Davies, E.H.; (2011) Developing markers of neurological manifestations in Neuronopathic Gaucher Disease. Doctoral thesis , UCL (University College London).

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Abstract

Gaucher disease is a rare inherited lysosomal disorder caused by deficiency of the enzyme glucocerebrosidase. Classically, three forms of the disease are recognised: type I or nonneuronopathic, type 2 or acute neuronopathic, and type 3 or subacute or chronic neuronopathic. Neuronopathic Gaucher disease (NGD) is defined as a confirmed diagnosis of Gaucher disease in the presence of neurological symptoms and signs, for which there is no other cause. Horizontal gaze palsy is the clinical hallmark of NGD. Other neurological manifestations include seizures, cerebellar ataxia and pyramidal tract involvements. However, NGD is very heterogeneous and the neurological features vary greatly from patient to patient, not only in terms of manifestations involved but also in terms of severity. The emergence of enzyme replacement therapy has changed the ‘natural history’ of the disease, and patients are now living longer where previously they would have succumbed to the visceral complications of the disease. New emerging therapies are being developed for NGD, however a suitable surrogate marker to monitor neurological disease is lacking. In this study, three different assessment tools were explored to examine their value and sensitivity to assess neurological involvement in NGD. A Severity Scoring Tool developed specifically for NGD was modified and validated to offer a robust assessment tool, with demonstrated sensitivity to track disease progression and distinguish between phenotypes. Additional assessments utilised were gait analysis and diffusion tensor imaging, both of which were sensitive enough to distinguish between the NGD and Type I cohort studied. This is the largest cohort of NGD patients (recruited across three European countries) to be studied prospectively and systematically. It is also the first study to describe the gait pattern of NGD children, and to provide an in-vivo insight of the Gaucher brain utilising diffusion tensor imaging.

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