Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1
- Susan Elizabeth Tomlinson1,2,3,4,
- Sanjeev Rajakulendran1,2,
- Stella Veronica Tan1,2,
- Tracey Dawn Graves1,2,
- Doris-Eva Bamiou1,
- Robyn W Labrum1,2,
- David Burke3,
- Carolyn M Sue5,
- Paola Giunti1,2,
- Stephanie Schorge2,
- Dimitri M Kullmann1,2,
- Michael G Hanna1,2
- 1MRC Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, London, UK
- 2Institute of Neurology, University College London, London, UK
- 3Institute of Clinical Neuroscience, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia
- 4Department of Neurology, St Vincent's Hospital, Sydney, New South Wales, Australia
- 5Department of Neurology, Royal North Shore Hospital and Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
- Correspondence to Professor Dimitri M Kullmann, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;
- Received 24 October 2012
- Revised 18 December 2012
- Accepted 27 December 2012
- Published Online First 24 January 2013
Background and objective Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations.
Methods 15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry.
Results Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of Kv1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia.
Conclusions The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of Kv1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between Kv1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.