Spinocerebellar Ataxia with Axonal Neuropathy Type 1

Excerpt

Clinical characteristics: Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia and distal sensorimotor axonal neuropathy. Gaze nystagmus and dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation in the hands and feet become impaired; vibration sense is lost in hands and lower thighs. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent. Cognitive dysfunction – present in some – manifests as mild intellectual disability and poor executive function. To date only seven affected individuals have been described from three apparently unrelated consanguineous families (one from Saudi Arabia and two from Oman); therefore, it is likely that the full phenotypic spectrum of this disorder is not yet known.

Diagnosis/testing: The diagnosis of SCAN1 is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TDP1 identified by molecular genetic testing.

Management: Treatment of manifestations: Supportive care provided by specialists in neurology, rehabilitation medicine, occupational therapy, physical therapy, speech-language pathology, and clinical genetics.

Surveillance: Routine follow up as determined by treating specialists to monitor the response to supportive care and to assess for changes in existing manifestations and/or emergence of new manifestations.

Agents/circumstances to avoid: Because TDP1 codes for a DNA repair enzyme, genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin are likely to be extremely harmful and possibly fatal; exposure to radiation is also likely to be extremely harmful and possibly fatal.

Genetic counseling: SCAN1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TDP1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the TDP1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.