Phenotyping paroxysmal conditions to empower genetic research

Thomas, Rhys Huw ORCID: https://orcid.org/0000-0003-2062-8623 2012. Phenotyping paroxysmal conditions to empower genetic research. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

I describe the process of preparing cohorts of individuals with two paediatric onset paroxysmal disorders – hyperekplexia and juvenile myoclonic epilepsy – for second generation sequencing. This involves: i) listening to the individual; ii) identifying subgroups; iii) using non-­‐core features to create subgroups; iv) and assessing the importance of copy number variation. Using focus groups and an interpretative phenomenological approach clinicians and people with epilepsy produced 398 questions focused on epilepsy treatment. The most important themes for the professionals were – teatment pogrammes or non-­‐epileptic attack disorder and concerns about side effectsinutero.For patients cognitive drug side effects and managing the consequences of drug side effects were most important. Studying ninety-­‐seven individuals with hyperekplexia confirmed that all gene-­‐positive cases present in the neonatal period and that clonazepam is the treatment of choice (95% found it efficacious). Patients with SLC6A5 and GLRB mutations were more likely to have developmental delay (RR1.5 p<0.01; RR1.9 p<0.03) than those with GLRA1 mutations; 92% of GLRB cases reported a mild to severe delay in speech acquisition. Juvenile myoclonic epilepsy is challenging to subdivide based on seizure and EEG features. The neuropsychological profile of limited number of patients 39) as examined in great detail including tests Q WAIS), emory TYM,WMS),executive function (BADS, DKEFS), affect (HADS). TYM was as sensitive as a full WMS for identifying cognitive errors and the zoo map and key search tests were performed particularly poorly. Personality profiling (EPQ-­‐BV) identifies the cohort as having high levels of neurotic and introvert traits. Three atypical ‘hyperekplexia’ cases had alternative diagnoses suggested by copy number analysis. The juvenile myoclonic epilepsy patients had an 8% frequency of recognised pathogenic CNVs– but no recurrent variants were identified.A number of non-­‐epilepsy related findings were identified including a potentially preventable cause of SUDEP.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Date of First Compliant Deposit:	30 March 2016
Last Modified:	24 Oct 2022 10:33
URI:	https://orca.cardiff.ac.uk/id/eprint/44849

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