Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Abstract

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

Hereditary spastic paraplegia type 56: what a mouse can tell - a narrative review

“…Patients carrying pathogenic mutations often present with early-onset spastic paraplegia, with a mean age at diagnosis of 3.4 ± 6.86 years. As reported in Elsayed et al, [3] patients often present with neuroregression between 0 and 3 years of age (Fig. 1B).…”

“…A wide heterogeneity characterizes not only HSPs’ clinical manifestations, but also extends to the underlying genetic background. The recent introduction of next-generation sequencing (NGS) techniques in everyday diagnostic processes has greatly increased the power of genetic diagnosis, allowing to steadily increase the number of loci involved in HSPs onset, with more than 100 loci and 80 Spastic Paraplegia Genes (SPGs) reported to date [3] . Yet, despite these advances, the difficulty in connecting an observed phenotype with a specific candidate gene, and the fact that pathogenic mutations can be inherited through all known inheritance patterns or manifest sporadically, continues to make HSPs genetic diagnosis particularly challenging [3] .…”

“…The recent introduction of next-generation sequencing (NGS) techniques in everyday diagnostic processes has greatly increased the power of genetic diagnosis, allowing to steadily increase the number of loci involved in HSPs onset, with more than 100 loci and 80 Spastic Paraplegia Genes (SPGs) reported to date [3] . Yet, despite these advances, the difficulty in connecting an observed phenotype with a specific candidate gene, and the fact that pathogenic mutations can be inherited through all known inheritance patterns or manifest sporadically, continues to make HSPs genetic diagnosis particularly challenging [3] . An additional aspect further complicating HSPs genetic landscape is the extreme phenotypic variability observed even among patients sharing the same causative mutation, suggesting the presence of additional variants acting as modifiers, as already observed in other neurological disorders [4–6] …”

Phosphorylation of Spastin Promotes the Surface Delivery and Synaptic Function of AMPA Receptors

“…Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by distinct lower limb spasticity and weakness (Novarino et al, 2014 ; Walusinski, 2020 ). To date, there are about 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP (Elsayed et al, 2021 ). More than 40% of HSP cases originate from mutations in the SPG4 gene, which encodes SPASTIN, a microtubule-severing protein (Kara et al, 2016 ; Erfanian Omidvar et al, 2021 ).…”

GRID1/GluD1 homozygous variants linked to intellectual disability and spastic paraplegia impair mGlu1/5 receptor signaling and excitatory synapses

“…Intellectual disability (ID) and spastic paraplegia (SPG) are central nervous system disorders with marked clinical and genetic heterogeneity. In both groups, non-specific and syndromic forms have been described with numerous genes identified in the past few years (Ellison et al ., 2013; Elsayed et al ., 2021). The association of SPG with ID or MR (mental retardation, the out of use designation of ID) is frequent with 106 and 127 entries in the OMIM (Online Mendelian Inheritance in Man) database, respectively.…”