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  • Review Article
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Mechanisms of disease in hereditary sensory and autonomic neuropathies

Abstract

Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders of the PNS. Progressive degeneration, predominantly of sensory and autonomic neurons, is the main pathological feature in patients with HSAN, and causes prominent sensory loss and ulcerative mutilations in combination with variable autonomic and motor disturbances. Advances in molecular genetics have enabled identification of disease-causing mutations in 12 genes, and studies on the functional effects of these mutations are underway. Although some of the affected proteins—such as nerve growth factor and its receptor—have obvious nerve-specific roles, others are ubiquitously expressed proteins that are involved in sphingolipid metabolism, vesicular transport, transcription regulation and structural integrity. An important challenge in the future will be to understand the common molecular pathways that result in HSANs. Unraveling the mechanisms that underlie sensory and autonomic neurodegeneration could assist in identifying targets for future therapeutic strategies in patients with HSAN. This Review highlights key advances in the understanding of HSANs, including insights into the molecular mechanisms of disease, derived from genetic studies of patients with these disorders.

Key Points

  • Hereditary sensory and autonomic neuropathies (HSANs) are a diverse group of diseases of the PNS, characterized by profound distal sensory loss, acral mutilations and variable autonomic disturbances

  • The genetic spectrum of HSANs encompasses autosomal dominant and autosomal recessive forms, with causative mutations identified in 12 genes

  • The genetic cause of disease remains unresolved in at least two-thirds of patients with HSAN

  • The molecular mechanisms that underlie HSANs are incompletely understood, but emerging evidence suggests that axonal transport, control of neuronal membrane excitability and neuronal development might be affected

  • Supportive care is the only therapy available for patients with HSAN; future studies should aim to identify common mechanisms of disease that could be targets for therapeutic strategies

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Figure 1: Functions of the proteins encoded by the 12 HSAN-associated genes in sensory neurons.
Figure 2: Putative mechanisms by which SPTLC1 and SPTLC2 mutations could cause peripheral neuropathy.
Figure 3: Downstream effector molecules of Rab-7a.

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Acknowledgements

The authors' research is supported by the University of Antwerp, Belgium, the Fund for Scientific Research (Flanders), the Queen Elisabeth Medical Foundation, the Association Belge contre les Maladies Neuromusculaires, the Muscular Dystrophy Association, the Interuniversity Attraction Poles P6/43 program of the Belgian Federal Science Policy Office and a Methusalem excellence grant from the Flemish Government. A. Rotthier's and J. Baets' Ph.D. fellowships are funded by the Institute for Science and Technology and the Fund for Scientific Research (Flanders), respectively. K. Janssens undertook consecutive postdoctoral fellowships funded by the Federation of European Biochemical Societies and the Belgian Federal Science Policy Office.

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A. Rotthier and K. Janssens researched data for the article and wrote the article. All authors provided substantial contributions to discussion of the content. J. Baets and V. Timmerman reviewed and/or edited the manuscript before submission.

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Correspondence to Vincent Timmerman.

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Rotthier, A., Baets, J., Timmerman, V. et al. Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev Neurol 8, 73–85 (2012). https://doi.org/10.1038/nrneurol.2011.227

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