title: Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting.
abstract: 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 HSP are usually associated with diverse additional features (referred to as complicated forms), contrary to autosomal dominant HSP, 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.
authors.affiliation: Department of neurology, university hospital Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Klebe
authors.affiliation: Sorbonne 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.
authors.forename: G
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: Sorbonne 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: christel.depienne@upmc.fr.
authors.forename: C
authors.initials: C
authors.lastname: Depienne
mesh_terms: D003937:Diagnosis, Differential; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000235:genetics*
keywords: Clinical variability; Diagnosis; Diagnostic; Genetic heterogeneity; Hereditary spastic paraplegia; Hétérogénéité génétique; Paraplégies spastiques héréditaires; Variabilité phénotypique