Clinical Guidance

Probands. A strong correlation exists between the number of CAG repeats and severity of disease: the larger the CAG repeat, the earlier the onset and more severe the disease. However, the correlation is broad: only 36%-70% of age-at-onset variance can be explained by CAG repeat size [, , , , , , ]. Routine testing does not determine the presence of interruptions if the expansion is longer than 44 repeats; however, the presence of interruptions in such alleles delays the age at onset beyond that predicted by the total repeat size . In a large European study of 317 individuals with SCA1, the size of both the expanded and normal alleles were significant determinants in the prediction of the age at onset of symptoms .

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"

Penetrance

Penetrance is considered to be greater than 95% but is age dependent. Onset after age 60 years has occasionally been reported . A woman with 44 CAG repeats with CAT repeat interruptions had an affected father but was herself asymptomatic at age 66 years , possibly representing reduced penetrance.

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"

Diagnostic Criteria

The phenotypic manifestations of spinocerebellar ataxia type 1 (SCA1) are not specific, and no formal clinical diagnostic criteria exist.

Suggestive Findings

SCA1 should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Progressive cerebellar ataxia

• Dysarthria

• Eventual deterioration of bulbar functions

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SCA1 is established in a proband with and a heterozygous abnormal CAG trinucleotide expansion in ATXN1 identified by molecular genetic testing .

Allele sizes

• Normal alleles

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"

Differential Diagnosis

The inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurologic disorders that defy easy differentiation on the basis of clinical criteria alone. See Hereditary Ataxia Overview, Evaluation Strategies to Identify the Genetic Cause of Hereditary Ataxia in a Proband. Rarely, SCA1 may present with features of hereditary spastic paraparesis (see Hereditary Spastic Paraplegia Overview).

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual with molecularly confirmed spinocerebellar ataxia type 1 (SCA1), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 1

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"

Clinical Guidance

Affected individuals should avoid alcohol as well as medications known to be neurotoxic such as those that cause neuropathy (e.g., isoniazid, large-dose vitamin B6) or those associated with central nervous system toxicity (e.g., diphenylhydantoin). Circumstances that could lead to physical harm, such as operating machinery or climbing to great heights, should also be avoided.

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"

Therapies Under Investigation

Riluzole has been shown to provide some symptomatic relief of ataxia in a mixed group of individuals including persons with SCA1 ; however, further investigation is needed, particularly longer-term disease-specific trials. The number of individuals included with SCA1 was small and did not allow for conclusions regarding treatment efficacy in those with SCA1. Double-blind randomized placebo control trials of riluzole prodrug BHV4157 (troriluzole) are ongoing (NCT02960893, NCT03408080, NCT03701399), and troriluzole has received Fast Track designation from the FDA. Intrathecal injection of 3,000 mesenchymal stem cells in SCA1 transgenic mice mitigated the cerebellar neuronal disorganization, atrophy of dendrites, and motor disturbances .

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"

Surveillance Guidelines

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

Table 5.

Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 1

System/Concern | Evaluation | Frequency

Neurologic

| • Neurologic assessment for progression of ataxia, UMN or LMN signs, history of falls

• Monitor ataxia progression w/standardized scale (SARA).

• Physiatry OT/PT assessment of mobility self-help skills as they relate to ataxia, spasticity, weakness

| Every 3-6 mos

Dysarthria

| Assess need for alternative communication method or speech therapy. | At each visit or as needed

Dysphagia

| Assess aspiration risk feeding methods.

Cognitive/

Psychiatric

| Evaluate mood, signs of psychosis, cognition to identify need for pharmacologic psychotherapeutic interventions.

Family/

Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning). | At each visit

LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for Assessment and Rating of Ataxia; UMN = upper motor neuron

Source: GeneReviews — "Spinocerebellar Ataxia Type 1"