2023a, Pellerin et al 2024c]. The frequency and duration of these episodes are highly variable: they may last from minutes to days and occur daily to monthly [Ashton et al 2023]. Alcohol intake and physical activity are common triggers [Bonnet et al 2023, Pellerin et al 2024c]. Caffeine has also been reported to trigger episodes [Ashton et al 2023].

Although some individuals eventually require assistance with mobility, the use of a wheelchair is uncommon even after protracted disease duration.

Dysarthria, which does not develop in all individuals (40%-60%), often remains mild to moderate [Iruzubieta et al 2023, Pellerin et al 2023a, Wilke et al 2023, Méreaux et al 2024, Pellerin et al 2024c]. Speech remains easy to understand in most individuals, although occasional words may be unintelligible.

Dysphagia develops in less than half of individuals. Although it may increase the risk of aspiration, dysphagia is very rarely severe enough to require enteral nutrition or cause cachexia.

Visual disturbances, such as diplopia, oscillopsia, or visual blurring, are common.

Cerebellar oculomotor signs, which may include horizontal gaze-evoked nystagmus, downbeat nystagmus, dysmetric saccades, saccadic pursuit, rebound nystagmus, and impaired visual fixation suppression of the vestibuloocular reflex, occur in almost all individuals. Horizontal gaze-evoked nystagmus and downbeat nystagmus are common. Downbeat nystagmus may present episodically or occur at disease onset with other cerebellar oculomotor signs in the absence of other neurologic findings [Pellerin et al 2024b].

Vertigo and/or dizziness may occur during episodes of ataxia or interictally. It may lead to gait unsteadiness.

Unilateral or bilateral vestibular hypofunction is common [Pellerin et al 2023a, Rafehi et al 2023, Wilke et al 2023, Pellerin et al 2024b, Pellerin et al 2024c]. Some individuals experience gait unsteadiness and dizziness due to vestibular hypofunction.

Postural or rest tremor of the upper limbs is observed in some patients [Pellerin et al 2023a, Wilke et al 2023, Wirth et al 2023, Méreaux et al 2024].

Afferent sensory deficit manifests as reduced vibration sense and hyporeflexia; however, sensory neuropathy is not commonly demonstrated on nerve conduction studies [Iruzubieta et al 2023, Pellerin et al 2023a, Rafehi et al 2023, Wilke et al 2023, Pellerin et al 2024c]. When peripheral neuropathy is present, nerve conduction studies are consistent with mild axonal sensory or sensorimotor polyneuropathy [Pellerin et al 2023a, Wirth et al 2023, Pellerin et al 2024c]. Whether the polyneuropathy is pathophysiologically related to GAA-FGF14-related ataxia or simply reflective of an age-related disease process remains to be established. Muscle stretch reflexes can be normal, decreased, or brisk.

Spasticity of the lower limbs is most often mild and is not a common manifestation.

Parkinsonism is uncommon (4%-12%) [Rafehi et al 2023, Wilke et al 2023, Pellerin et al 2024c].

Autonomic dysfunction is rare at disease onset but may develop later in the disease course. Urinary urgency and erectile dysfunction occur in 28%-57% of individuals and 13% of males, respectively. In comparison, population-based surveys in the United States have shown that the prevalence of urinary urge incontinence ranges from 1.7% to 36.4% of the general population [Milsom et al 2014], and cross-sectional studies have revealed a prevalence of erectile dysfunction of 18.4% of adult males ages 20 years or older [Selvin et al 2007].

Frank autonomic dysfunction manifested by orthostatic hypotension is rare in GAA-FGF14-related ataxia [Wilke et al 2023, Wirth et al 2023, Méreaux et al 2024, Pellerin et al 2024c].

Hearing loss, namely presbycusis, has been described in some individuals [Rafehi et al 2023].

Cognitive impairment is relatively infrequent, even in advanced stages of GAA-FGF14-related ataxia [Wilke et al 2023].

Of note, age-related mechanisms as well as other additional diseases (age related or not age related; acquired or inherited) can contribute to or aggravate the clinical features of GAA-FGF14-related ataxia [Wilke et al 2023, Pellerin et al 2024b].

The possibility of concurrent medical illnesses, which are common in the elderly, must be considered in late-onset diseases such as GAA-FGF14-related ataxia. It has been shown that these are frequent and add to the neurologic spectrum and disease burden of underlying hereditary late-onset ataxia [Wilke et al 2023, Pellerin et al 2024b].

Life span does not appear to be shortened in individuals with GAA-FGF14-related ataxia [Wirth et al 2023].

Genotype-Phenotype Correlations

Age of onset inversely correlates with the size of the GAA repeat expansion in some cohorts [Pellerin et al 2023a, Rafehi et al 2023, Pellerin et al 2024b, Pellerin et al 2024c] but not all [Bonnet et al 2023, Iruzubieta et al 2023, Wilke et al 2023, Méreaux et al 2024].

