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Spinocerebellar ataxia with axonal neuropathy type 2
A rare autosomal recessive cerebellar ataxia (ARCA), characterized by progressive cerebellar ataxia associated with frequent oculomotor apraxia, severe neuropathy and an elevated serum alpha-fetoprotein (AFP) level.
ORPHA:64753Classification level: Disorder
The prevalence of AOA2 in France is estimated to be 1/900,000.
AOA2 is mostly an adolescent onset disorder (age at onset ranges between 10 and 25 years), with a mean age of 14-15 years, that manifests as progressive cerebellar ataxia associated with peripheral neuropathy (98%), cerebellar atrophy (96%), occasional oculomotor apraxia (OMA; 51%; inability to coordinate eyes ± head movements: when the head turns toward a lateral target; the head reaches the target before the eyes), pyramidal signs (21%), head tremor (14%), dystonia (14%), strabismus (12%), chorea (10%) and saccadic pursuit without OMA (4.5%).
AOA2 results from mutations in SETX gene (9q34), encoding senataxin protein, a DNA/RNA helicase localized in nucleus which is implicated in DNA break repair. Some correlations between genotype and phenotype have been established for example deletions and nonsense mutations are correlated to more severe phenotypes than missense mutations. Mutations in the gene PIK3R5 (17p13.1) have also been implicated in the pathogenesis of AOA2. PIK3R5 encodes a regulatory subunit that interacts with class 1B phosphoinositide-3-kinase (key enzymes in various signal transduction pathways that regulate cell survival and growth, metabolism, immune, and cardiac functions).
Diagnosis is based on clinical features, progressive evolution leading to important motor handicap, absence of extra-neurologic findings and family history. Laboratory findings show an elevated AFP serum level (above 7 µg/L). Electromyography findings reveal axonal sensory-motor neuropathy. Oculographic recordings can demonstrate OMA. Cerebral magnetic resonance imagery displays cerebellar atrophy. Diagnosis is confirmed by molecular analysis of the pathogenic gene.
Differential diagnosis includes Friedreich ataxia, ataxia with vitamin E deficiency, AOA1, ataxia-telangiectasia, ataxia-telangiectasia-like disorder, autosomal recessive spastic ataxia of Charlevoix-Saguenay.
Carrier testing for at-risk family members and prenatal testing are possible if the disease-causing alleles in a family are known.
Transmission of AOA2 is autosomal recessive. Genetic counseling is recommended as each sib of an affected individual has 25% chance of being affected, 50% chance of being an asymptomatic carrier, and 25% chance of being neither affected nor a carrier.
Management and treatment
No specific treatment exists for AOA2 and management is mainly supportive. It includes physical therapy for cerebellar ataxia and disabilities resulting from peripheral neuropathy; educational support for reading and writing difficulties, speech therapy for dysarthria and cognitive impairment. Routine follow-up with a neurologist or a neurogenetician is recommended.
AOA2 is a progressive neurodegenerative disorder and most patients will become wheelchair bound at a mean age of 29.9 years ± 3.84 after a mean disease duration of 15.3 years ± 3.52.