Elsevier

Experimental Neurology

Volume 261, November 2014, Pages 518-539
Experimental Neurology

Review
Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

https://doi.org/10.1016/j.expneurol.2014.06.011Get rights and content
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open access

Highlights

  • An update on recent genetic insights in HSP

  • Genotype–phenotype correlations in HSP forms

  • Reorganized frequency of hereditary spastic paraplegia genes

  • Characterization of molecular mechanisms in hereditary spastic paraplegia

  • Molecular networks between HSP and other neurodegenerative diseases

Abstract

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by pathophysiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. The prominent features of this pathological condition are progressive spasticity and weakness of the lower limbs. To date, 72 spastic gait disease-loci and 55 spastic paraplegia genes (SPGs) have been identified. All modes of inheritance (autosomal dominant, autosomal recessive, and X-linked) have been described. Recently, a late onset spastic gait disorder with maternal trait of inheritance has been reported, as well as mutations in genes not yet classified as spastic gait disease. Several cellular processes are involved in its pathogenesis, such as membrane and axonal transport, endoplasmic reticulum membrane modeling and shaping, mitochondrial function, DNA repair, autophagy, and abnormalities in lipid metabolism and myelination processes. Moreover, recent evidences have been found about the impairment of endosome membrane trafficking in vesicle formation and about the involvement of oxidative stress and mtDNA polymorphisms in the onset of the disease. Interactome networks have been postulated by bioinformatics and biological analyses of spastic paraplegia genes, which would contribute to the development of new therapeutic approaches.

Graphical abstract

Schematic representation of proteins and functional modules involved in HSP pathogenesis.

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Abbreviations

AAA
ATPases associated with diverse cellular activities
AD
autosomal dominant
AEPs
auditory evoked potentials
AP
adaptor protein complex
AR
autosomal recessive
BiP
binding immunoglobulin protein
BMP
bone morphogenetic protein
CMT
Charcot–Marie–Tooth disease
DCVs
dense core vesicles
DTI
diffusion tensor imaging
ER
endoplasmic reticulum
EGFR
epidermal growth factor receptor
ERAD
ER-associated degradation
ESCRT
endosomal sorting complex required for transport
HSP
hereditary spastic paraplegia
JALS
juvenile amyotrophic lateral sclerosis
MEPs
motor evoked potentials
MIT
microtubule interacting and transport (domain)
NBIA
neurodegeneration with brain iron accumulation
RHD
reticulon homology domain
UPR
unfolded protein response
SCA
spinocerebellar ataxias
SEPs
sensory evoked potentials
SMA
spinal muscolar atrophy
SPG
spastic paraplegia gene
TCC
thin corpus callosum
VEPs
visual evoked potentials
WASH
Wiskott-Aldrich syndrome protein and scar homolog (complex)
WMLs
white matter lesions
XL
X-linked

Keywords

Hereditary spastic paraplegia
Molecular genetics
Neurodegenerative mechanisms
Neurology
Phenotype

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