Multifocal motor neuropathy and progressive atrophy: Pathophysiological similarities and differences

Progressive muscular atrophy (PMA) and multifocal motor neuropathy (MMN) share many clinical similarities. They are both characterized by progressive asymmetric muscle weakness with atrophy and fasciculations. Tendon reflexes are normally low or absent, although in some patients with MMN normal or even brisk reflexes in weakened muscles have been reported,1 making the clinical differentiation between PMA and MMN, but also early stages of amyotrophic lateral sclerosis (ALS), even harder. Most patients with PMA experience generalized weakness and develop respiratory failure as is seen in patients with ALS.2 A subset of PMA patients, however, have a slowly progressive disease course or segmental distribution of weakness in which symptoms remain limited to one limb,3,4 resembling the clinical phenotype of MMN. Although MMN and PMA are clinically much alike, the pathogenesis of both disorders is thought to be totally different. MMN on one hand belonging to the group of immune-mediated disorders of the peripheral nervous system such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP) and polyneuropathy associated with IgM monoclonal gammopathy. PMA on the other hand is considered a neurodegenerative disorder and part of the spectrum of motor neuron disorders, including ALS and primary lateral sclerosis (PLS), in which genetic vulnerability plays an important role. At the start of this research project, little was known about the contribution of inflammation to PMA pathogenesis and only few studies had addressed genetic heterogeneity in both PMA and MMN. Therefore, the main aim of this thesis was to investigate the contribution of genetic and inflammatory mechanisms in the pathogenesis of MMN and PMA, and to identify to what extent these pathophysiological processes overlap and differ between these two disorders and with ALS.