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Title: A clinical and genetic study of ion channel disorders in child neurology
Author: Zuberi, Sameer Mustafa
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2010
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Ion channels are macromolecular proteins in cell membranes that control the passage of charged particles including sodium, potassium and calcium ions in and out of cells. Rapid electrical signalling in the nervous system is mediated through the passage of ions through these channels. It is therefore not surprising that genetic mutations in the genes coding for these channels can result in neurological disease. Ion channel disorders or channelopathies have emerged in the last ten to fifteen years as an important new way of understanding neurological disease. Many of these conditions are paroxysmal in nature and include generalised and focal epilepsies, movement disorders and neuromuscular disorders. Some of these conditions follow simple Mendelian inheritance and are rare forms of common disorders such as epilepsy but they provide a useful model for more common neurological diseases with complex inheritance. Some conditions such as Dravet syndrome, a severe infantile onset epilepsy and sodium channelopathy produce devastating consequences for the affected child. In this thesis I will describe the clinical work I have undertaken defining phenotypes of this emerging group of disorders. Detailed phenotyping is the first essential step in characterising new aspects of these genetic disorders. I have collaborated closely with molecular geneticists and cell physiologists in units around the world exchanging ideas in order to better understand the mechanisms of disease and hopefully translate this into better care for patients. The main themes covered in the thesis are episodic ataxias type 1 and 2 (EA1 & 2), benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and Dravet syndrome and other SCN1A related epileptic encephalopathies. In the course of this work I have described novel relationships between EA1 and EA2 and epilepsy, described a novel gene and phenotypes associated with frontal lobe epilepsy, a novel presentation of a potassium channelopathy, a family with a new genetic mechanism for their neonatal convulsions and epilepsy, and children with a novel mechanism for Startle disease (hyperekplexia). I have demonstrated the clinical utility of this translational research by establishing a molecular genetic diagnostic service for sodium channel (SCN1A) related infantile epilepsies. A study of the results from this national UK service shows that genetic diagnosis allows early diagnosis of these epilepsies. This can result in earlier focused treatment, and the hope for better epilepsy control and developmental outcome. I discuss the implications of this work and ongoing and future research projects.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available