Of note, one study found no association between disease progression or severity and the length of the GAA repeat expansion [Wilke et al 2023]. Another study showed that the sum of the two allele sizes does not correlate better with age of onset [Pellerin et al 2023a].

Biallelic FGF14 GAA repeat expansions have been reported in a number of individuals [Ashton et al 2023, Bonnet et al 2023, Brais et al 2023, Novis et al 2023, Pellerin et al 2023a, Zeng et al 2023, Pellerin et al 2024b]. Four of 12 individuals had disease onset in their twenties. In some – but not all – individuals with biallelic FGF14 GAA repeat expansions, disease manifestations and progression appear to be more severe compared to individuals heterozygous for an FGF14 GAA repeat expansion [Ashton et al 2023, Pellerin et al 2023a, Wilke et al 2023].

Penetrance

Reduced penetrance has been reported in persons heterozygous for 250-300 FGF14 GAA repeats [Pellerin et al 2023a, Rafehi et al 2023]. It is likely that knowledge of GAA repeat length-related penetrance will evolve significantly as more data become available.

Intergenerational Instability

The FGF14 GAA repeat is highly unstable and almost always changes in size upon parent-to-offspring transmission when the size of parent's GAA repeat expansion is greater than 75 repeats [Pellerin et al 2024b].

The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission [Pellerin et al 2023a, Pellerin et al 2024b].

The instability of the GAA repeat locus upon maternal transmission, which is at high risk of further expansion, partly accounts for the high incidence of simplex cases of GAA-FGF14-related ataxia (i.e., a single occurrence of a disorder in a family), whereby an unaffected mother transmits an expanded pathogenic allele to her offspring.

In contrast, contraction of the size of the GAA repeat upon male transmission may lead to transmission of reduced-penetrance alleles to the offspring, resulting in "generation skipping" of the disease [Pellerin et al 2023a]. This differential transmission dynamic also likely accounts for the reduced male transmission of the disease observed in two studies [Pellerin et al 2023a, Méreaux et al 2024].

The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract. GAA repeat expansions may be pure (GAA)_n in sequence or may be interrupted with regions of non-GAA sequences. During intergenerational transmission, pure GAA repeats have been shown to be more unstable than non-GAA-pure repeats. Only pure GAA repeats are believed to be pathogenic, while non-GAA-pure repeats are believed to be not pathogenic for ataxia [Hengel et al 2023, Pellerin et al 2023b].

Nomenclature

Prior to establishing the molecular diagnosis, individuals with phenotypes consistent with GAA-FGF14-related ataxia may have been diagnosed with idiopathic late-onset cerebellar ataxia (ILOCA), sporadic adult-onset ataxia (SAOA), or autosomal dominant cerebellar ataxia type III (pure cerebellar ataxia).

The current alphanumeric designation for GAA-FGF14-related ataxia is SCA27B (OMIM 620174). To clarify the nomenclature and to distinguish GAA-FGF14-related ataxia from the allelic spinocerebellar ataxia (SCA27) associated with point, frameshift, or structural variants in FGF14, OMIM changed SCA27 to SCA27A and created a new designation, SCA27B, for GAA-FGF14-related ataxia.

Prevalence

The prevalence of GAA-FGF14-related ataxia is difficult to estimate given that only about 400 individuals have been reported to date. The prevalence of late-onset cerebellar ataxia of unknown cause is one to nine in 100,000 individuals (see Orphanet). GAA-FGF14-related ataxia has been identified in cohorts with adult-onset ataxia of previously unknown cause at rates ranging from 9% to 61%.

Excluding French Canadian cohorts, we have estimated the prevalence of GAA-FGF14-related ataxia to be in the range of 0.1 to three in 100,000 individuals of European ancestry [Pellerin, Danzi, Renaud, Houlden, Synofzik, Zuchner, & Brais, personal observation]. This prevalence, like that of spinocerebellar ataxia 1, 2, 3, and 6, has recently been validated by a systematic comparative study of consecutive patient cohorts in a single-center European study [Hengel et al 2023]. Although a large degree of uncertainty remains regarding the prevalence of GAA-FGF14-related ataxia, to date it appears to be among the most common causes of inherited adult-onset ataxia as well as of autosomal dominant ataxia (of any age) [Hengel et al 2023]. However, GAA-FGF14-related ataxia may not be as common in East Asian populations, as it was not identified in 312 patients with suspected spinocerebellar degeneration of unknown cause from Hokkaido Island in northern Japan in one study [Mizushima et al 2024], and was identified in only 11 of 940 individuals (1.2%) from Japan with chronic progressive cerebellar ataxia in another study [Ando et al 2024].

