Diagnostic Criteria

Formal diagnostic criteria for RFC1 CANVAS / spectrum disorder have not been established.

Suggestive Findings

RFC1 CANVAS / spectrum disorder should be suspected in individuals with onset after age 35 years of one or more the following findings (with electrodiagnostic, vestibular, and imaging findings and family history).

Clinical Findings

Complex impairment of balance and coordination of peripheral, vestibular, and cerebellar origin

• Symptoms include unsteadiness (imbalance, dizziness), falls, clumsiness of hands.

• Examination reveals progressive ataxia of gait and limb dysmetria.

Sensory neuropathy or neuronopathy

Source: GeneReviews — "RFC1 CANVAS / Spectrum Disorder"

Differential Diagnosis

AAGGG expansions in RFC1 were identified in 82%-97% of individuals with clinical features consistent with the full CANVAS phenotype , suggesting that locus heterogeneity for the full CANVAS phenotype (albeit limited) is possible. AAGGG expansions in RFC1 represent one of the more common causes of hereditary adult-onset ataxia (see Hereditary Ataxia Overview). In individuals with adult-onset ataxia, RFC1 AAGGG expansions were identified in 14%-22% of individuals . Given the multisystem involvement of RFC1 CANVAS / spectrum disorder and the possible asynchronous involvement of different systems during disease progression, the differential diagnosis is broad and includes: • Genetic causes of inherited ataxia (see Hereditary Ataxia Overview); • Genetic causes of inherited neuropathy (see Charcot-Marie-Tooth Hereditary Neuropathy Overview); • Mitochondrial disorders that can manifest with ataxia, neuropathy and (more occasionally) bilateral vestibular areflexia (see Mitochondrial Disorders Overview). Selected genes and disorders of interest are summarized in [, , , , , , , , ]. Table 3. Genes of Interest in the Differential Diagnosis of RFC1 CANVAS / Spectrum Disorder

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with RFC1 CANVAS / spectrum disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with RFC1 CANVAS / Spectrum Disorder

Source: GeneReviews — "RFC1 CANVAS / Spectrum Disorder"

Clinical Guidance

Medications of known toxicity for peripheral nerves (e.g., neurotoxic chemotherapy agents, pyridoxine), the cerebellum (e.g., phenytoin), or the vestibular system (e.g., aminoglycosides) as well as chronic alcohol consumption may worsen the condition.

Source: GeneReviews — "RFC1 CANVAS / Spectrum Disorder"

Surveillance Guidelines

Table 6.

Recommended Surveillance for Individuals with RFC1 CANVAS / Spectrum Disorder

System/Concern | Evaluation | Frequency

Neurologic

| • Neurologic assessment for progression of ataxia; sensory impairment; vestibular dysfunction; dysautonomia

• No validated clinical scale exists for RFC1 CANVAS / spectrum disorder; consider monitoring disease w/validated scales for cerebellar disorder (e.g., SARA) and neuropathy (e.g., CMTNS).1

| Annually; more often for an acute exacerbation

Physiatry, OT/PT assessment of mobility, self-help skills

Dysarthria

| Need for alternative communication method or speech therapy (rarely required) | Per symptom progression

Dysphagia

| Assess aspiration risk feeding methods.

CMTNS = Charcot-Marie-Tooth Neuropathy Score; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia

1. ,

Source: GeneReviews — "RFC1 CANVAS / Spectrum Disorder"