Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1
| Autor: | David Burke, Carolyn M. Sue, Michael G. Hanna, Dimitri M. Kullmann, Paola Giunti, Sanjeev Rajakulendran, Tracey D. Graves, Robyn Labrum, Stella Veronica Tan, Susan E. Tomlinson, Doris-Eva Bamiou, Stephanie Schorge |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Neuromyotonia DNA Mutational Analysis Genetic Carrier Screening medicine.disease_cause Neurophysiol Clinical Disability Evaluation 0302 clinical medicine Cerebellum Neurogenetics Cell Line Transformed Motor Neurons Genetics 0303 health sciences Mutation Movement Disorders Pedigree 3. Good health Psychiatry and Mental health Phenotype Neuromuscular Female medicine.symptom Ataxia Cerebellar Ataxia Adolescent In Vitro Techniques Biology Transfection 03 medical and health sciences medicine Humans Myokymia 030304 developmental biology Episodic ataxia Kv1.1 Potassium Channel Epilepsy Chromosomes Human Pair 12 Cerebellar ataxia Electromyography Sequence Analysis DNA medicine.disease Shaker Superfamily of Potassium Channels Surgery Isaacs Syndrome Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neurology, Neurosurgery, and Psychiatry |
| ISSN: | 1468-330X 0022-3050 |
| Popis: | 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 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 . |
| Databáze: | OpenAIRE |
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