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Infantile Nystagmus and Late Onset Ataxia Associated with a CACNA1A Mutation in the Intracellular Loop Between S4 and S5 of Doma

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Infantile Nystagmus and Late Onset Ataxia Associated with a CACNA1A Mutation in the Intracellular Loop Between S4 and S5 of Doma Eye (2009) 23, 2251–2255 & 2009 Macmillan Publishers Limited All rights reserved 0950-222X/09 $32.00 www.nature.com/eye 1,2 3 4 1 Infantile nystagmus J Self , C Mercer , EMJ Boon , M Murugavel , LABORATORY STUDY F Shawkat1, S Hammans5, P Hodgkins1, H Griffiths2 and late onset ataxia and A Lotery1,2 associated with a CACNA1A mutation in the intracellular loop between s4 and s5 of domain 3 Abstract in cases of apparent isolated congenital nystagmus. 1 Purpose Mutations in the 1A-subunit of the Eye (2009) 23, 2251–2255; doi:10.1038/eye.2008.389; Southampton Eye Unit, Southampton General brain P/Q-type calcium channel gene published online 30 January 2009 CACNA1A are responsible for spinocerebellar Hospital, Southampton, UK ataxia type 6 (SCA6), familial haemiplegic Keywords: nystagmus; CACNA1A; ataxia; gene; migraine (FHM) and episodic ataxia type 2 mutation; infantile 2Division of Clinical (EA2). Considerable clinical and genetic Neurosciences, overlap exists between these 3 allelic Southampton University, UK Introduction disorders. Clinical findings are varied and may 3 include nystagmus. Nystagmus before six months of age can be Wessex Clinical Genetics Objective To study the clinical phenotype defined as early onset nystagmus.1 It may be Service, Southampton General Hospital, and identify a causative mutation in a family divided into three categories: sensory defect Southampton, UK who presented when the youngest member nystagmus (SDN), congenital idiopathic was diagnosed with apparent isolated nystagmus (CIN) and neurological nystagmus 4Centre for Human and congenital nystagmus (age 3 months). (NN), which is associated with neurological Clinical Genetics, Leiden Patients and Methods 8 patients from one disease.1 University Medical Centre, family underwent detailed clinical Nystagmus can be a clinical feature in three Leiden, Holland phenotyping comprising; ophthalmic and allelic disorders namely spinocerebellar ataxia 5Wessex Neurological neurological examination, nystagmology, type 6 (SCA6, MIM 183086), familial haemiplegic Centre, Southampton electrodiagnostic tests and brain imaging. The migraine (FHM, MIM 141500) and episodic General Hospital, CACNA1A gene was screened for mutations by ataxia type 2 (EA2, MIM 108500). SCA6 is Southampton, UK direct sequencing in one patient. characterised by adult-onset, slowly progressive Co-segregation of the disease and an identified cerebellar ataxia, dysarthria, nystagmus, and Correspondence: A Lotery, sequence variation was shown using direct impaired sensations of vibration and Division of Clinical Neurosciences, Mail point sequencing. 2 proprioception. FHM is characterised by 806, Results Phenotyping revealed isolated migraine attacks preceded by symptoms, such as South Lab and Path Block, atypical nystagmus in 4 family members and unilateral limb paresis or paralysis, Southampton General nystagmus in addition to late onset ataxia in paraesthesias, dysphasia, and interictal Hospital, 1 family member. Direct sequencing of the cerebellar signs, which are reported in about 50% Southampton SO16 6YD, UK CACNA1A gene identified a novel missense 3 of patients. EA2 is characterised by a complex Tel: þ 023 8079 5049; mutation; (c.4110T4G p.Phe1370Leu and highly variable phenotype, widely Fax: þ 023 8079 4542; (NM_000068.3)). overlapping that of SCA6.4 The main features are E-mail: a.j.lotery@ Conclusions We have shown that a mutation episodes of vertigo or ataxia of variable southampton.ac.uk in the intracellular domain between s4 and s5 frequency and duration, a permanent cerebellar of repeat 3 can cause atypical nystagmus/ deficit of variable severity, and a cerebellar Received: 18 August 2008 Accepted in revised form: cerebellar phenotypes, including isolated atrophy typically starting from the anterior 18 November 2008 5 nystagmus in an infant. We also illustrate the portion of the vermis. Significant clinical Published online: necessity for detailed examination of relatives overlap exists between these three disorders.6 30 January 2009 Infantile nystagmus due to a novel CACNA1A gene mutation J Self et al 2252 I:1 I:2 I:3 II:1 (54 yrs) II:2 (57 yrs) III:1 (22 yrs) III:2 (31 yrs) III:3 (30 yrs) III:4 (33 yrs) IV:1 (3 months) IV:2 (7 yrs) IV:3 (6 yrs) IV:4 (1 yr) Affected female Unaffected male Unaffected female ? Unexamined male ? Unexamined female Diseased individual Figure 1 Cosegregation of a CACNA1A variation (c.4110T4G) in a pedigree with atypical hereditary nystagmus. A pedigree diagram is presented with subject IDs, age, and genotyping. Variant sequence shows a heterozygote peak at position 3, and wild-type sequence