Ataxia with oculomotor apraxia

Ataxia with oculomotor apraxia comprises the subtypes AOA1, AOA2, AOA3, and AOA4. It typically presents with progressive gait and limb ataxia, dysarthria, and oculomotor apraxia, which may lead affected individuals to use compensatory head movements when shifting their gaze. Axonal sensorimotor neuropathy commonly causes reduced or absent reflexes, distal weakness, muscle wasting, and sensory impairment. Extrapyramidal manifestations may include chorea, dystonia, tremor, or myoclonus. Serum alpha-fetoprotein levels are frequently elevated in some subtypes but may remain within the normal range. The age at onset and rate of progression vary by subtype, and loss of independent ambulation may develop over the disease course.

AOA disorders are rare, and their prevalence varies geographically; a reliable prevalence for AOA overall is not reported.

AOA is caused by germline biallelic pathogenic variants in one of several genes, with the subtype defined by the gene involved. Pathogenic variants in APTX, SETX, PIK3R5, and PNKP cause AOA1, AOA2, AOA3, and AOA4, respectively.

AOA is inherited in an autosomal recessive manner across the subtypes. The parents of an affected individual are usually heterozygous carriers and are generally clinically unaffected. For each pregnancy of two carriers, the probability of an affected child is 25%, the probability of an unaffected carrier is 50%, and the probability of a child who is neither affected nor a carrier is 25%. Prenatal molecular testing is possible once the familial pathogenic variants have been identified.

The diagnosis of AOA is established by molecular genetic testing in an individual with a compatible clinical phenotype. Supportive findings include elevated serum alpha-fetoprotein, brain MRI showing cerebellar atrophy, and nerve conduction studies revealing an axonal sensorimotor neuropathy. A multigene panel covering the causative genes determines the subtype and clarifies the genetic aetiology.

Main differential diagnoses include:

• Ataxia-telangiectasia: cerebellar ataxia with oculomotor apraxia and elevated alpha-fetoprotein, distinguished by oculocutaneous telangiectasia, immunodeficiency and malignancy risk; ATM.
• Ataxia-telangiectasia-like disorder: an AOA-like phenotype without telangiectasia or immunodeficiency and with normal alpha-fetoprotein; MRE11.
• : distinguished by absence of oculomotor apraxia, hypertrophic cardiomyopathy and a homozygous GAA repeat expansion or, less commonly, compound heterozygosity for a GAA expansion and a sequence variant; FXN.

• Molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Moreira MC, Koenig M. Ataxia with oculomotor apraxia type 2. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• da Costa SCG, Rezende Filho FM, de Freitas JL, de Assis Pereira Matos PCA, Della-Ripa B, Franca MC Jr, et al. Clinical and genetic characterization of Brazilian patients with ataxia and oculomotor apraxia. Mov Disord. 2022;37(6):1309-1316. PMID: .