Functional genetics of rare neurological disorders

The study of rare Mendelian disorders is able to provide unique insights into neurological disorders that may seem unrelated. This thesis reports mechanistic investigations of five neurological disorders presenting with progressive or episodic neurological symptoms. First, riboflavin transporter neuronopathy represents a phenotypic spectrum of motor, sensory and cranial nerve neuropathy, often with respiratory problems. Our main findings implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects and validate riboflavin esters as a potential therapeutic strategy. Second, novel sequence variants in the SBF1 gene are described as potential mutations in patients with severe axonal neuropathy and bulbar features. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy in addition to demyelinating Charcot-Marie-Tooth disease. Third, novel frameshift mutations in SPG11, investigated using mRNA, are described in patients with complex hereditary spastic paraplegia (HSP) consistent with SPG11. The findings that mutations in SPG11 are the cause of a spectrum of clinical features including the late manifestation of severe axonal neuropathy are extended. Fourth, a family with HSP carrying a de novo mutation in KCNA2 is described. Our results using two-electrode voltage clamp recordings confirm that the mutation is pathogenic, exerting a loss-of-function effect. The discovery of KCNA2 mutations in epilepsy, ataxia, and HSP extends the phenotypes that can be associated with this gene. Finally, a novel KCNA1 mutation associated with episodic ataxia and a possible link with malignant hyperthermia is reported. Our work broadens the phenotypes associated with KCNA1 mutations to include possible susceptibility to malignant hyperthermia, and shows the potential of using induced pluripotent stem cell derived neurons to determine the neuronal consequences of the Kv1.1 mutation. The diverse methods used in this thesis advance the understanding, and potential treatment, of a group of neurological disorders caused by single gene defects