Objective: Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia due to SETX gene mutation characterized by progressive cerebellar atrophy,  neuropathy, oculomotor apraxia and elevated serum alpha-fetoprotein. Various mutations have been described, most of which are missense, nonsense and frameshift mutations. We report the clinical features and genetic testing of 3 siblings sharing a unique, large, homozygous deletion of exon 20 in the SETX gene.

Background: Ataxia with oculomotor apraxia 2 (AOA2) is the second most common autosomal recessive ataxia characterized by progressive cerebellar atrophy, neuropathy, oculomotor apraxia and elevated serum alpha-fetoprotein [1]. Mean age of onset is 10-14 with progressive onset of ataxia, dystonia, chorea and tremor [2]. Despite the syndrome’s name, oculomotor apraxia is absent in approximately 50% of patients with AOA2 [1]. AOA2 is associated with mutation in the gene coding for senataxin (SETX) located on chromosome 9q34. SETX plays an important role in RNA homeostasis and maintenance of genomic integrity [3,4]. Absence of senataxin in the neural progenitor cells is associated with oxidative stress and cell death [3,4, 5]. AOA2 has been associated with a variety of autosomal recessive mutations across the SETX gene resulting in loss of function of the gene [6].

Method: Three siblings born to non-consanguineous parents of Mexican descent were found to have SETX gene mutations. Deletion/duplication analysis revealed a novel homozygous 1.9kb in-frame deletion of chromosome 20 with breakpoints in introns 19 and 20 corresponding to a minimum deletion boundary via aCGH of chr9: 135,156,150-1356,158,050 (GRCh37/hg19) in Case 1 and a similar homozygous deletion encompassing exon 20 with genomic breakpoints at nucleotide positions g135,158,116 in exon 19 and g135,156, 150 in intron 20 in Cases 2 and 3.

Results: Clinical characteristics are outlined in Table 1.

Conclusion: A variety of mutations distributed throughout the SETX gene have been linked to AOA2. Most SETX deletions reported are small and considerably fewer span entire or multiple exons [1,7.8]. The 3 siblings described above exhibit a unique, large, in-frame homozygous deletion of exon 20, not previously described. The homozygosity of the deletion also suggests consanguinity that is unknown to the family. This case series highlights the phenotypic heterogeneity of the same genetic mutation in siblings.

References: 1. Anheim, M. et al. Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain 2009;132:2688-2698 2. Pearson, T.S., 2016. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes. Tremor Other Hyperkinet Mov (N Y) 2016;6:368. 3. Bennett, C.L., La Spada, A.R. Unwinding the role of senataxin in neurodegeneration. Discov Med. 2015;19, 127-136. 4. Moreira, M. et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 2004;36:225-227 (2004). 5. Chen, YZ., et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 1996;74:1128-1135 6. Fogel, B.L., et al. Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2. Hum Mol Genet. 2014;23: 4758-4769. 7. Criscuolo C. et al. Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology 2006;66(8):1207-1210 8. Nanetti, L. et al. SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha-fetoprotein. Orphanet J Rare Dis. 2013;8:123

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ataxia-without-oculomotor-apraxia-a-unique-setx-mutation-in-3-siblings/