| The aim of this doctoral thesis is to further broaden our current knowledge of hereditary neuropathies by systematic confrontation of both clinical and genetic aspects. The hereditary neuropathies consist of a large number of different disorders that can be further subdivided based on distinctive clinical aspects and genetic classifications. In this dissertation, several large-scale studies on sizable patient cohorts were performed allowing new insights in the intricate network of genotype-phenotype correlations of this diverse group of disorders.;First we studied the genetic spectrum of hereditary motor and sensory neuropathies (HMSN) with very early disease onset. These rare but severe disorders are particularly challenging in terms of patient management and molecular diagnosis.;Subsequently, we focus on two distinct groups of patients who do not show mixed motor and sensory involvement. The first are hereditary sensory and autonomic neuropathies (HSAN), characterized by pronounced distal sensory and acromutilations. The second are hereditary motor neuropathies (HMN), heterogeneous disorders that are characterized by the progressive distal to proximal axonal loss in long motor neurons.;Thirdly, we study axonal neuropathies of pure or predominantly motor subtype by establishing the clinical diversity of the specific phenotypes associated with mutations in TRPV4. We found unusual clinical characteristics that are specific for mutations in TRPV 4. Likewise we studied rare dominant mutations in GDAP1, causing predominantly mild axonal HMSN phenotypes.;In a final part of the dissertation, the study is expanded into the field of more complex disorders featuring other clinical characteristics besides peripheral neuropathy. We studied one such disorder in detail, namely autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) a neurodegenerative disorder caused by mutations in SACS. The phenotype typically consists of a childhood onset triad of cerebellar ataxia, peripheral neuropathy and pyramidal tract signs.;With the results of these studies we aim to contribute to the further improvement of clinical diagnosis, the design of rational strategies for molecular diagnosis and genetic counselling and to the development of specific model systems to study the pathophysiology of various hereditary neuropathies. The ultimate goal of these studies is to help unveil potential therapeutic targets in this group of yet incurable disorders. |
