Risk factors for motor neuron diseases : genes, environment and lifestyle

Abstract

The main focus of this thesis is to identify susceptibility factors in diseases affecting the motor neuron: both motor neuron disease (MND), in which primarily the cell body is affected, and multifocal motor neuropathy (MMN), in which primarily the axon is affected, are covered. Due to its relentless course the most notorious of this spectrum of disorders is amyotrophic lateral sclerosis (ALS), in which both the lower and upper motor neurons are affected causing progressive muscle weakness. The course of the disease is heterogeneous and varies from patient to patient. As ALS cannot be cured, mean disease duration is 3 years when progressive weakness of the respiratory muscles ultimately leads to death of the patient. ALS does occur in families, but the majority concerns a sporadic form. Sporadic ALS is considered a multifactorial disease in which environmental factors in a genetically susceptible host cause motor neuron degeneration. Both the purely lower motor neuron (LMN) and the upper motor neuron (UMN) variants are heterogeneous, although disease progression is generally slower. These variants may represent the same disease entity and the heterogeneity can be used to identify risk factors. MMN is characterized by the presence of progressive, asymmetric, predominantly distal, atrophy and weakness. Its clinical features can mimic MND. Treatment with intravenously applied immunoglobulin improves muscle strength. A multifactorial etiology is implied with a large role for immune-mediated mechanisms which cause demyelinisation of motor nerves. The aim of this thesis was to identify genetic, environmental and lifestyle factors which increase susceptibility to MND and MMN. Proposed disease mechanisms covered in this thesis are oxidative stress, vascularisation, immune-mediated mechanisms and hypermetabolism. Several candidate gene studies were studied. A positive association between ALS and HFE H63D seems to be population-wide, but the association with VEGF could not be consistently detected in different populations. Studies on occupational risk factors and exposure to chemical agents and metals could not show strong evidence in favor of a specific risk factor for ALS and emphasizes the need for future well-designed studies. Based on findings from this thesis as well as newly published studies, smoking seems a consistently associated risk factor for ALS. In contrary to our hypothesis, vascular risk factors did not increase ALS risk. On the other hand, low lipid status seemed to be associated with increased risk for ALS. HLA-DRB1*15 was associated with MMN; monoclonal immunoglobulin was associated with MMN and slowly progressive muscular atrophy, but not the other forms of MND. These findings suggest a possible role for oxidative stress and hypermetabolism in ALS pathogenesis and immune-mediated mechanisms to play a role in MMN, but also some variants of MND. Future studies are needed to elucidate these findings and suggestions are made for study design.