Abstract
Hereditary Spastic Paraplegia (HSP) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations, such as cognitive impairment, seizures, ataxia or neuropathy. HSP occurs worldwide, with different populations having different frequencies of causative genes. The Greek population has not yet been characterised. The purpose of this study was to describe the clinical presentation and molecular epidemiology of the largest cohort of HSP in Greece, comprising 54 patients from 40 families. We used a targeted next-generation sequencing (NGS) approach to genetically assess a proband from each family. We made a genetic diagnosis in >50% of cases and identified 11 novel variants. Variants in SPAST and KIF5A were the most common causes of autosomal dominant HSP, whereas SPG11 and CYP7B1 were the most common cause of autosomal recessive HSP. We identified a novel variant in SPG11, which led to disease with later onset and may be unique to the Greek population and report the first nonsense mutation in KIF5A. Interestingly, the frequency of HSP mutations in the Greek population, which is relatively isolated, was very similar to other European populations. We confirm that NGS approaches are an efficient diagnostic tool and should be employed early in the assessment of HSP patients.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Fink JK : Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013; 126: 307–328.
Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A : Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol 2014; 261: 518–539.
Noreau A, Dion PA, Rouleau GA : Molecular aspects of hereditary spastic paraplegia. Exp Cell Res 2014; 325: 18–26.
Ruano L, Melo C, Silva MC, Coutinho P : The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 2014; 42: 174–183.
Buermans HPJ, den Dunnen JT : Next generation sequencing technology: advances and applications. Biochim Biophys Acta 2014; 1842: 1932–1941.
ExAC . Exome Aggregation Consortium. Available at http://exac.broadinstitute.org (last accessed 23 April 2015).
Arnoldi A, Crimella C, Tenderini E et al: Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin Genet 2012; 81: 150–157.
Kumar KR, Blair NF, Vandebona H et al: Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia. J Neurol 2013; 260: 2516–2522.
Klebe S, Depienne C, Gerber S et al: Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain 2012; 135: 2980–2993.
De Bot ST, van den Elzen RTM, Mensenkamp AR et al: Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations. J Neurol Neurosurg Psychiatry 2010; 81: 1073–1078.
Goizet C, Boukhris A, Mundwiller E et al: Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum Mutat 2009; 30: E376–E385.
Liu Y-T, Laurá M, Hersheson J et al: Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy. Neurology 2014; 83: 612–619.
Crimella C, Baschirotto C, Arnoldi A et al: Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. Clin Genet 2012; 82: 157–164.
Lo Giudice M, Neri M, Falco M et al: A missense mutation in the coiled-coil domain of the KIF5A gene and late-onset hereditary spastic paraplegia. Arch Neurol 2006; 63: 284–287.
Ebbing B, Mann K, Starosta A et al: Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Hum Mol Genet 2008; 17: 1245–1252.
Denora PS, Schlesinger D, Casali C et al: Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion. Hum Mutat 2009; 30: E500–E519.
Crimella C, Arnoldi A, Crippa F et al: Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus callosum. J Med Genet 2009; 46: 345–351.
Zhan Z-X, Liao X-X, Du J et al: Exome sequencing released a case of X-linked adrenoleukodystrophy mimicking recessive hereditary spastic paraplegia. Eur J Med Genet 2013; 56: 375–378.
Mitchell R, Nivison-Smith I, Anazodo A et al: Outcomes of haematopoietic stem cell transplantation for inherited metabolic disorders: a report from the Australian and New Zealand Children’s Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry. Pediatr Transplant 2013; 17: 582–588.
Acknowledgements
The authors would like to thank all the patients in this study for their essential help with this work. This study was supported by the Medical Research Council, The Leonard Wolfson Experimental Neurology Centre, The Wellcome Trust and The Brain Research Trust. This study was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on European Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Lynch, D., Koutsis, G., Tucci, A. et al. Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing. Eur J Hum Genet 24, 857–863 (2016). https://doi.org/10.1038/ejhg.2015.200
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2015.200
This article is cited by
-
Power of NGS-based tests in HSP diagnosis: analysis of massively parallel sequencing in clinical practice
neurogenetics (2023)
-
An integrated modelling methodology for estimating global incidence and prevalence of hereditary spastic paraplegia subtypes SPG4, SPG7, SPG11, and SPG15
BMC Neurology (2022)
-
Neuropsychology and MRI correlates of neurodegeneration in SPG11 hereditary spastic paraplegia
Orphanet Journal of Rare Diseases (2022)
-
Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations
BMC Neurology (2022)
-
Genotype–phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients
Journal of Neurology (2021)
