Clinical and genetic characterisation of hereditary motor neuropathies

Abstract

Inherited peripheral neuropathies or Charcot-Marie-Tooth disease (CMT) are common neuromuscular conditions, characterised by distal motor atrophy and weakness with variable range of sensory impairment and classified according to demyelinating (CMT1) or axonal (CMT2) pathology. The number of genes causing CMT has rapidly increased due to improved genetic testing technology, even though gene identification has remained challenging in some subgroups of CMT. Hereditary motor neuropathies (HMN) encompass heterogeneous groups of disorders caused by motor axon and neuron pathology. The distal hereditary motor neuropathies (dHMN) are rare length-dependent conditions, which show significant clinical and genetic overlap with motor neuron diseases. Several (>30) causative genes have been identified for ~20% of dHMN patients, which predicts extreme genetic heterogeneity in this group. My study was designed to investigate the prevalence, clinical presentation, molecular cause and phenotype-genotype correlations of hereditary motor neuropathies in a large cohort of patients. I aimed to identify novel disease genes and reassessed mutation detection rate in dHMN. Furthermore, I studied common pathomechanisms and targets for therapy approaches in hereditary motor neuropathies. Detailed neurological and electrophysiological assessments and next generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor CMT2, 16 patients) or complex neurological disease predominantly affecting the motor nerves (dHMN plus, 25 patients). I calculated the dHMN prevalence 2.14 affected individuals per 100.000 inhabitants (95% CI: 1.62-2.66) in the North of England. Causative mutations were identified in overall 47.9% in the motor neuropathy patient cohort. In the dHMN group the diagnostic rate was 42.5%, significantly higher than the previously reported 20%. The significant increase in the mutation detection rate could be attributed to the development of next generation techniques. Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms. I examined the phenotypic variability and the correlations with the identified genetic background. We described the novel phenotype of non-progressive motor neuropathy with fatigable weakness due to presynaptic neuromuscular transmission defect caused by synaptotagmin 2 mutations. I indentified further novel genes involved in intracellular signal transduction and ii transcriptional regulatory cascades, which might indicate common pathways and highlight further targets in the therapy of motor neuropathies. We detected a potentially treatable defect of neuromuscular transmission in some genetic forms, which raise the possibility that neuromuscular junction defects can cause or accompany motor neuropathy. The preliminary results suggested the potential treatability of the neuromuscular transmission defect, although long term effects will still need to be evaluated. In summary, detailed clinical characterisation and segregation analysis improved the detection rate in our cohort and highlighted that clinical expertise are still essential in confirming the diagnosis of inherited motor neuropathies. Increasing knowledge on disease pathways will not only help to identify new genes with shared pathomechanisms but will provide a basis for novel therapy approaches.