It is important to note that although the frequency of FGF14 alleles longer than 250 triplets is estimated to be about 1%-2% in the population [Pellerin et al 2023a, Rafehi et al 2023, Méreaux et al 2024, Pellerin et al 2024a], this does not reflect a prevalence of GAA-FGF14-related ataxia nearing 1-2 in 100 individuals. In fact, 88.9% of alleles longer than 250 triplets in 2,191 controls undergoing long-read sequencing were identified to be non-GAA-pure and seem to have no association with GAA-FGF14-related ataxia [Pellerin et al 2024a].

Geographic variation in prevalence. Rates of GAA-FGF14-related ataxia are reported to be as high as 60% in individuals of French Canadian descent with adult-onset ataxia of previously unknown cause [Pellerin et al 2023a], making GAA-FGF14-related ataxia one of the most common genetic causes of late-onset ataxia within the French Canadian population [Brais, personal observation]. The enrichment in this population is likely due to a founder effect, as such effects have been previously described in this population [Scriver 2001], and some French Canadian individuals with GAA-FGF14-related ataxia appear to share a common haplotype at the FGF14 locus [Pellerin et al 2023a].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GAA-FGF14-related ataxia, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

GAA-FGF14-Related Ataxia: Recommended Evaluations Following Initial Diagnosis

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 (see Table 5).

Table 5.

GAA-FGF14-Related Ataxia: Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

GAA-FGF14-Related Ataxia: Recommended Surveillance

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.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although GAA-FGF14-related ataxia rarely manifests during child-bearing age, measures to support mobility should be taken in affected pregnant women.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

GAA-FGF14-related ataxia is inherited in an autosomal dominant manner.

Note: Although GAA-FGF14-related ataxia is inherited in an autosomal dominant manner, the combined effects of intergenerational instability and reduced penetrance can result in the appearance of "generation skipping" of the disorder in family histories and seemingly autosomal recessive inheritance (e.g., multiple affected individuals in a single generation) [Pellerin et al 2023a].

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with GAA-FGF14-related ataxia inherited an abnormal GAA repeat expansion from a parent who has a likely pathogenic (reduced penetrance) or pathogenic GAA repeat expansion. A parent with an abnormal GAA repeat expansion in FGF14 may or may not have manifestations of GAA-FGF14-related ataxia.
• Fifteen to 50% of individuals diagnosed with GAA-FGF14-related ataxia represent simplex cases (i.e., the only family member known to be affected) [Pellerin et al 2023a, Wilke et al 2023]. Note: Simplex cases may be observed with transmission of a GAA repeat (expanded to the pathogenic or likely pathogenic range in the proband) by an unaffected mother who has a GAA repeat that is either at the high end of normal size or in the reduced penetrance range.
• The FGF14 GAA repeat is highly unstable and almost always changes in size upon parent-to-offspring transmission when the size of the parent's GAA repeat expansion is greater than 75 repeats [Pellerin et al 2024a] (see Clinical Characteristics, Intergenerational Instability). Because the size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission, transmission of GAA-FGF14-related ataxia from an affected mother to offspring is more commonly seen than transmission from an affected father to offspring [Méreaux et al 2024, Pellerin et al 2024a].
• The family history of some individuals diagnosed with GAA-FGF14-related ataxia may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the heterozygous parent.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has an FGF14 GAA expansion in the likely pathogenic or pathogenic range, the risk to the sibs of inheriting the GAA-FGF14-related parental allele is 50%. The likelihood that a sib who inherits the GAA-FGF14-related parental allele will have a GAA repeat size in the pathogenic, reduced penetrance, or non-pathogenic range is influenced by intergenerational instability (i.e., changes in repeat size upon parent-to-offspring transmission).
  • The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
  • The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [Pellerin et al 2024a] (see Clinical Characteristics, Intergenerational Instability).
• Sibs who inherit an expansion of 250-300 GAA repeats may or may not develop GAA-FGF14-related ataxia. Reduced penetrance has been reported in individuals heterozygous for 250-300 GAA repeats [Pellerin et al 2023a, Rafehi et al 2023, Méreaux et al 2024]; however, GAA repeat length-related penetrance is not fully characterized at this time.
• Sibs who inherit an FGF14 allele containing at least 300 GAA-pure repeats are expected to develop GAA-FGF14-related ataxia (see Clinical Characteristics, Penetrance). There is no known correlation between the penetrance of GAA-FGF14-related ataxia and the sex of the individual with the GAA repeat expansion. Age of onset and clinical presentation can vary within the same family.
• If the parents have not been tested for the FGF14 GAA repeat expansion but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for GAA-FGF14-related ataxia because of the possibility of reduced or age-related penetrance in a heterozygous parent or the presence of a near-pathogenic GAA repeat size in the mother.

Offspring of a proband

• 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 in transmission to offspring if the proband is female and to contract in transmission if the proband is male (see Clinical Characteristics, Intergenerational Instability).

