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Update on the Genetics of Spastic Paraplegias

  • Genetics (V. Bonifati, Section Editor)
  • Published:
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Abstract

Purpose of Review

Hereditary spastic paraplegias are a genetically heterogeneous group of neurological disorders. Patients present lower limb weakness and spasticity, complicated in complex forms by additional neurological signs. We review here the major steps toward understanding the molecular basis of these diseases made over the last 10 years.

Recent Findings

Our perception of the intricate connections between clinical, genetic, and molecular aspects of neurodegenerative disorders has radically changed in recent years, thanks to improvements in genetic approaches. This is particularly true for hereditary spastic paraplegias, for which > 60 genes have been identified, highlighting (i) the considerable genetic heterogeneity of this group of clinically diverse disorders, (ii) the fuzzy border between recessive and dominant inheritance for several mutations, and (iii) the overlap of these mutations with other neurological conditions in terms of their clinical effects. Several hypotheses have been put forward concerning the pathophysiological mechanisms involved, based on the genes implicated and their known function and based on studies on patient samples and animal models. These mechanisms include mainly abnormal intracellular trafficking, changes to endoplasmic reticulum shaping and defects affecting lipid metabolism, lysosome physiology, autophagy, myelination, and development. Several causative genes affect multiple of these functions, which are, most of the time, interconnected.

Summary

Recent major advances in our understanding of these diseases have revealed unifying pathogenic models that could be targeted in the much-needed development of new treatments.

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Acknowledgments

We thank Drs F Mochel, F Darios, KH El-Hachimi, and V Anquetil for fruitful discussions.

Funding

The authors’ work is funded by the European Union H2020 program (SOLVE-RD, to GS), the Spastic Paraplegia Foundation [US] (to GS), the Association Strümpell-Lorrain [FR] (to GS), the Agence Nationale de la Recherche [FR] (Spatax-Quest, to GS), and the E-Rare Program (Prepare, to GS). MB and SM held PhD fellowships from the ED3C Doctoral School (France) and the Fundação para a Ciência e a Tecnologia (Portugal), respectively.

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  1. Maxime Boutry

    Present address: Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada

Authors and Affiliations

  1. Institut du Cerveau et de la Moelle épinière, Sorbonne Université UMR_S1127, INSERM Unit 1127, CNRS UMR7225, 75013, Paris, France

    Maxime Boutry, Sara Morais & Giovanni Stevanin

  2. Neurogenetics team, Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences Lettres (PSL) Research University, 75013, Paris, France

    Maxime Boutry, Sara Morais & Giovanni Stevanin

  3. UnIGENe, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Sara Morais

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Correspondence to Giovanni Stevanin.

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Conflict of Interest

Giovanni Stevanin reports grants from the European Union H2020 programme, grants from Spastic Paraplegia Foundation, grants from Association Strumpell Lorrain, grants from Agence Nationale de la Recherche, and grants from Erare Program, during the conduct of the study. In addition, Dr. Stevanin has been issued a patent on Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases. Maxime Boutry reports personal fees from French Ministry of Research (Doctoral School ED3C), during the conduct of the study. In addition, Dr. Boutry has been issued a patent on Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases. Sara Morais reports personal fees from FCT (Fundação para a Ciência e Tecnologia), Portugal, during the conduct of the study.

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This article is a review and reports only studies approved by editorial boards based on peer reviews. When we cited our own work, all the procedures performed in the studies involving human materials or animals were conducted in accordance with the ethical standards of our institution, with informed consent obtained from patients and approval from ethics committees.

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Boutry, M., Morais, S. & Stevanin, G. Update on the Genetics of Spastic Paraplegias. Curr Neurol Neurosci Rep 19, 18 (2019). https://doi.org/10.1007/s11910-019-0930-2

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