shows a single red peak corresponding to a thymine base. These disorders can all be caused by mutations in the completed, including LogMAR visual acuity, slit-lamp CACNA1A gene (OMIM 601011). CACNA1A codes for the ophthalmic examination, full orthoptic assessment, and Cav2.1 a-1A subunit of P/Q-type voltage gated Ca2þ clinical neurological examination. Subjects in whom channels (Ca(V)2.1) expressed in the brain, and nystagmus was found also had eye movement particularly in cerebellar Purkinje and granule cells, as recordings using a Skalar IRIS IR Light Eye Tracker well as in neuromuscular junctions.7,8 The protein has equipment (Cambridge Research Systems Ltd., Rochester four domains or repeats, each formed by six UK, www.crsltd.com) as previously described by us.11 transmembrane hydrophobic segments. Typically, point Subject IV:1 (infant) did not have eye movement mutations in this gene are responsible for EA2 and FHM recordings because of her age. Three patients also had (see Figure 3), whereas small expansions of a CAG repeat extensive electrophysiological examinations. The characterise SCA6. standardised electroretinograms (ERGs) of the Typically, nystagmus in these disorders comprises International Society for Clinical Electrophysiology of vertical jerk (downbeat, upbeat), gaze evoked, pendular, Vision (www.iscev.org) and visual-evoked potential periodic alternating, or rebound nystagmus.9,10 Smooth (VEP) recordings were recorded in three female subjects pursuit is typically saccadic, optokinetic nystagmus (III:1, II:1, and IV:1). Magnetic resonance brain scans were (OKN) absent or of low gain, and saccades may be performed and sagittal t1 and axial dual echo images dysmetric.9,10 Here, we present a family with a novel were obtained in individuals II:1 and IV:1. CACNA1A mutation with presentation as an isolated case of atypical CIN in an infant. Molecular genetic methods Genomic DNA was isolated from venous blood by Materials and methods standard techniques. The complete CACNA1A gene (exons 1–47) Clinical phenotyping methods (NM_000068.3) was screened in III:I by direct Eight individuals in a single pedigree (Figure 1) were sequencing. Cosegregation of a sequence variation in the interviewed, and detailed clinical examination was pedigree was performed by direct sequencing in all eight Eye Infantile nystagmus due to a novel CACNA1A gene mutation J Self et al 2253 O0055 LRVLRVLRPLKTIKRLPKLKAVFDCVVNSLKNVFNILIVYMLFMFIFAVVAVQLFKGKFF HUMAN P27884 LRVLRVLRPLKTIKRLPKLKAVFDCVVNSLKNVFNILIVYMLFMFIFAVVAVQLFKGKFF RABBIT P97445 LRVLRVLRPLKTIKRLPKLKAVFDCVVNSLKNVFNILIVYMLFMFIFAVVAVQLFKGKFF MOUSE Q5RHB1 LRVLRVLRPLKTIKRLPKLKAVFDCVVNSLKNVLNILIVYMLFMFIFAVVAVQLFKGRFF ZEBRAFISH P91645 LRVLRVLRPLKTIKRVPKLKAVFDCVVNSLKNVVNILIVYILFQFIFSVIGVQLFNGKFF FRUITFLY Figure 2 Conservation of the phenylalanine amino acid, which is altered by the CACNA1A c.4110T4G p.Phe1370Leu (NM_000068.3) variation. The phenylalanine amino acid (F) is surrounded by red box. Sequences are from the UNIPROT database (http:// beta.uniprot.org/). Extracellular space Membrane 1 2345 6 12345 6 12345 6 12345 6 Segment Domain 132 4 Cytoplasm number gln NH2 COOH Figure 3 Published mutations in of the CACNA1A gene within the Ca(V)2.1 protein product. Non-truncating (red dots) and truncating (orange dots) mutations in subjects with EA2 are presented with mutations from patients with FHM (green dots) and the c.4110T4G mutation identified in this work (red circle with yellow centre). family members. A total of 150 control subjects seen 2 years after the clinical phenotyping in this family were subsequently screened for this variation by (now age 32 years), and at that stage had developed a high-resolution melt (HRM) analysis on a Rotor-GeneTM mild cerebellar ataxia with no other clinical signs besides 6000 realtime thermocycler (Corbett Life Science Ltd., nystagmus. MR brain scanning in subject IV:1 identified Brisbane, Australia). Assays were performed according no anomalies and a normal cerebellum, although a scan to the manufacturer’s instructions and primer sequences of subject II:1, when she was 50 years old, had shown a are available on request. ‘borderline,’ small cerebellar vermis. VEP and ERG recordings were normal for all examined subjects. Detailed nystagmology revealed a similar pattern in all Results subjects with downbeat nystagmus in primary gaze, average nystagmus amplitude of 2.5 degrees and Clinical frequency of 2.5 beats/s, gaze-evoked nystagmus in Nystagmus was identified in five of the eight subjects other positions of gaze, low gain OKN, saccadic pursuit, examined (Figure 1). Subject; II:1, a 54-year-old female, and dysmetric saccades. Exceptions were: steady fixation also described a mild ataxia starting at the age of 35 years (IV:3) and left-beating nystagmus (III:3) in primary gaze. with slow progression thereafter. She had noticed Rebound nystagmus was only seen in III:1. All fluctuations in her ataxia
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