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an FGF14 GAA repeat expansion, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once a pathogenic or likely pathogenic GAA repeat expansion in intron 1 of FGF14 has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Of note:
  • It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics, Genotype-Phenotype Correlations).
  • An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-FGF14-related ataxia.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of GAA-FGF14-related ataxia, it is appropriate to consider testing of symptomatic individuals regardless of age, although GAA-FGF14-related ataxia has never been described in children and alternative genetic causes should also be explored and excluded in these individuals.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once a GAA repeat expansion in intron 1 of FGF14 has been identified in an affected family member, 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 pathogenic variant is not possible. In addition, the current lack of knowledge regarding somatic instability of the repeat prenatally makes the interpretation of prenatal genetic test results challenging.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

FGF14 encodes fibroblast growth factor 14 (FGF14), which is primarily expressed in the brain, most abundantly in the cerebellum. FGF14 regulates spontaneous and evoked firing of Purkinje cells by interacting with and modulating the function of voltage-gated sodium channels at the axon initial segment [Lou et al 2005, Xiao et al 2013, Yan et al 2014, Bosch et al 2015, Di Re et al 2017].

FGF14 contains a variable GAA repeat in intron 1 of its major isoform. Expansion of the size of the GAA repeat is associated with disease (see Table 9).

Mechanism of disease causation. Likely loss of function via haploinsufficiency

Note: Expansion of non-GAA-pure repeats appears to be not pathogenic for ataxia, as it has been shown that non-GAA-pure repeat expansions do not segregate with disease in families with ataxia [Pellerin et al 2023a, Pellerin et al 2023b, Hengel et al 2023].

FGF14-specific laboratory technical considerations. See Table 7.

Table 7.

FGF14-Specific Laboratory Technical Considerations

Methods to characterize FGF14 GAA repeats. Due to the technical challenges of detecting and sizing FGF14 GAA repeat expansions, multiple methods may be needed to rule out or detect an expanded allele (see Table 8). Repeats in the normal range (6-249 GAA repeats) may be detected by traditional PCR. However, detection of apparent homozygosity for a normal GAA repeat does not rule out the presence of an expanded GAA repeat; thus, testing by repeat-primed PCR is required (see Table 8).

Table 8.

Methods to Characterize FGF14 GAA Repeats

Table 9.

FGF14 Variants Referenced in This GeneReview

Author Notes

David Pellerin (ku.ca.lcu@12.nirellep.divad), Matt Danzi (ude.imaim.dem@iznad.m), Mathilde Renaud (rf.ycnan-urhc@2duaner.m), Henry Houlden (ku.ca.lcu@nedluoh.h), Matthis Synofzik (ed.negnibeut-inu@kizfonys.sihttam), Stephan Zuchner (gro.noitadnuof-pgt@renhcuzs), and Bernard Brais (ac.lligcm@siarb.dranreb) are actively involved in clinical research regarding individuals with GAA-FGF14-related ataxia. They would be happy to communicate with persons who have any questions regarding diagnosis of GAA-FGF14-related ataxia or other considerations.

Drs Pellerin, Danzi, Zuchner, Synofzik, and Brais are also interested in hearing from clinicians treating families affected by adult-onset ataxia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Drs Pellerin, Danzi, Zuchner, or Brais to inquire about review of FGF14 variants of uncertain significance.

Acknowledgments

This work has been supported, in part, by the Canadian Institutes of Health Research (CIHR) grant no. 189963 (to B.B.), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) no. 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP no. 825575 (to M.S., B.B., and – as an associated partner – S.Z.).

Revision History

• 25 January 2024 (bp) Review posted live
• 30 June 2023 (dp) Original submission

Literature Cited

• Amado A, Blanco MO, Repáraz-Andrade A. Spinocerebellar ataxia 27: clinical phenotype of twin sisters with FGF14 deletion. Neuropediatrics. 2017;48:131. [PubMed: 28192817]

• Ando M, Higuchi Y, Yuan J, Yoshimura A, Kojima F, Yamanishi Y, Aso Y, Izumi K, Imada M, Maki Y, Nakagawa H, Hobara T, Noguchi Y, Takei J, Hiramatsu Y, Nozuma S, Sakiyama Y, Hashiguchi A, Matsuura E, Okamoto Y, Takashima H. Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan. Ann Clin Transl Neurol. 2024;11:96-104. [PMC free article: PMC10791012] [PubMed: 37916889]

• Ashton C, Indelicato E, Pellerin D, Clément G, Danzi MC, Dicaire MJ, Bonnet C, Houlden H, Züchner S, Synofzik M, Lamont PJ, Renaud M, Boesch S, Brais B. Spinocerebellar ataxia 27B: episodic symptoms and acetazolamide response in 34 patients. Brain Commun. 2023;5:fcad239. [PMC free article: PMC10495284] [PubMed: 37705681]

• Baloh RW. Episodic ataxias 1 and 2. Handb Clin Neurol. 2012;103:595-602. [PubMed: 21827920]

