Objective: To report clinical and mutation spectrum of AOA2 in Indian population

Background: The Autosomal Recessive Cerebellar Ataxias (ARCAs) are less explored in Indian population. Ataxia with Oculomotor Apraxia-2 (AOA2) frequently reported from worldwide but never reported from Indian population. First time, we have clinically and genetically characterized AOA2 patients in India.

Methods: In our routine investigation process at ataxia clinic, we screen hereditary spinocerebellar ataxia patients for FRDA, SCA1-3, SCA6-8, SCA12, SCA17, SCA26, SCA36 and DRPLA. Patients who are found negative in these investigations considered for further screening process. We considered 18 ARCA patients for whole exome sequencing (WES) experiment to uncover the mutation spectrum of the ARCA in Indian population. All identified AOA2 patients through WES and Sanger sequencing experiments were considered for clinical evaluation.

Results: A total 6 patients were identified with AOA2. The mean (SD), range of the age of the patient was 28 (14.0), 16-48 yrs and mean age of onset was 20 (15.2), 4-39 yrs. The mean (SD), range of the duration of the disease was 8 (4.6), 3-9 years. This is the first time we are reporting a patient with AOA2 whose age at onset is 39 years. First symptom of all the patient was gait ataxia except one. Cerebellar features were present in all the patients. Only one patient was complaining of head tremor. Areflexia was noted in all the patients. Saccadic intrusion was present in all three clinically evaluated patients. There were no extrapyramidal features. Nerve conduction study showed sensory motor neuropathy in both upper and lower limbs in all the patients except one (AT1945, Sensory motor axonal neuropathy). Slow saccades were present in 75% patients (3 out of 4 patients). Scoliosis was not observed in any of the patient and pes cavus was noted in one patient (AT1898). MRI brain showed cerebellar atrophy in all the patients.

Conclusions: We hypothesized that AOA2 may not very uncommon in Indian population. Mid to late onset hereditary ataxia patients with or without recessive inheritance should be considered for the SETX gene screening. Although all coding exons should be considered for the mutation screening of SETX gene but we recommend at least following mutations must be screened in Indian AOA2 suspected patients- N2010S, Q575*, S1655*, c.6422_6423insA, R502W

References: 1. Anheim M, Fleury M-C, Franques J, Moreira M-C, Delaunoy J-P, Stoppa-Lyonnet D, et al. Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families. Arch Neurol. 2008 Jul;65(7):958–62. 2. Le Ber I, Bouslam N, Rivaud-Péchoux S, Guimarães J, Benomar A, Chamayou C, et al. Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain. 2004 Apr;127(Pt 4):759–67.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-mutation-spectrum-of-ataxia-with-oculomotor-apraxia-2-an-indian-perspective/