Episodic ataxia in a child with senataxin mutation
S Sesh, Ashalatha Radhakrishnan
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
Date of Web Publication
15-May-2018
Correspondence Address: Dr. Ashalatha Radhakrishnan Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695 011, Kerala India
Source of Support: None, Conflict of Interest: None
Episodic ataxias (EA) are a heterogeneous group of neurological disorders characterized by discrete episodes of incoordination and imbalance, lasting for minutes to hours.[1] Interictally, these patients can have vertigo, myokymia, migraine in various combinations, and they are often associated with a progressive ataxic syndrome.[2] Episodic ataxia in a patient with senataxin gene mutation has hitherto not been described. We describe a 4-year old boy, presenting with the classic features of EA, who on evaluation, was detected to be having senataxin gene mutation, which has previously not been described with EA.
A 4-year old boy, born of non-consanguineous parentage, with normal birth and developmental milestones, presented with a 1-year history of intermittent episodes of gait ataxia, with each episode lasting for 20–30 minutes, and the child becoming completely normal after each episode. During the ictus, the child could barely walk with two-persons' support [Video 1]. After the episode subsided, the child became normal [Video 2]. There was no history of upper limb incoordination, slurred speech, cranial nerve symptoms, weakness or stiffness of limbs, sensory symptoms, seizures, or cognitive impairment. There were no precipitating factors and no family history of ataxia. He was of normal intelligence. The child had 4-5 such episodes in a year. On examination, there was no conjunctival telangiectasia or any neurocutaneous markers. Saccades were normal and there was no nystagmus. Rest of the neurologic examination was normal except for the presence of mild impairment in tandem walking intermittently. The clinical history was suggestive of EA. The odd features were absence of family history (EA being autosomal dominant), interictal myokymia, migraine, or vertigo.
Investigations revealed a normal magnetic resonance imaging (MRI) of the brain including his craniovertebral junction. His cerebrospinal flow (CSF) study was normal. Routine blood investigations, thyroid functions, and nerve conduction studies were normal. Electroencephalography (EEG) showed bilateral independent temporo-parieto-occipital spike and wave discharges.
Considering the clinical picture of EA, genetic testing (next generation clinical exome sequencing) was done. The test was positive for senataxin (SETX) gene mutation. Genetic testing did not reveal any of the common mutations that may cause EA such as the KCNA1, CACNA1A, CACNB4, andSLC1A3 gene mutations that cause EA1, 2, 5, and 6, respectively.[2] A heterozygous three-base pair deletion in exon 10 of the SETX gene (chr9:135203911_135203913delTCA; Depth: 186x) that results in an in-frame deletion of amino acid, aspartic acid, at codon 1024 (p. Asp1024del; ENST00000224140) was detected.
Till date, based on the clinical phenotype, eight different types of EA have been described.[1] However, only five different genes have been attributed to EA, and all of them have autosomal dominant inheritance.[1] Mutations in KCNA1 (EA1) and CACNA1A (EA2) account for most EA cases worldwide [Table 1].[2]
Table 1: Clinical features of common episodic ataxia syndromes
SETX gene mutations [Table 2] are associated with two distinct clinical syndromes: (OMIM: 608465)– one is spinocerebellar ataxia, autosomal recessive-1, also referred to as ataxia oculomotor apraxia type 2 (AOA2); and, the other one is juvenile amyotrophic lateral sclerosis 4 (ALS4).[3],[4],[5] The clinical manifestations of AOA2 include an onset between the age of 10 and 22 years, progressive cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, cerebellar atrophy seen on MRI, and elevated serum alpha-fetoprotein (AFP) levels.[6] ALS4 (juvenile-onset motor neuron disease with dominant inheritance) is characterized by the mean age of onset at 17 years, slowly progressive distal amyotrophy, pyramidal signs, normal sensory examination, and lack of bulbar involvement.[7]
Table 2: Literature review on SETX mutation and its clinical correlation
SETX gene mutation, presenting phenotypically with discrete episodes of ataxia alone, with completely normal neurological status in between is previously unreported. In our patient, we postulate that the heterozygosity of the gene might be one of the factors which was preventing the complete manifestation of the disease. This finding adds to the spectrum of phenotypic manifestation of SETX gene mutation. His parents and siblings could not be screened for the same mutation due to financial constraints.
The patient needs to be followed up to look for progression of ataxic symptoms and development of new neurological deficits. We could pick up the mutation only because whole clinical exome sequencing was done with next generation sequencing (NGS). If we had tested only for known mutations for EA, SETX gene mutation would have been missed, which highlights the importance of whole exome sequencing to detect novel mutations.[1] Moreover, it is a well-established fact that many of the degenerative spinocerebellar ataxias are related to EA. EA 2 is mostly associated with SCA-6, both of which occur due to mutations in CACNA1A gene in chromosome 19.[8] Phenotypic presentation of both entities varies, but has several common features. As a single genetic mutation can have phenotypic variability causing multiple clinical presentations, instead of performing single genetic testing for the particular disease, whole clinical exome sequencing by NGS of the commonly related diseases will be more yielding.[16]
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Criscuolo C, Chessa L, Di Giandomenico S, Mancini P. Ataxia with oculomotor apraxia type 2: A clinical, pathologic, and genetic study. Neurology 2006;66:1207-10.
Mantuano E, Veneziano L, Jodice C, Frontali M. Spinocerebellar ataxia type 6 and episodic ataxia type 2: Differences and similarities between two allelic disorders. Cytogenet Genome Res 2003;100:147-53. [PUBMED]
Moreira MC, Klur S, Watanabe M, Németh AH, Le Ber I, Moniz JC, et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nature Genet 2004;36:225-7.
Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004;74:1128-35. [PUBMED]
Duquette A, Roddier K, McNabb-Baltar J, Gosselin I, St-Denis A, Dicaire MJ, et al. Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy. Ann Neurol 2005;57:408-14. [PUBMED]
Anheim M, Fleury MC, Franques J, Moreira MC, Delaunoy JP, Stoppa-Lyonnet D, et al. Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families. Arch Neurol 2008;65:958-62. [PUBMED]
Airoldi G, Guidarelli A, Cantoni O, Panzeri C, Vantaggiato C, BonatoS, et al. Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin. Neurogenetics 2010;11:91-100.
Nanetti L, Cavalieri S, Pensato V, Erbetta A, Pareyson D, Panzeri M, 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. [PUBMED]