• Bonnet C, Pellerin D, Roth V, Clément G, Wandzel M, Lambert L, Frismand S, Douarinou M, Grosset A, Bekkour I, Weber F, Girardier F, Robin C, Cacciatore S, Bronner M, Pourié C, Dreumont N, Puisieux S, Iruzubieta P, Dicaire MJ, Evoy F, Rioux MF, Hocquel A, La Piana R, Synofzik M, Houlden H, Danzi MC, Zuchner S, Brais B, Renaud M. Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Sci Rep. 2023;13:9737. [PMC free article: PMC10272173] [PubMed: 37322040]

• Borsche M, Thomsen M, Szmulewicz DJ, Lübbers B, Hinrichs F, Lockhart PJ, Lohmann K, Helmchen C, Brüggemann N. Bilateral vestibulopathy in RFC1-positive CANVAS is distinctly different compared to FGF14-linked spinocerebellar ataxia 27B. J Neurol. 2024;271:1023-7. [PMC free article: PMC10827886] [PubMed: 37861706]

• Bosch MK, Carrasquillo Y, Ransdell JL, Kanakamedala A, Ornitz DM, Nerbonne JM. Intracellular FGF14 (iFGF14) is required for spontaneous and evoked firing in cerebellar Purkinje neurons and for motor coordination and balance. J Neurosci. 2015;35:6752-69. [PMC free article: PMC4412895] [PubMed: 25926453]

• Brais B, Pellerin D, Danzi MC. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. Reply. N Engl J Med. 2023;388:e70. [PMC free article: PMC10042577] [PubMed: 36516086]

• Brusse E, de Koning I, Maat-Kievit A, Oostra BA, Heutink P, van Swieten JC. Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): a new phenotype. Mov Disord. 2006;21:396-401. [PubMed: 16211615]

• Bürk K, Sival DA. Scales for the clinical evaluation of cerebellar disorders. Handb Clin Neurol. 2018;154:329-39. [PubMed: 29903450]

• Ceroni F, Osborne D, Clokie S, Bax DA, Cassidy EJ, Dunn MJ, Harris CM, Self JE, Ragge NK. Analysis of fibroblast growth factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia. Eur J Hum Genet. 2023;31:353-9. [PMC free article: PMC9995494] [PubMed: 36207621]

• Choquet K, La Piana R, Brais B. A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia. Neurogenetics. 2015;16:233-6. [PubMed: 25566820]

• Claassen J, Spiegel R, Kalla R, Faldon M, Kennard C, Danchaivijitr C, Bardins S, Rettinger N, Schneider E, Brandt T, Jahn K, Teufel J, Strupp M, Bronstein A. A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus--effects on slowphase eye velocity, postural stability, locomotion and symptoms. J Neurol Neurosurg Psychiatry. 2013;84:1392-9. [PubMed: 23813743]

• Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M. The inherited cerebellar ataxias: an update. J Neurol. 2023;270:208-22. [PMC free article: PMC9510384] [PubMed: 36152050]

• Coebergh JA, Fransen van de Putte DE, Snoeck IN, Ruivenkamp C, van Haeringen A, Smit LM. A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene. Eur J Paediatr Neurol. 2014;18:413-5. [PubMed: 24252256]

• Di Re J, Wadsworth PA, Laezza F. Intracellular fibroblast growth factor 14: emerging risk factor for brain disorders. Front Cell Neurosci. 2017;11:103. [PMC free article: PMC5396478] [PubMed: 28469558]

• Dolzhenko E, Deshpande V, Schlesinger F, Krusche P, Petrovski R, Chen S, Emig-Agius D, Gross A, Narzisi G, Bowman B, Scheffler K, van Vugt JJFA, French C, Sanchis-Juan A, Ibáñez K, Tucci A, Lajoie BR, Veldink JH, Raymond FL, Taft RJ, Bentley DR, Eberle MA. ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions. Bioinformatics. 2019;35:4754-6. [PMC free article: PMC6853681] [PubMed: 31134279]

• Dolzhenko E, van Vugt JJFA, Shaw RJ, Bekritsky MA, van Blitterswijk M, Narzisi G, Ajay SS, Rajan V, Lajoie BR, Johnson NH, Kingsbury Z, Humphray SJ, Schellevis RD, Brands WJ, Baker M, Rademakers R, Kooyman M, Tazelaar GHP, van Es MA, McLaughlin R, Sproviero W, Shatunov A, Jones A, Al Khleifat A, Pittman A, Morgan S, Hardiman O, Al-Chalabi A, Shaw C, Smith B, Neo EJ, Morrison K, Shaw PJ, Reeves C, Winterkorn L, Wexler NS; US–Venezuela Collaborative Research Group; Housman DE, Ng CW, Li AL, Taft RJ, van den Berg LH, Bentley DR, Veldink JH, Eberle MA. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 2017;27:1895-903. [PMC free article: PMC5668946] [PubMed: 28887402]

• Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015;372:249-63. [PubMed: 25587949]

• Groth CL, Berman BD. Spinocerebellar ataxia 27: a review and characterization of an evolving phenotype. Tremor Other Hyperkinet Mov (N Y). 2018;8:534. [PMC free article: PMC5801325] [PubMed: 29416937]

• Hassan A. Episodic ataxias: primary and secondary etiologies, treatment, and classification approaches. Tremor Other Hyperkinet Mov (N Y). 2023;13:9. [PMC free article: PMC10064912] [PubMed: 37008993]

• Hengel H, Pellerin D, Wilke C, Fleszar Z, Brais B, Haack T, Traschütz A, Schöls L, Synofzik M. As frequent as polyglutamine spinocerebellar ataxias: SCA27B in a large German autosomal dominant ataxia cohort. Mov Disord. 2023;38:1557-8. [PubMed: 37528564]

• Ibañez K, Polke J, Hagelstrom RT, Dolzhenko E, Pasko D, Thomas ERA, Daugherty LC, Kasperaviciute D, Smith KR; WGS for Neurological Diseases Group; Deans ZC, Hill S, Fowler T, Scott RH, Hardy J, Chinnery PF, Houlden H, Rendon A, Caulfield MJ, Eberle MA, Taft RJ, Tucci A; Genomics England Research Consortium. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 2022;21:234-45 [PMC free article: PMC8850201] [PubMed: 35182509]

• Imbrici P, Eunson LH, Graves TD, Bhatia KP, Wadia NH, Kullmann DM, Hanna MG. Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A. Neurology. 2005;65:944-6. [PubMed: 16186543]

• Iruzubieta P, Pellerin D, Bergareche A, Albajar I, Mondragón E, Vinagre A, Fernández-Torrón R, Moreno F, Equiza J, Campo-Caballero D, Poza JJ, Ruibal M, Formica A, Dicaire MJ, Danzi MC, Zuchner S, Croitoru I, Ruiz M, Schlüter A, Casasnovas C, Pujol A, Brais B, Houlden H, López de Munain A, Ruiz-Martínez J. Frequency and phenotypic spectrum of spinocerebellar ataxia 27B and other genetic ataxias in a Spanish cohort of late-onset cerebellar ataxia. Eur J Neurol. 2023;30:3828-33. [PubMed: 37578187]

• Jacobi H, Rakowicz M, Rola R, Fancellu R, Mariotti C, Charles P, Dürr A, Küper M, Timmann D, Linnemann C, Schöls L, Kaut O, Schaub C, Filla A, Baliko L, Melegh B, Kang JS, Giunti P, van de Warrenburg BP, Fimmers R, Klockgether T. Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument. Cerebellum. 2013;12:418-28. [PubMed: 23090211]

• Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology. 2004;62:17-22. [PubMed: 14718690]

• Jen JC, Wan J. Episodic ataxias. Handb Clin Neurol. 2018;155:205-15. [PubMed: 29891059]

• Loeffler MA, Synofzik M, Cebi I, Klocke P, Hormozi M, Gasser T, Gharabaghi A, Weiss D. Case Report: Deep brain stimulation improves tremor in FGF-14 associated spinocerebellar ataxia. Front Neurol. 2022;13:1048530. [PMC free article: PMC9795845] [PubMed: 36588880]

• Lou JY, Laezza F, Gerber BR, Xiao M, Yamada KA, Hartmann H, Craig AM, Nerbonne JM, Ornitz DM. Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. J Physiol. 2005;569:179-93. [PMC free article: PMC1464207] [PubMed: 16166153]

• Martineau L, Noreau A, Dupré N. Therapies for ataxias. Curr Treat Options Neurol. 2014;16:300. [PubMed: 24832479]

• Milsom I, Coyne KS, Nicholson S, Kvasz M, Chen CI, Wein AJ. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur Urol. 2014;65:79-95. [PubMed: 24007713]

• Méreaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, Monin ML, Anheim M, Le Ber I, Thobois S, Gobert F, Guillot-Noël L, Forlani S, Jornea L, Heinzmann A, Sangare A, Gaymard B, Guyant-Maréchal L, Charles P, Marelli C, Honnorat J, Degos B, Tison F, Sangla S, Simonetta-Moreau M, Salachas F, Tchikviladzé M, Castelnovo G, Mochel F, Klebe S, Castrioto A, Fenu S, Méneret A, Bourdain F, Wandzel M, Roth V, Bonnet C, Riant F, Stevanin G, Noël S, Fauret-Amsellem AL, Bahlo M, Lockhart PJ, Brais B, Renaud M, Brice A, Durr A. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions. EBioMedicine. 2024;99:104931. [PMC free article: PMC10784672] [PubMed: 38150853]

