Cerebellum (2009) 8:448–453 DOI 10.1007/s12311-009-0130-8 Aberrant Splicing of the Senataxin Gene in a Patient with Ataxia with Oculomotor Apraxia Type 2 Brent L. Fogel & Ji Yong Lee & Susan Perlman Published online: 2 September 2009 # The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Ataxia with oculomotor apraxia type 2 (AOA2) is caused by a diversity of mutations within the coding region of the senataxin gene. Recently, rare noncoding senataxin mutations affecting RNA processing have been identified in AOA2. Here, we report the case of an 18-year-old woman, with classic clinical features of AOA2, who was found to harbor a mutation within senataxin intron 16. This mutation disrupts the local 5′ splice site architecture via a novel intronic frameshift mechanism, causing skipping of exon 16 with predicted disruption of the conserved DNA/RNA helicase domain. RNA processing mutations expand the growing complexity of pathogenic senataxin mutations. Keywords AOA2 . Ataxia . Helicase . RNA splicing . Senataxin Introduction Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive hereditary ataxia caused by mutation of the senataxin gene (SETX) on chromosome 9q34 [1–4]. The disease is characterized primarily by vermian cerebellar atrophy with prominent gait ataxia, a peripheral sensorimotor neuropathy, areflexia, and elevated levels of α-fetoprotein [1–3, 5–7]. Eye findings commonly include saccadic ocular pursuit with nystagmus; however, despite the name, oculo- motor apraxia is not found in many patients [1–3, 5–7]. B. L. Fogel (*) : J. Y. Lee : S. Perlman Department of Neurology, UCLA Program in Neurogenetics, David Geffen School of Medicine, University of California at Los Angeles (UCLA), 710 Westwood Plaza, Los Angeles, CA 90095, USA e-mail: bfogel@ucla.edu AOA2 is thought to be one of the most common autosomal recessive ataxias after Friedreich’s ataxia [2, 4, 7]. The clinical phenotype associated with SETX mutations also has an interesting, although rare, variability. Notably, an autoso- mal dominant phenotype of juvenile-onset amyotrophic lateral sclerosis (ALS4) has been associated with mutations in this gene distinct from those which cause AOA2 [8–10]. The senataxin gene is quite polymorphic, and a variety of homozygous and compound heterozygous coding muta- tions have been reported which cause AOA2 including missense [1, 3, 5–7, 9, 11, 12], nonsense [1, 3, 6, 7, 13], frameshift [1, 3, 5–7, 12, 14–16], gene rearrangement [5], deletion [7] or duplication [14]. One coding mutation at the terminus of exon 15 has also been reported to disrupt RNA splicing [16]. In contrast to these many coding mutations, only two pathogenic noncoding mutations have been reported which result in AOA2 [5, 7, 17]. Here, we report a patient from a large consanguineous family who was found to possess a novel homozygous mutation in intron 16 which results in aberrant splicing of the SETX pre-mRNA and clinical AOA2. Case Report The patient is an 18-year-old woman who presented with complaints of imbalance, falls, and difficulty walking. Onset was at age 14, and course was slowly progressive. Past medical history included polycystic ovarian syndrome diagnosed at age 16. Neurological examination was notable for a mild appendicular and gait ataxia, slowing of vertical saccades, and a mild dysarthria. Deep tendon reflexes were absent, and there was reduced sensation in the feet to pinprick, temperature, and vibration, which was most severely impaired. There was no oculomotor apraxia.