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Hereditary spastic paraplegia
ICD-10 G114
ICD-9 334.1
OMIM [1]
DiseasesDB 33207
MedlinePlus [2]
eMedicine pmr/45
MeSH {{{MeshNumber}}}

Hereditary Spastic Paraplegia (HSP), also called Familial Spastic Paraplegias or Strumpell-Lorrain disease, is a form of paraplegia, group of inherited diseases whose main feature is progressive stiffness and contraction (spasticity) in the lower limbs with eventual paralysis,[1] as a result of damage to dysfunction of the nerves.[2] [3] It sometimes also affects the optic nerve and retina of the eye, causes cataracts, ataxia (lack of muscle coordination), epilepsy, cognitive impairment, peripheral neuropathy, and deafness.[4] HSP is caused by defects in the mechanisms that transport proteins and other substances through the cell. Long nerves are affected because they have to transport cellular material through long distances, and are particularly sensitive to defects of cellular transport.[5]

Hereditary Spastic Paraplegia was first described in 1883 by Adolph Strümpell, a German neurologist, and was later described more extensively in 1888 by Maurice Lorrain, a French physician.

NeuropathologyEdit

The major neuropathologic feature of HSP is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis.[6] The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating fibers are preserved and there is no evidence of primary demyelination.[7] Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal.[8]

ClassificationEdit

Hereditary spastic paraplegias are classified based on the symptoms; on their mode of inheritance; on the patient’s age at onset; and, ultimately, on the gene associated with the condition.

Based on symptomsEdit

Spasticity in the lower limbs alone is described as pure HSP. On the other hand, HSP is classified as complex or complicated when associated with other neurological signs, including ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction or epilepsy, or with extraneurological signs. Complicated forms are diagnosed as HSPs when pyramidal signs are the predominant neurological characteristic. This classification, however, is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia, mental retardation or leukodystrophy.[9]

Based on mode of inheritanceEdit

HSP being a group of genetic disorders, they follow general inheritance rules and can be inherited in an autosomal dominant, autosomal recessive or x-linked recessive manner. The mode of inheritance involved has a direct impact on the chances of inheriting the disorder.

Based on patient's age at onsetEdit

In the past, HSP also has been classified as type I or type II on the basis of the patient's age at the onset of symptoms, which influences the amount of spasticity versus weakness. Type I is characterized by age onset below 35 years, whereas Type II is characterized by onset over 35 years. In the type I cases, delay in walking is not infrequent and spasticity of the lower limbs is more marked than weakness. In the type II muscle weakness, urinary symptoms and sensory loss are more marked. Furthermore, type II form of HSP usually evolves more rapidly.[10]

Based on associated geneEdit

The symptoms previously described are the results of a degeneration of the corticospinal tracts. The longest fibers, innervating the lower extremities, are the most affected. This explains why the spasticity and pyramidal signs are often limited to the lower limbs in patients. This neuronal degeneration is thought to be caused by mutations at specific genes. Genetic mapping has identified at least 52 different HSP loci, designated SPG (Spastic ParapleGia) 1 through 52 [11] in order of their discovery. Different genetic types of HSP usually cannot be distinguished by clinical and neuroimaging parameters alone. This reflects both the clinical similarity between different types of HSP and the phenotypic variability within a given genetic type of HSP. Furthermore, there may be significant clinical variability within a given family in which all subjects have the same HSP gene mutation; between families with the same genetic type of HSP; and between families with different genetic types of HSP.[12]