• Miura S, Kosaka K, Fujioka R, Uchiyama Y, Shimojo T, Morikawa T, Irie A, Taniwaki T, Shibata H. Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14. Eur J Med Genet. 2019;62:172-6. [PubMed: 30017992]

• Mizushima K, Shibata Y, Shirai S, Matsushima M, Miyatake S, Iwata I, Yaguchi H, Matsumoto N, Yabe I. Prevalence of repeat expansions causing autosomal dominant spinocerebellar ataxias in Hokkaido, the northernmost island of Japan. J Hum Genet. 2024;69:27-31. [PubMed: 37848721]

• Nachbauer W, Nocker M, Karner E, Stankovic I, Unterberger I, Eigentler A, Schneider R, Poewe W, Delazer M, Boesch S. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J Neurol. 2014;261:983-91. [PubMed: 24658662]

• Novis LE, Frezatti RS, Pellerin D, Tomaselli PJ, Alavi S, Della Coleta MV, Spitz M, Dicaire MJ, Iruzubieta P, Pedroso JL, Barsottini O, Cortese A, Danzi MC, França MC Jr, Brais B, Zuchner S, Houlden H, Raskin S, Marques W, Teive HA. Frequency of GAA-FGF14 ataxia in a large cohort of Brazilian patients with unsolved adult-onset cerebellar ataxia. Neurol Genet. 2023;9:e200094. [PMC free article: PMC10461713] [PubMed: 37646005]

• Paucar M, Lundin J, Alshammari T, Bergendal Å, Lindefeldt M, Alshammari M, Solders G, Di Re J, Savitcheva I, Granberg T, Laezza F, Iwarsson E, Svenningsson P. Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27. J Intern Med. 2020;288:103-15. [PMC free article: PMC10123866] [PubMed: 32112487]

• Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, Scriba CK, Ashton C, Yanick C, Beijer D, Rebelo A, Rocca C, Jaunmuktane Z, Sonnen JA, Larivière R, Genís D, Molina Porcel L, Choquet K, Sakalla R, Provost S, Robertson R, Allard-Chamard X, Tétreault M, Reiling SJ, Nagy S, Nishadham V, Purushottam M, Vengalil S, Bardhan M, Nalini A, Chen Z, Mathieu J, Massie R, Chalk CH, Lafontaine AL, Evoy F, Rioux MF, Ragoussis J, Boycott KM, Dubé MP, Duquette A, Houlden H, Ravenscroft G, Laing NG, Lamont PJ, Saporta MA, Schüle R, Schöls L, La Piana R, Synofzik M, Zuchner S, Brais B. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med. 2023a;388:128-41. [PMC free article: PMC10042577] [PubMed: 36516086]

• Pellerin D, Del Gobbo GF, Couse M, Dolzhenko E, Nageshwaran SK, Cheung WA, Xu IRL, Dicaire MJ, Spurdens G, Matos-Rodrigues G, Stevanovski I, Scriba CK, Rebelo A, Roth V, Wandzel M, Bonnet C, Ashton C, Agarwal A, Peter C, Hasson D, Tsankova NM, Dewar K, Lamont PJ, Laing NG, Renaud M, Houlden H, Synofzik M, Usdin K, Nussenzweig A, Napierala M, Chen Z, Jiang H, Deveson IW, Ravenscroft G, Akbarian S, Eberle MA, Boycott KM, Pastinen T; All of Us Research Program Long Read Working Group; Brais B, Zuchner S, Danzi MC. A common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locus. Nat Genet. 2024a. Epub ahead of print. [PubMed: 38937606]

• Pellerin D, Heindl F, Wilke C, Danzi MC, Traschütz A, Ashton C, Dicaire MJ, Cuillerier A, Del Gobbo G, Boycott KM, Claassen J, Rujescu D, Hartmann AM, Zuchner S, Brais B, Strupp M, Synofzik M. GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort. EBioMedicine. 2024b;102:105076. [PMC free article: PMC10960126] [PubMed: 38507876]

• Pellerin D, Iruzubieta P, Tekgül Ş, Danzi MC, Ashton C, Dicaire MJ, Wandzel M, Roth V, Lamont PJ, Bonnet C, Renaud M, Synofzik M, Zuchner S, Brais B, Başak NA, Houlden H. Non-GAA repeat expansions in FGF14 are likely not pathogenic-reply to: "Shaking up ataxia: FGF14 and RFC1 repeat expansions in affected and unaffected members of a Chilean family". Mov Disord. 2023b;38:1575-7. [PubMed: 37565404]

• Pellerin D, Wilke C, Traschütz A, Nagy S, Currò R, Dicaire MJ, Garcia-Moreno H, Anheim M, Wirth T, Faber J, Timmann D, Depienne C, Rujescu D, Gazulla J, Reilly MM, Giunti P, Brais B, Houlden H, Schöls L, Strupp M, Cortese A, Synofzik M. Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy. J Neurol Neurosurg Psychiatry. 2024c;95:175-9. [PMC free article: PMC10850669] [PubMed: 37399286]

