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Gail Maconachie, Mervyn George Thomas, Cris Constantinescu, Viral Sheth, Rebecca McLean, Irene Gottlob; Genetic screening using next generation sequencing in an atypical presentation of episodic ataxia with dominant inheritance.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5983.
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© ARVO (1962-2015); The Authors (2016-present)
Episodic ataxia (EA) is typically characterised by intermittent periods of ataxia and abnormal visual problems of variable expression. We aim to characterise the phenotypic spectrum and explore the genetic basis, using next generation sequencing (NGS), of familial EA which presented with episodic diplopia, ataxia and environmental triggers similar to those reported by other EA types.
Three affected brothers, with onset within the third decade, their affected mother, the unaffected father and 4 offspring were recruited. All affected subjects and their offspring underwent a full ophthalmology and neurological assessment including eye movement recordings (EMR) and MRI. Genetic analysis was undertaken using NGS, screening for candidate loci known to be associated with EA. Affected subjects were prescribed a trial of both acetazolamide and 4-aminopyridine to help with symptoms.
The primary presentation of all 3 brothers was vertical diplopia of variable severity and duration, which reversed throughout the day. The mother reported diplopia when she was younger although resolved during pregnancy. All affected subjects and offspring were noted to have abnormal vertical saccades, smooth pursuit and fixation. Two subjects had endpoint nystagmus and one subject reported migraines. All MRI scans were normal. The eldest brother had dysarthria and ataxia prior to starting treatment. NGS excluded all previously reported EA genes including KCNA1, CACNA1A, CACNB4 and SLC1A3 genes suggesting a potential novel gene within this family. Acetazolamide did not subjectively improve symptoms, however, 4-aminopyridine was found to subjectively reduce the frequency of symptoms in the most severely affected subjects.
We report a dominant inheritance of an atypical episodic ataxia which may harbour a potential novel gene. We show this EA type responds well to 4-aminopyridine which suggests that this could be an inherited channelopathy. This finding may help narrow the selection for possible causative gene mutations.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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