Gene testing advances show complex picture
As at June 2015, 76 different types of HSP involving a myriad of genetic mutations in 59 genes have been discovered and described.
Next Generation Sequencing genetic testing technology has enabled these discoveries and together with clinical examination has revealed overlaps in both genes and symptom profiles (phenotypes) with other neurodegenerative and neurodevelopmental disorders including neuropathies, cerebellar ataxias and intellectual disability.
Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs, and are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance have been described, and the recent technological revolution in molecular genetics has led to the identification of 76 different spastic gait disease-loci with 59 corresponding spastic paraplegia genes.
Autosomal recessive HSPs are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSPs, which are mostly pure. However, the identification of additional mutations and families has considerably enlarged the clinical spectra, and has revealed a huge clinical variability for almost all HSP. Complicated forms have also been described for primary pure HSP subtypes, adding further complexity to the genotype-phenotype correlations.
In addition, the introduction of next generation sequencing in clinical practice has revealed a genetic and phenotypic overlap with other neurodegenerative disorders (amyotrophic lateral sclerosis, neuropathies, cerebellar ataxias, etc.) and neurodevelopmental disorders, including intellectual disability.
This review aims to describe the most recent advances in the field and to provide genotype-phenotype correlations that could help clinical diagnoses of this heterogeneous group of disorders.
SOURCE: Rev Neurol (Paris). 2015 Jun-Jul;171(6-7):505-30. doi: 10.1016/j.neurol.2015.02.017. Epub 2015 May 23. Copyright © 2015 Elsevier Masson SAS. All rights reserved. PMID: 26008818 [PubMed – in process]
Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting.
- 1Department of neurology, university hospital Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany.
- 2Sorbonne universités, UPMC université Paris 06, 91-105, boulevard de l’Hôpital, 75013 Paris, France; ICM, CNRS UMR 7225, Inserm U 1127, 47/83, boulevard de l’Hôpital, 75013 Paris, France; École pratique des hautes études, 4-14, rue Ferrus, 75014 Paris, France; Département de génétique, AP-HP, hôpital Pitié-Salpêtrière, 47/83, boulevard de l’Hôpital, 75013 Paris, France.
- 3Sorbonne universités, UPMC université Paris 06, 91-105, boulevard de l’Hôpital, 75013 Paris, France; ICM, CNRS UMR 7225, Inserm U 1127, 47/83, boulevard de l’Hôpital, 75013 Paris, France; Département de génétique, AP-HP, hôpital Pitié-Salpêtrière, 47/83, boulevard de l’Hôpital, 75013 Paris, France. Electronic address: [email protected]