• Piarroux J, Riant F, Humbertclaude V, Remerand G, Hadjadj J, Rejou F, Coubes C, Pinson L, Meyer P, Roubertie A. FGF14-related episodic ataxia: delineating the phenotype of episodic ataxia type 9. Ann Clin Transl Neurol. 2020;7:565-72. [PMC free article: PMC7187715] [PubMed: 32162847]

• Poewe W, Stankovic I, Halliday G, Meissner WG, Wenning GK, Pellecchia MT, Seppi K, Palma JA, Kaufmann H. Multiple system atrophy. Nat Rev Dis Primers. 2022;8:56. [PubMed: 36008429]

• Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14. American journal of human genetics. 2023;110:1018. [PMC free article: PMC10257192] [PubMed: 37267898]

• Schesny M, Joncourt F, Tarnutzer AA. Acetazolamide-responsive episodic ataxia linked to novel splice site variant in FGF14 gene. Cerebellum. 2019;18:649-53. [PubMed: 30607796]

• Scriver CR. Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet. 2001;2:69-101. [PubMed: 11701644]

• Seemann J, Traschütz A, Ilg W, Synofzik M. 4-Aminopyridine improves real-life gait performance in SCA27B on a single-subject level: a prospective n-of-1 treatment experience. J Neurol. 2023;270:5629-34. [PMC free article: PMC10576659] [PubMed: 37439944]

• Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. 2007;120:151-7. [PubMed: 17275456]

• Strupp M, Teufel J, Zwergal A, Schniepp R, Khodakhah K, Feil K. Aminopyridines for the treatment of neurologic disorders. Neurol Clin Pract. 2017;7:65-76. [PMC free article: PMC5310209] [PubMed: 28243504]

• van de Warrenburg BP, van Gaalen J, Boesch S, Burgunder JM, Dürr A, Giunti P, Klockgether T, Mariotti C, Pandolfo M, Riess O. EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. Eur J Neurol. 2014;21:552-62. [PubMed: 24418350]

• van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, Maat-Kievit A, Leegwater P, Dooijes D, Oostra BA, Heutink P. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am J Hum Genet. 2003;72:191-9. [PMC free article: PMC378625] [PubMed: 12489043]

• Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, Palma JA, Meissner WG, Krismer F, Berg D, Cortelli P, Freeman R, Halliday G, Höglinger G, Lang A, Ling H, Litvan I, Low P, Miki Y, Panicker J, Pellecchia MT, Quinn N, Sakakibara R, Stamelou M, Tolosa E, Tsuji S, Warner T, Poewe W, Kaufmann H. The Movement Disorder Society Criteria for the diagnosis of multiple system atrophy. Mov Disord. 2022;37:1131-48. [PMC free article: PMC9321158] [PubMed: 35445419]

• Wilke C, Pellerin D, Mengel D, Traschütz A, Danzi MC, Dicaire MJ, Neumann M, Lerche H, Bender B, Houlden H, Schöls L, Brais B, Synofzik M. GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response. Brain. 2023;146:4144-57. [PubMed: 37165652]

• Wirth T, Clément G, Delvallée C, Bonnet C, Bogdan T, Iosif A, Schalk A, Chanson JB, Pellerin D, Brais B, Roth V, Wandzel M, Fleury MC, Piton A, Calmels N, Namer IJ, Kremer S, Tranchant C, Renaud M, Anheim M. Natural history and phenotypic spectrum of GAA-FGF14 sporadic late-onset cerebellar ataxia (SCA27B). Mov Disord. 2023;38:1950-6. [PubMed: 37470282]

• Xiao M, Bosch MK, Nerbonne JM, Ornitz DM. FGF14 localization and organization of the axon initial segment. Mol Cell Neurosci. 2013;56:393-403. [PMC free article: PMC3791165] [PubMed: 23891806]

• Yan H, Pablo JL, Wang C, Pitt GS. FGF14 modulates resurgent sodium current in mouse cerebellar Purkinje neurons. Elife. 2014;3:e04193. [PMC free article: PMC4356139] [PubMed: 25269146]

• Zeng YH, Gan SR, Chen WJ. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med. 2023;388:e70. [PubMed: 37224214]

• Zesiewicz TA, Wilmot G, Kuo SH, Perlman S, Greenstein PE, Ying SH, Ashizawa T, Subramony SH, Schmahmann JD, Figueroa KP, Mizusawa H, Schöls L, Shaw JD, Dubinsky RM, Armstrong MJ, Gronseth GS, Sullivan KL. Comprehensive systematic review summary: treatment of cerebellar motor dysfunction and ataxia: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90:464-71. [PMC free article: PMC5863491] [PubMed: 29440566]