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hereditary spastic paraplegias

Friday 26 September 2003

Definition: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disorder that is characterized by progressive and cell-specific axonal degeneration.

Spastic paraparesis is characterized by insidiously progressive bilateral lower extremity weakness and spasticity. The primary pathology in spastic paraparesis is neurodegeneration of the distal ends of the long spinal axons of the cortical motor neurons. Some PS mutations are associated with alzheimer diseaase (AD) and spastic paraparesis.

The hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper-motor-neuron degenerative diseases characterized by selective axonal loss in the corticospinal tracts and dorsal columns.

Although numerous mechanisms involving defective subcellular transportation, mitochondrial malfunction, and increased oxidative stress have been proposed, the pathogenic basis underlying the neuronal loss is unknown.

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.


- autosmal dominant hereditary spastic paraplegias
- autosmal recessive hereditary spastic paraplegia


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]

- sequence alterations of CYP7A1 in a pure form of hereditary spastic paraplegias (HSPs) (18252231)


- Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton MA, Hentati A, Lamont PJ, Siddique T, Crosby AH. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet. 2008 Feb;82(2):510-5. PMID: 18252231


- 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