Spaull, Robert; (2025) Precision therapies for rare childhood neurogenetic movement disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Genetic childhood movement disorders are a heterogeneous group of individually rare conditions that cause abnormal movements such as dystonia, chorea, myoclonus, tremor, and parkinsonism. Many also cause delayed development, epilepsy, and significant disability. Genetic aetiologies are broad, with most delineated conditions caused by variants in single genes with dominant or recessive inheritance. Commonly these may cause neurotransmitter defects or impact on neuronal development and excitability. Despite understanding the genetic, and often the biochemical, basis underlying these conditions, there are very few precision therapies or disease-modifying treatments available. Three such disorders considered in detail in this thesis are the neuronal ceroid lipofuscinosis CLN2-Batten disease, the neurotransmitter disorder aromatic L-amino acid decarboxylase deficiency (AADC deficiency), and pantothenate kinase-associated neurodegeneration (PKAN) which causes neurodegeneration with brain iron accumulation. I describe work to understand several aspects of precision therapies in these rare disorders. First, I delineate the progression of movement disorders in a cohort of children with CLN2-Batten disease receiving enzyme replacement therapy, describing a stereotypic phenotypic progression despite targeted therapy. Next, I describe the adverse events, biomarker changes and neurodevelopmental outcomes in the UK cohort of children with AADC deficiency who have received brain-targeted gene therapy. Several chapters describe work to develop and implement a clinical trial for PKAN focussing on understanding and tracking disease progression in our cohort, assessing and validating clinical outcome measures, developing novel ophthalmological outcome measures, and finally statistical work underpinning the UK clinical trial. This thesis describes clinical research at different stages to advance precision therapies of different modalities for three childhood neurogenetic movement disorders. It emphasises the importance of selecting and validating outcome measures, how to design clinical trials for a rare disorder, and that ongoing assessment following implementation is essential in these conditions.

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