SPASTIC PARAPLEGIA

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative diseases with an estimated prevalence of approximately 1.8/100,000 (Ruano et al. 2014 Neuroepidem 42:174). Clinically, HSP is classified as “pure” (or “uncomplicated”) and ‘complex’ (or “complicated”) forms. In autosomal dominant HSPs (ADHSP), which usually represent the “pure” form, the age of onset varies greatly.

Symptoms

The main features of pure HSP are hyperreflexia, muscle hypertonia or bilateral spasticity of the legs, bladder dysfunction, and impaired vibration sensation. In the complicated forms, additional neurological or extra-neurological symptoms are noticeable, such as intellectual disability, cerebellar ataxia, peripheral neuropathy, epilepsy, retinopathy, optic atrophy, dystonia, and parkinsonism. A major symptom of HSP is retrograde axonal degeneration of the distal portion of the corticospinal and spinocerebellar tracts, which are among the longest motor and sensory axons in the central nervous system.

Causes

Currently, more than 70 genes are known whose pathogenic variants cause defects in certain biological pathways, such as axonal transport, lipid metabolism, endoplasmic reticulum (ER) formation, mitochondrial function, and endosomal transport.

Pathogenic variants in the SPAST gene are found in 17-79% of cases. Variants of the ATL1 (SPG3A), REEP1 (SPG31), and KIF5A (SPG10) genes are also common and, together with pathogenic SPAST variants, account for 50-60% of ADHSP cases. In autosomal recessive forms of HSP (ARHSP), pathogenic variants in the SPG11 gene are common (21%) and cause the “complex” form of HSP. Other genes in which pathogenic variants are frequently detected are CYP7B1 (SPG5), SPG7, and ZFYVE26 (SPG15).

Genes whose pathogenic variants cause HSP play a role in the homeostasis and morphology of the endoplasmic reticulum (ER), among other things. Genes such as ATL1 (SPG3A) and SPAST (SPG4) are involved in maintaining ER morphology and regulating ER stress. The ER plays a key role in the quality control of newly synthesized proteins.

References

Boutry et al. 2019, Curr Neurol Neurosci Rep 19:18 / Gumeni et al. 2021, Front Neurosci 15:660714