Pandraud, A; (2014) A Genetic and Functional Investigation of Inherited Neuropathies: Charcot-Marie Tooth Disease and Brown-Vialetto-Van Laere Syndrome. Doctoral thesis , UCL (University College London).

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Abstract

Charcot-Marie-Tooth (CMT) disease and Brown-Vialetto-Van Laere syndrome (BVVL) are two inherited neuropathies. Although most CMT type 1A patients carry the same sized duplication containing the peripheral myelin protein 22 (PMP22) gene, they present with a wide range of severities both within and between families. Some CMT1A patients exhibit chronic inflammatory demyelinating polyneuropathy (CIDP)-like features. An association study was performed in a CMT1A and a CIDP cohort to identify the genetic factors modifying the CMT1A phenotype. Variants associated with CIDP and/or with autoimmune/inflammatory diseases were determined to be unlikely to modulate disease severity in CMT1A, or to contribute to CMT1A pathogenesis. A susceptibility locus for CIDP was identified in the PXK gene. CMT1 genes were screened in CMT1 patients from the UK, Greece and Russia, thereby establishing mutation frequencies and expanding phenotype-genotype correlations. Some cases of CMT1 remain without a genetic diagnosis; two potential CMT1 candidate genes were identified by exome sequencing in two families. The genetic causes of selected canine neuropathies were investigated and several CMT genes were ruled out. BVVL is a rare, recessive motor neurone disease (MND) with early onset; a severe sensory-motor neuropathy is part of the phenotype. Mutations have been found in genes encoding riboflavin transporters, leading to flavin deficiency. To characterise the disease and facilitate early access to therapy, the riboflavin transporter genes were screened in patients with BVVL-like phenotypes; SLC52A2 mutations were most common. A candidate gene for complex axonal neuropathy resembling BVVL was uncovered by exome sequencing. Riboflavin and its active metabolites play a role in energy metabolism. Three cell models were used to investigate BVVL in vitro: patient fibroblasts, as well as a neuroblastoma cell line and mouse motor neurones in which one of the riboflavin transporters was knocked down. Mitochondrial dysfunction was suggested as a potential pathway leading to neuronal damage in BVVL.

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