The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment

Abstract

Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, endoplasmic reticulum shaping, axon transport, endosome trafficking, and mitochondrial function. With the inheritance patterns of autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial inheritance, HSP is prevalent around the globe at a rate of 1–5 cases in every 100,000 individuals. Recent technology and medical interventions somewhat aid in recognizing and managing the malaise. However, HSP still lacks an appropriate and adequate therapeutic approach. Current therapies are based on the clinical manifestations observed in the patients, for example, smoothing the relaxant spastic muscle and physiotherapies. The limited clinical trial studies contribute to the absence of specific pharmaceuticals for HSPs. Our current work briefly explains the causative genes, epidemiology, underlying mechanism, and the management approach undertaken to date. We have also mentioned the latest approved drugs to summarise the available knowledge on therapeutic strategies for HSP.

Case report: Novel mutations in the SPG11 gene in a case of autosomal recessive hereditary spastic paraplegia with a thin corpus callosum

“…In the current study, we identified two novel SPG 11 gene mutations: a frameshift (c.5687_5691del) and a non-sense mutation (c.751C>T). SPG11-associated HSP is supposed to be the most frequent type of complicated autosomal recessive HSP, especially for patients with a thin corpus callosum and intelligence disorder (Paisanruiz et al, 2008;Meyyazhagan et al, 2022). The SPG 11 gene, which is located at chromosome 15q13-15, encodes the spatacsin protein that is primarily expressed in the pineal gland, cerebral cortex, cerebellum, and hippocampus (Paisanruiz et al, 2008;Samaranch et al, 2008;Panza et al, 2022).…”

“…(Figure 3). The diagnosis of autosomal recessive HSP with a thin corpus callosum was finally confirmed according to the clinical manifestations and genetic test results of the patient (Patel et al, 2016;Zhang et al, 2016;Meyyazhagan et al, 2022). The Spastic Paraplegia Rating Scale (SPRS) was 16 points according to a previous study (Schüle et al, 2006).…”

The interconnection of endoplasmic reticulum and microtubule and its implication in Hereditary Spastic Paraplegia

“…Hereditary spastic paraplegias (HSPs) are a diverse group of heritable neurological disorders, which are clinically characterized by spastic and weakness in lower-extremities, and pathologically by retrograde axonal degeneration. To date, no etiological treatments for prevention or reversal of motor neuron degeneration in HSP have been documented [9] . Symptomatic treatments via physical or occupational therapy and drugs have improved muscle spasticity only temporarily and improved balance, strength, and agility.…”

Ap4s1 truncation leads to axonal defects in a zebrafish model of spastic paraplegia 52

“…Clinically, HSPs are classified as pure or complex based on the presence of any other neurological manifestations besides paraparesis, such as seizures, dementia, intellectual disability, peripheral neuropathy, or developmental delay (Lallemant‐Dudek & Durr, 2021). A spastic paraplegia gene (SPG) designation is used to classify HSP based on genetic sequencing of the chromosomal loci or genes, and over 80 SPG genes have been identified to date (Meyyazhagan et al, 2022).…”