Name
Alternate names
OMIM Gene Locus Inheritance Characteristics
SPG1
Masa syndrome
Gareis-Mason syndrome
Crash syndrome
303350 L1CAM Xq28 X-linked Mutations in this protein interfere with its role in neurite outgrowth guidance, neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts.[13]
SPG2 312920 PLP1 Xq22 X-linked Mutations in the proteolipid protein cause progressive leukodystrophy and dysmyelination, resulting in axonal degeneration.[14]
SPG3A 182600 ATL1 14q11–q21 Autosomal dominant SPG3A HSP is pure and almost indistinguishable from SPG4 HSP, except that it usually begins earlier, in childhood or adolescence. Atlastin contains conserved motifs for GTPase binding site and hydrolysis and is structurally homologous to guanylate binding protein 1 (GBP1).[15] The functional importance of atlastin’s GTPase motif is indicated by a recently identified HSP mutation that showed a disrupted GTPase motif which is usually conserved. GBP1, to which atlastin shows homology, is a member of the dynamin family of large GTPases.[16] Dynamins play essential roles in a wide variety of vesicle trafficking events: regulation of neurotrophic factors;[17] recycling of synaptic vesicles;[18] maintenance and distribution of mitochondria;[19] maintenance of the cytoskeleton via association to actin and microtubules.[20] The important and diverse functions of dynamins raise many interesting possibilities by which atlastin mutations could cause axonal degeneration. These possibilities include defective synaptic vesicle recycling leading to abnormal synaptic structure and impaired neurotransmission, impaired activation of selected neurotrophic factors, and impaired mitochondria distribution. Also known as Strumpell disease.
SPG4 182601 SPAST 2p22–p21 Autosomal dominant SPG4 mutations are pathogenic because of haploinsufficiency (that is, decreased abundance of functionally normal spastin) rather that a dominant negative mechanism.[21] Emerging evidence suggests that spastin may interact with microtubules. A recent research showed that antitubulin antibodies could precipitate spastin in vitro, hence indicating that spastin can bind to tubulin. More recently, another study showed that a spastin fusion protein colocalized with microtubules in Cos-7 and HeLa cells transfected with wild type and mutant SPG4 expression vectors. Findings that spastin may interact with microtubules support the hypothesis that disturbances in axonal cytoskeleton or transport underlie some forms of HSP.[22]
SPG5A 270800 CYP7B1 8q21.3 Autosomal recessive
SPG5B 600146 SPG5B  ? Autosomal recessive Described in one person.
SPG6 600363 NIPA1 15q11.1 Autosomal dominant The function of NIPA1 is unknown. It is widely expressed in the central nervous system. The presence of nine alternating hydrophobic-hydrophilic domains suggests that NIPA1 might encode a transmembrane protein. This feature makes NIPA1 unique among HSP related proteins. The mutation on the NIPA1 gene appears to act through a dominant negative gain of function. This prediction is based on the fact that subjects who are missing one NIPA1 gene entirely do not develop HSP.[23]
SPG7 607259 SPG7 16q24.3 Autosomal recessive HSP Because paraplegin is a protein found on the mitochondria, mutations in this protein cause mitochondrial malfunction in neurons, eventually leading to axonal degeneration. SPG7 knockout mice exhibit signs of HSP. Recent studies were conducted on homozygous SPG7/Paraplegin knockout mice. Histological analysis of the spinal cord showed axonal swelling, particularly in the lateral columns of the lumbar spinal cord, consistent with a retrograde axonopathy.[24]
SPG8 603563 KIAA0196 8q24.13 Autosomal dominant
SPG9 601162 SPG9 10q23.3–q24.1 Autosomal dominant
SPG10 604187 KIF5A 12q13 Autosomal dominant KIF5A is a motor protein that participates in the intracellular movement of organelles and microtubules in both anterograde and retrograde directions. Subjects with KIF5A mutation exhibit either uncomplicated HSP or HSP associated with distal muscle atrophy. The HSP-specific KIF5A mutation disrupted an asparagine residue, present on the kinesin heavy chain motor protein, that prevented stimulation of the motor ATPase by microtubule binding.[25]
SPG11 604360 SPG11 15q21.1 Autosomal recessive
SPG12 604805 RTN2 19q13 Autosomal dominant
SPG13 605280 HSPD1 2q33.1 Autosomal dominant Although chaperonin 60 is known to encode mitochondrial proteins, the specific mechanisms by which mutations in that protein cause HSP are not yet known.[26]
SPG14 605229 SPG14 3q27–q28 Autosomal recessive
SPG15
Kjellin syndrome
270700 ZFYVE26 14q24.1 Autosomal recessive Characterized by progressive stiffness and increased reflexes in the leg muscles as well as retinal degeneration.[27]
SPG16 300266 SPG16 Xq11.2 X-linked
SPG17
Silver syndrome
270685 BSCL2 11q13 Autosomal dominant Phenotype overlapping with distal spinal muscular atrophy type 5A.
SPG18 611225 ERLIN2 8p11.23 Autosomal recessive Characterised by joint contractures and intellectual disability.
SPG19 607152 SPG19 9q Autosomal dominant
SPG20
Troyer syndrome
275900 SPG20 13q12.3 Autosomal recessive HSP Mutations in this gene have shown to cause distal muscle wasting.[28]
SPG23
Lison syndrome
270750 SPG23 1q24–q32 Autosomal recessive
SPG24 607584 SPG24 13q14 Autosomal recessive
SPG25 608220 SPG25 6q23–q24.1 Autosomal recessive
SPG26 609195 SPG26 12p11.1–q14 Autosomal recessive
SPG27 609041 SPG27 10q22.1–q24.1 Autosomal recessive
SPG28 609340 SPG28 14q21.3–q22.3 Autosomal recessive
SPG29 609727 SPG29 1p31.1–p21.1 Autosomal dominant
SPG30 610357 KIF1A 2q37.3 Autosomal recessive
SPG31 610250 REEP1 2p11.2 Autosomal dominant
SPG32 611252 SPG32 14q12–q21 Autosomal recessive
SPG33 610244 ZFYVE27 10q24.2 Autosomal dominant
SPG34 300750 SPG34 Xq24–q25 X-linked
SPG35 612319 FA2H 16q21–q23.1 Autosomal recessive
SPG36 613096 SPG36 12q23–q24 Autosomal dominant
SPG37 611945 SPG37 8p21.1–q13.3 Autosomal dominant
SPG38 612335 SPG38 4p16–p15 Autosomal dominant
SPG39
NTE-related motor neuron disorder
612020 PNPLA6 19p13.2 Autosomal recessive
SPG41 613364 SPG41 11p14.1–p11.2 Autosomal dominant
SPG42 612539 SLC33A1 3q25.31 Autosomal dominant
SPG44 613206 GJC2 1q42.13 Autosomal recessive Described in one family.[29]
SPG45 613162 SPG45 10q24.3–q25.11 Autosomal recessive
SPG46 614409 SPG46 9p21.2–q21.12 Autosomal recessive Childhood onset, slowly progressive, associated with cerebellar signs, mild cognitive decline, cataracts, and thin corpus callosum on brain imaging.[30]
SPG47 614066 AP4B1 1p13.2 Autosomal recessive Formerly called cerebral palsy – spastic quadriplegic type 5 (CPSQ5).
SPG48 613647 AP5Z1 7p22.1 Autosomal recessive Described only in two patients.
SPG50 612936 AP4M1 7q22.1 Autosomal recessive Formerly called cerebral palsy – spastic quadriplegic type 3 (CPSQ3). Characterised by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation.[31]
SPG51 613744 AP4E1 15q21.2 Autosomal recessive Formerly called cerebral palsy – spastic quadriplegic type 4 (CPSQ4).
SPG52 614067 AP4S1 14q12 Autosomal recessive Formerly called cerebral palsy – spastic quadriplegic type 6 (CPSQ6).
SPOAN 609541  ? 11q13 Autosomal recessive Spastic paraplegia with optic atrophy and neuropathy
SPAR 607565  ?  ?  ? Spastic paraplegia with ataxia and mental retardation
SPPP 182820  ?  ?  ? Spastic paraplegia with precocious puberty
Fryns macrocephaly 600302  ?  ?  ?
Kallmann syndrome 308750  ?  ?  ?

