Autosomal recessive cerebellar ataxia type 3 (ARCA3) is a rare inherited disorder caused by mutations in the ANO10 gene. The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline. We performed mutational screening in 80 patients with sporadic or autosomal recessive adult-onset ataxia. We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel. Age at onset ranged between 27 and 53 years. All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI. Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10). Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions. Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures. Our observational study indicates a high frequency of ARCA3 disease in sporadic patients with adult-onset cerebellar ataxia. We extended the ANO10 mutational spectrum with the identification of novel gene variants, and further defined the clinical, cognitive, and neurophysiological features in a new cohort of patients. These findings may contribute to the refinement of the complex ARCA3 phenotype and be valuable in clinical management and natural history studies.
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This work was supported in part by research grants from the Italian Ministry of Health: RF-2011-02351165 (to F.T.), RF-2011-02347420 (to C.M.)
Research Grant RF-2011-02351165 from the Italian Ministry of Health to F.T., and RF-2011-02347420 to C.M.
Compliance with ethical standards
Conflicts of interest
All authors declare that they have no conflict of interest.
All patients gave written informed consent for the clinical and genetic tests in agreement with the procedures approved by the Local Ethic Committee. The consent forms routinely used in our Hospital specifically enquire the patient consent for diagnostic and research purposes. Ethics committee approval is not required for retrospective anonymized observational studies.
Table S2. Review of the literature summarizing genetic and clinical features in ARCA3 patients. (PDF 84 KB)
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