hereditary spastic paraplegias
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disorder that is characterized by progressive and cell-specific axonal degeneration.
The term "hereditary spastic paraplegia" (or "hereditary spastic paraparesis") (HSP) is used to describe a group of clinically heterogeneous neurodegenerative disorders in which the predominant feature is progressive spasticity associated with mild weakness of the lower limbs, which may be accompanied by bladder disturbances and subtle vibratory sense impairment.
These disorders are classified as either "pure" (or "uncomplicated"), when the above features occur in isolation, or "complicated," in the presence of additional neurological manifestations, such as mental retardation, extrapyramidal symptoms, deafness, or optic neuropathy.
m-AAA protease (SPG7) at 16q24.3 [MIM.600146]
An autosomal recessive form of the disease is caused by mutations in paraplegin, which is a conserved subunit of the ubiquitous and ATP-dependent m-AAA protease in mitochondria.
The m-AAA protease carries out protein quality control in the inner membrane of the mitochondria, suggesting a pathogenic role of misfolded proteins in HSP.
The m-AAA protease regulates ribosome assembly and translation within mitochondria by controlling proteolytic maturation of a ribosomal subunit. Here, we will discuss implications of the dual role of the m-AAA protease in protein activation and degradation for mitochondrial dysfunction and axonal degeneration.
Types
autosmal dominant hereditary spastic paraplegias
autosmal recessive hereditary spastic paraplegia
Etiology
20 loci chromosomally mapped and eight genes identified in 2003.
SPG1 [MIM.312900]
SPG2 [MIM.312920]
SPG3A [MIM.182600]
SPG4 [MIM.182601]
SPG5A [MIM.270800]
SPG6 [MIM.600363] at 15q11-q13): mutations in NIPA1 encoding a putative membrane transporter or receptor (autosomal dominant HSP)
SPG7 [MIM.600146] at 16q24.3: mutations in SPG7 coding for paraplegin
SPG8 [MIM.603563]
SPG9 [MIM.601162]
SPG10 [MIM.604187]: mutation in KIF5A enciding neuronal kinesin heavy chain (KIFs) (12355402)
SPG11 [MIM.604360]
SPG12 [MIM.604805]
SPG13 [MIM.605280]
SPG14 [MIM.605229]
SPG15 [MIM.606859]
SPG16 [MIM.300266]
SPG17 [MIM.270685]
SPG19 [MIM.607152]
SPG20 [MIM.275900]
References
Rugarli EI, Langer T. Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia. Trends Mol Med. 2006 Jun;12(6):262-9. PMID: 16647881
- Gould RM, Brady ST. Neuropathology: many paths lead to hereditary spastic paraplegia. Curr Biol. 2004 Oct 26;14(20):R903-4. PMID: 15498485