Hereditary Spastic Paraplegia: An Update

Abstract

Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disorder with the predominant clinical manifestation of spasticity in the lower extremities. HSP is categorised based on inheritance, the phenotypic characters, and the mode of molecular pathophysiology, with frequent degeneration in the axon of cervical and thoracic spinal cord's lateral region, comprising the corticospinal routes. The prevalence ranges from 0.1 to 9.6 subjects per 100,000 reported around the globe. Though modern medical interventions help recognize and manage the disorder, the symptomatic measures remain below satisfaction. The present review assimilates the available data on HSP and lists down the chromosomes involved in its pathophysiology and the mutations observed in the respective genes on the chromosomes. It also sheds light on the treatment available along with the oral/intrathecal medications, physical therapies, and surgical interventions. Finally, we have discussed the related diagnostic techniques as well as the linked pharmacogenomics studies under future perspectives.

Keywords: hereditary spastic paraplegia; neurodegenerative disease; neurogenetics.

Figure 1

Chromosomal and genetic markers in HSP. The above diagram illustrates all the genes and their location on the chromosomes related to the HSP phenotypes: AD, autosomal dominant forms; AR, autosomal recessive forms; XLR, X-linked recessive forms; and mitochondrial inheritance. The solid line represents the AD forms of HSP, whereas the dotted lines show the AR forms. The spiky green cloud with a dotted line represents the XLR HSP form.

Figure 2

Biological dysfunction in HSP. The neurons in the corticospinal zone of the brain undergo mutations in the genes, causing a breakdown of organelle shaping and trafficking and dysfunction in the mitochondrial cells at the neuron’s nuclear region. Few gene mutations lead to faulty transmission in the axons, and some mutations cause degeneration of the myelin sheath of the corticospinal neuron. Likewise, an endoplasmic reticulum shaping genes’ mutation causes defective metabolism, especially lipid droplet formations. All these characteristics lead to lower limb spasticity and weakness, causing HSP phenotypes.

Figure 3

Differential diagnosis of HSP—Being an extremely heterogeneous disorder in clinical and genetic aspects, HSP is often misinterpreted with acquired myelopathies, neurometabolic disorders, inherited metabolic paraparesis, and some neurodegenerative disorders. ARSACS: Autosomal recessive spastic ataxia of Charlevoix–Saguenay; SCAs: Spinocerebellar ataxias; CMV: Cytomegalovirus; CRMP-5: Collapsin response mediator protein-5; GAD: Glutamate decarboxylase; HTLV: Human T lymphotropic virus; HIV: Human immunodeficiency virus; PSEN: Presenilin; SPAX: Spastic ataxia.

Figure 4

Therapies and treatment are administered to HSP individuals. The picture illustrates the pharmacological, physical, interventional, and surgical treatments given to HSP people to soothe the spasticity and improve their gait. A pharmacogenomics approach is also reported.