Laboratory Study
Eye advance online publication 30 January 2009; doi: 10.1038/eye.2008.389
Infantile nystagmus and late onset ataxia associated with a CACNA1A mutation in the intracellular loop between s4 and s5 of domain 3
J Self1,2, C Mercer3, E M J Boon4, M Murugavel1, F Shawkat1, S Hammans5, P Hodgkins1, H Griffiths2 and A Lotery1,2
- 1Southampton Eye Unit, Southampton General Hospital, Southampton, UK
- 2Division of Clinical Neurosciences, Southampton University, UK
- 3Wessex Clinical Genetics Service, Southampton General Hospital, Southampton, UK
- 4Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, Holland
- 5Wessex Neurological Centre, Southampton General Hospital, Southampton, UK
Correspondence: A Lotery, Division of Clinical Neurosciences, Mail point 806, South Lab and Path Block, Southampton General Hospital, Southampton SO16 6YD, UK. Tel: +023 8079 5049; Fax: +023 8079 4542; E-mail: a.j.lotery@southampton.ac.uk
Received 18 August 2008; Revised 18 November 2008; Accepted 18 November 2008; Published online 30 January 2009.
Abstract
Purpose
Mutations in the 1A-subunit of the brain P|[sol]|Q-type calcium channel gene CACNA1Aare responsible for spinocerebellar ataxia type 6 (SCA6), familial haemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). Considerable clinical and genetic overlap exists between these 3 allelic disorders. Clinical findings are varied and may include nystagmus.
Objective
To study the clinical phenotype and identify a causative mutation in a family who presented when the youngest member was diagnosed with apparent isolated congenital nystagmus (age 3 months).
Patients and Methods
8 patients from one family underwent detailed clinical phenotyping comprising; ophthalmic and neurological examination, nystagmology, electrodiagnostic tests and brain imaging. The CACNA1Agene was screened for mutations by direct sequencing in one patient. Co-segregation of the disease and an identified sequence variation was shown using direct sequencing.
Results
Phenotyping revealed isolated atypical nystagmus in 4 family members and nystagmus in addition to late onset ataxia in 1 family member. Direct sequencing of the CACNA1Agene identified a novel missense mutation; (c.4110T>G p.Phe1370Leu (NM_000068.3)).
Conclusions
We have shown that a mutation in the intracellular domain between s4 and s5 of repeat 3 can cause atypical nystagmus|[sol]|cerebellar phenotypes, including isolated nystagmus in an infant. We also illustrate the necessity for detailed examination of relatives in cases of apparent isolated congenital nystagmus.
Keywords:
nystagmus, CACNA1A, ataxia, gene, mutation, infantile
