Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1.
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 K(v)1.1 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 K(v)1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between K(v)1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.
MRC Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, London, UK.
Susan Elizabeth
SE
Tomlinson
Sanjeev
S
Rajakulendran
Stella Veronica
SV
Tan
Tracey Dawn
TD
Graves
Doris-Eva
DE
Bamiou
Robyn W
RW
Labrum
David
D
Burke
Carolyn M
CM
Sue
Paola
P
Giunti
Stephanie
S
Schorge
Dimitri M
DM
Kullmann
Michael G
MG
Hanna
D000293:Adolescent; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000503:physiopathology; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D004252:DNA Mutational Analysis; D004185:Disability Evaluation; D004576:Electromyography; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D066298:In Vitro Techniques; D020386:Isaacs Syndrome / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D051662:Kv1.1 Potassium Channel / Q000235:genetics*; D008297:Male; D009046:Motor Neurons / Q000502:physiology; D020385:Myokymia / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics / Q000502:physiology; D014162:Transfection
C496946:KCNA1 protein, human; D051637:Shaker Superfamily of Potassium Channels; D051662:Kv1.1 Potassium Channel
Cerebellar Ataxia; Epilepsy; Neurogenetics; Neuromuscular; Neurophysiol, Clinical