Objective: Clinical and genetic characterization of a patient

Background: In recent years mutations more than 100 different genes have been shown to underlie spinocerebellar ataxias. The wider availability of gene panels and whole-exome sequencing has greatly improved diagnostic accuracy.

Method: We clinically characterize the patient. The ANO 10 mutations were discovered using a 142 ataxia gene panel in the proband and confirmed by Sanger sequencing in the proband and the parents.

Results: Symptom onset was at age 25, with speech, gait and balance disturbance. She had a previous history of depressions treated with lithium. She was first diagnosed with lithium-induced cerebellar degeneration. However, she never experienced a lithium intoxication and her symptoms progressed even after stopping lithium. When she presented in 1997 there were no parkinsonian signs, oculomotor apraxia or associated neuropathy. She later developed an additional pyramidal syndrome. At the age of 45 she could not walk unaided. Cerebellar ataxia was evident, as well as cerebellar dysarthria. Her smooth pursuit was saccadic, her saccades were dysmetric and there was a downbeat nystagmus.There was no family history. The brain MRI showed marked cerebellar atrophy. The laboratory testing showed no abnormalities. Sequencing demonstrated 2 novel ANO10 mutations (the parents were heterozygous for one of the mutations). Both variants are absent in the ExAc database. She was thus diagnosed with SCAR 10 or ARCA 3.The two mutations occur in highly conserved sites within ANO10. The Exon 8: 1219-1G>T mutation is a splice site mutation and the Exon 7: C1170G: p.H390Q mutation substitutes a highly conserved amino acid at the cytosolic border of the 5th predicted transmembrane domain.

Conclusion: In our patient novel elements during the disease course led to the questioning of the original diagnosis of a lithium-induced cerebellar degeneration. Mutations in anoctamin-10 (ANO10), like in our patient, have emerged in recent years as an important cause of autosomal recessive spinocerebellar ataxias.Our findings demonstrate the power of next generation sequencing techniques. Recently an algorithm, RADIAL, has been developed to predict possible causative genes in autosomal recessive spinocerebellar ataxias. Interestingly, ANO10 was the first predicted gene in our patient when using this algorithm.

References: – Balreira et al. J Neurol 2014. ANO10 mutations cause ataxia and coenzyme Q10 deficiency. – Pyle et al. Brain 2015. Exome sequencing in undiagnosed inherited and sporadic ataxias. – Renaud et al. Ann Neurol 2017. A recessive ataxia diagnosis algorithm for the next generation sequencing era.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/two-novel-ano10-mutations-causing-adult-onset-autosomal-recessive-spinocerebellar-ataxia/