Idiopathic polyneuropathy : a pathogenetic study

Sammanfattning: Polyneuropathy (PNP) stands for dysfunction in the peripheral nerves. The classical clinical manifestations of PNP are distal, symmetric sensory symptoms, such as numbness and pain, as well as distal weakness in a sock- and glove pattern. For most patients with PNP, the progression rate is slow and the degree of impairment is limited. Despite that, health-related quality of life is negatively affected in patients with PNP regardless of etiology. Further, PNP has a negative impact on daily activities at home, leisure and work. Patients with PNP have an increased risk of falls and fall-related injuries due to disturbed balance and walking difficulties. Polyneuropathy is a common neurological disorder with a prevalence of 1.6%. The frequency increases with age and is about 6.5% among the population older than 60 years. The etiology of PNP varies from systemic disorders, infections, hereditary, inflammatory, toxic to vitamin deficiencies etc. The most common identifiable cause of PNP is diabetes mellitus. About 25% of the PNP remain idiopathic despite a thorough etiological investigation. This is particularly common for patients with small fiber neuropathy (SFN) and for patients with chronic idiopathic axonal polyneuropathy (CIAP). There is no pharmaceutical treatment to offer patients with idiopathic PNP, since there is no cure for diffusely dysfunctional peripheral axons. Therefore, there is a need to further explore possible pathogenesis of idiopathic PNP, to hopefully in the future being able to modulate the condition. There are several hypotheses for the pathogenesis of idiopathic PNP, such as underdiagnosed hereditary disorders, microangiopathy in the microvessels in the vasa nervorum, axondegenerative factors and disturbed mitochondrial dynamics in the peripheral nerves. This thesis is based on four studies with the overall aim to explore possible etiologies of idiopathic PNP by probing into idiopathic PNP from different angles. In Study I we aimed to explore the etiological causes of seemingly idiopathic SFN by applying a standardized focused investigation and to investigate if late-onset Fabry disease could be a cause of idiopathic SFN. Forty-five adults younger than 60 years with seemingly idiopathic pure or predominantly SFN underwent a standardized focused investigation and a potential etiology was identified in 12 patients, with the most frequent being impaired glucose tolerance (58.3%, 7 of 12 patients). The patients deemed to have a true idiopathic SFN were offered genetic screening of the α-Galactosidase A GLA gene (Fabry disease). Four patients declined. Genetic alterations of unknown clinical significance in GLA were detected in 6 of the 29 patients with idiopathic SFN, but this rate did not differ significantly from that in healthy controls (n=203). All patients with genetic alterations of unknown clinical significance had in the end normal biomarkers and clinical evaluation in selected cases showed no Fabry-specific manifestiations in other organs. Idiopathic SFN in young to middle-aged Swedish patients does not seem to be due to late-onset Fabry disease. Study II was a retrospective histopathological ultrastructural study in which we examined the presence of microangiopathy and autophagy-related structures in sural nerve biopsies of ten patients with CIAP, eleven controls with inflammatory neuropathy and ten normal controls without sensory polyneuropathy. No significant difference in endoneurial microangiopathic parameters in patients with CIAP compared to normal controls were identified. Hence, our results do not support the hypothesis that CIAP is primarily caused by a microangiopathic process in endoneurial microvessels in peripheral nerves. However, a significantly higher density of endoneurial autophagy-related structures, particularly in patients with CIAP but also in patients with inflammatory neuropathy, compared to normal controls was detected. The present study confirmed a previous study that the autophagic machinery is activated in human peripheral nerve. However, whether the alteration in the autophagy pathway is a consequence or a cause of the neuropathy is not clear. Study III was a register-based nation-wide nested case-control study in which we included 2659 patients with CIAP identified from the Swedish Patient Register during the period 2001-2010 and 13295 age- and sex-matched controls to assess the associations of mitochondrial disease (MD), vascular dementia (VD) and Alzheimer’s disease (AD) with the subsequent risk of CIAP. To reassure that our CIAP cases were truly idiopathic, all individuals with comorbid diseases known to be associated with PNP were excluded from the study base. Individuals with MD had a four-fold increased risk of subsequent CIAP, whereas individuals with VD and AD had a decreased risk (OR 0.17, 95% CI 0.04-0.69; OR 0.18, 95% CI 0.06-0.59). The lower risks of VD and AD before CIAP might be due surveillance bias, i.e. reduced investigation of disturbed balance and walking difficulties among patients with dementia. We also conducted a follow-up study of the cases and controls to assess the risk of MD, VD or AD among patients with CIAP, in comparison to individuals without CIAP. Patients with CIAP had a nine-fold increased risk of subsequent MD and a two-fold increased risk of VD, but no increased risk of AD, compared to individuals without CIAP. This results might indicate that microangiopathy in the PNS and CNS do co-exist. Study IV was a multicenter study in which we aimed to explore the value of genetic screening for Fabry disease and hereditary ATTR amyloidosis in patients with idiopathic SFN or mixed neuropathy in a clinical setting in the Nordic region. In total 172 patients were enrolled in the study at nine participating neurological departments from four different Nordic countries. Seventeen patients were excluded due to exclusion factors found out later in the screening process. Genetic sequencing of the TTR gene and GLA gene was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient did have an earlier described possible pathogenic variant, R118C, in the GLA gene, but the clinical investigation showed no firm signs of Fabry disease. In conclusion, screening for hereditary ATTR amyloidosis and Fabry disease in patients with idiopathic small SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population seems not to be of value in a clinical setting.

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