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  • Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia

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Neurogenetics
Research paper
Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia
  1. Viorica Chelban1,2,3,
  2. Arianna Tucci1,2,4,5,
  3. David S Lynch1,2,
  4. James M Polke1,2,6,
  5. Liana Santos6,
  6. Hallgeir Jonvik1,2,
  7. Stanislav Groppa3,
  8. Nicholas W Wood1,2,
  9. Henry Houlden1,2,6
  1. 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  2. 2 National Hospital for Neurology and Neurosurgery, London, UK
  3. 3 Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Chisinau, Republic of Moldova
  4. 4 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
  5. 5 Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy
  6. 6 Neurogenetics Laboratory, UCL Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK
  1. Correspondence to Dr Viorica Chelban, Institute of Neurology, Queen Square, London WC1N 3BG, UK; v.chelban{at}ucl.ac.uk

Abstract

Background The hereditary spastic paraplegias (HSPs) are a rare and heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive lower limb spasticity. They are classified as either ‘pure’ or ‘complex’ where spastic paraplegia is complicated with additional neurological features. Mutations in the spastin gene (SPAST) are the most common cause of HSP and typically present with a pure form.

Methods We assessed in detail the phenotypic and genetic spectrum of SPAST-related HSP focused on 118 patients carrying SPAST mutations.

Results This study, one of the largest cohorts of genetically confirmed spastin patients to date, contributes with the discovery of a significant number of novel SPAST mutations. Our data reveal a high rate of complex cases (25%), with psychiatric disorders among the most common comorbidity (10% of all SPASTpatients). Further, we identify a genotype–phenotype correlation between patients carrying loss-of-function mutations in SPAST and the presence of psychiatric disorders.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/jnnp-2017-315796

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    Footnotes

    • Contributors VC: research project—conception, organisation and execution; statistical analysis—design and execution; manuscript preparation—writing of the first draft and review and critique. AT: research project—conception; statistical analysis—design and review and critique; manuscript preparation—writing of the first draft and review and critique. DSL: research project—execution; manuscript preparation—writing of the first draft and review and critique. JP and LS: research project—execution; manuscript preparation—review and critique. HJ: research project—organisation and execution; manuscript preparation—review and critique. SG and NW: research project—conception; manuscript preparation—review and critique. HH: research project—conception and organisation; manuscript preparation—review and critique.

    • Funding The authors are grateful to the Spastic Paraplegia Foundation, the UK HSP Society, the Medical Research Council (MRC UK), the Wellcome Trust (equipment and the Synaptopathies strategic award (104033)) and the EU FP7/2007-2013 under grant agreement number 2012-305121 (NEUROMICS), Ataxia UK and British Neurological Surveillance Unit (BNSU). The authors are also supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC).

    • Competing interests None declared.

    • Ethics approval Research Ethics Committee and HRA.

    • Provenance and peer review Not commissioned; externally peer reviewed.