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.
Highlights
Hereditary spastic paraplegias (HSP) are a group of heterogeneous neurodegenerative disorders which are characterized by an insidiously progressive weakness and spasticity of the lower extremities as their core defining clinical features
Nonexhaustive illustrative examples of atypical HSP presentations that make it worth reconsidering our working case-definition include tetraplegic cerebral palsy forms associated with AP4 complex mentioned earlier (Verkerk et al, 2009; Abou Jamra et al, 2011; Bauer et al, 2012), HSP associated with hyperbilirubinemia and persistent vomiting caused by hiatus hernia (SPG29) (Orlacchio et al, 2005a), atypical HSP presentation with areflexia, apnoea, hypoventilation, ventriculomegaly, and gastro-oesophageal reflux disease in association with SPG49/TECPR2 (Oz-Levi et al, 2012, 2013), and HSP with cutis laxa and cataract (SPG9) (Coutelier et al, 2015, 2016)
autosomal dominant (AD) HSP forms with complex presentation tend to be at low level of complexity with one or two complicating signs that are usually limited to peripheral neuropathy and amyotrophy except for SPG9, SPG29 and to a lesser extent SPG80 which show high level of complexity (Orlacchio et al, 2005a; Coutelier et al, 2015, 2016; Farazi Fard et al, 2019) (Figure 1; Table 2)
Summary
Hereditary spastic paraplegias (HSP) are a group of heterogeneous neurodegenerative disorders which are characterized by an insidiously progressive weakness and spasticity of the lower extremities as their core defining clinical features. Intracellular protease Synaptic plasticity, restructuring; Axon maintenance and maturation Class II aminoacyl-tRNA synthetases Mitochondrial protein translation ATPases transport inorganic cations and other substrates across cell membranes Autophagy; Endolysosomal trafficking, Mitochondrial function DNA damage response, Thiol protease of peptidase C12 family Has ligase and hydrolase activities that may play roles in proteasomal protein degradation, a process critical for neuronal health Phosphatidylethanolamine synthesis
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