open access
Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey
, 2, 3, 3, 2, 1
Affiliations- Istanbul University, Istanbul Medical Faculty, Department of Neurology, Istanbul, Türkiye
- Bogazici University, Department of Molecular Biology and Genetics, Istanbul, Türkiye
- Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States
open access
Abstract
Objectives. Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients.
Patients and methods. We studied 21 patients from 17 families. Six of them presented with recessive inheritance. All index patients were screened for ATL1 and SPAST gene mutations to determine the prevalence of the most frequent types of HSP in our cohort. Whole exome sequencing was performed for an AD-HSP family, in combination with homozygosity mapping for five selected AR-HSP families.
Results. Two novel causative variants were identified in PLP1 and SPG11 genes, respectively. Distribution of HSP mutations in our AD patients was found to be similar to European populations.
Conclusion. Our genetic studies confirmed that clinical analysis can be misleading when defining HSP subtypes. Genetic testing is an important tool for diagnosis and genetic counselling. However, in the majority of AR HSP cases, a genetic diagnosis is not possible.
Abstract
Objectives. Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients.
Patients and methods. We studied 21 patients from 17 families. Six of them presented with recessive inheritance. All index patients were screened for ATL1 and SPAST gene mutations to determine the prevalence of the most frequent types of HSP in our cohort. Whole exome sequencing was performed for an AD-HSP family, in combination with homozygosity mapping for five selected AR-HSP families.
Results. Two novel causative variants were identified in PLP1 and SPG11 genes, respectively. Distribution of HSP mutations in our AD patients was found to be similar to European populations.
Conclusion. Our genetic studies confirmed that clinical analysis can be misleading when defining HSP subtypes. Genetic testing is an important tool for diagnosis and genetic counselling. However, in the majority of AR HSP cases, a genetic diagnosis is not possible.
Keywords
hereditary spastic paraplegia (HSP), atlastin (ATL1), spastin (SPAST), PLP1, rare diseases, Pelizaeus-Merzbacher Disease (PMD), SPG11
Supp./Additional Files (1)
About this articleTitle
Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey
Journal
Neurologia i Neurochirurgia Polska
Issue
Article type
Research Paper
Pages
176-184
Published online
2020-04-03
Page views
1670
Article views/downloads
521
DOI
Pubmed
Bibliographic record
Neurol Neurochir Pol 2020;54(2):176-184.
Keywords
hereditary spastic paraplegia (HSP)
atlastin (ATL1)
spastin (SPAST)
PLP1
rare diseases
Pelizaeus-Merzbacher Disease (PMD)
SPG11
Authors
Nihan H. Akçakaya
Burçak Özeş Ak
Michael A. Gonzalez
Stefan Züchner
Esra Battaloğlu
Yeşim Parman
References (16)- Bonneau D, Rozet JM, Bulteau C, et al. X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. J Med Genet. 1993; 30(5): 381–384.
- Burguez D, Polese-Bonatto M, Scudeiro LA, et al. Clinical and molecular characterization of hereditary spastic paraplegias: A next-generation sequencing panel approach. J Neurol Sci. 2017; 383: 18–25.
- Crippa F, Panzeri C, Martinuzzi A, et al. Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. Arch Neurol. 2006; 63(5): 750–755.
- Crosby AH, Proukakis C. Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet. 2002; 71(5): 1009–1016.
- Elert-Dobkowska E, Stepniak I, Krysa W, et al. Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. J Neurol Sci. 2015; 359(1-2): 35–39.
- Erichsen AK, Koht J, Stray-Pedersen A, et al. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain. 2009; 132(Pt 6): 1577–1588.
- Fink J. Hereditary spastic paraplegia. Neurol Clin. 2002; 20(3): 711–726.
- Gonzalez M, Falk MJ, Gai X, et al. Innovative genomic collaboration using the GENESIS (GEM.app) platform. Hum Mutat. 2015; 36(10): 950–956.
- Klebe S, Stevanin G, Depienne C. Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. Rev Neurol (Paris). 2015; 171(6-7): 505–530.
- Lynch DS, 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. 2016; 24(6): 857–863.
- Margraf R, Durtschi J, Krock B, et al. Novel PLP1 Mutations Identified With Next-Generation Sequencing Expand the Spectrum of PLP1-Associated Leukodystrophy Clinical Phenotypes. Child Neurology Open. 2018; 5: 2329048X1878928.
- Riverol M, Samaranch L, Pascual B, et al. Forceps minor region signal abnormality "ears of the lynx": an early MRI finding in spastic paraparesis with thin corpus callosum and mutations in the spatacsin gene (SPG11) on chromosome 15. J Neuroimaging. 2009; 19(1): 52–60.
- Ruano L, Melo C, Silva MC, et al. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014; 42(3): 174–183.
- Rubegni A, Battisti C, Tessa A, et al. SPG2 mimicking multiple sclerosis in a family identified using next generation sequencing. J Neurol Sci. 2017; 375: 198–202.
- Stevenson RE, Tarpey P, May MM, et al. Arena syndrome is caused by a missense mutation in PLP1. Am J Med Genet A. 2009; 149A(5): 1081.
- Stevanin G, Azzedine H, Denora P, et al. SPATAX consortium. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain. 2008; 131(Pt 3): 772–784.