SymptomsEdit

Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticity in the lower limbs, due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HSP are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia.[32] Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses insidiously over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices.[12] More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles.[10] In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, mental retardation, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.[2]

DiagnosisEdit

Initial diagnosis of HSPs relies upon family history, the presence or absence of additional signs and the exclusion of other nongenetic causes of spasticity, the latter being particular important in sporadic cases.[9]

Cerebral and spinal MRI is an important procedure performed in order to rule out other frequent neurological conditions, such as multiple sclerosis, but also to detect associated abnormalities such as cerebellar or corpus callosum atrophy as well as white matter abnormalities. Differential diagnosis of HSP should also exclude spastic diplegia which presents with nearly identical day-to-day effects and even is treatable with similar medicines such as baclofen and orthopedic surgery; at times, these two conditions may look and feel so similar that the only perceived difference may be HSP's hereditary nature versus the explicitly non-hereditary nature of spastic diplegia (however, unlike spastic diplegia and other forms of spastic cerebral palsy, HSP cannot be reliably treated with selective dorsal rhizotomy).

Ultimate confirmation of HSP diagnosis can only be provided by carrying out genetic tests targeted towards known genetic mutations.

PrognosisEdit

Although HSP is a progressive condition and usually starts in the legs and spreads to other muscles, ultimately leading to confinement to bed, the prognosis for individuals with HSP varies greatly. Some cases are seriously disabling while others are less disabling and are compatible with a productive and full life. The majority of individuals with HSP have a normal life expectancy.[2]

TreatmentEdit

No specific treatment is know that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being. Therapeutics offered to HSP patients include:

  • Baclofen – a voluntary muscle relaxant to relax muscles and reduce tone
  • Tizanidine – to treat nocturnal or intermittent spasms
  • Diazepam and Clonazepam – to decrease intensity of spasms
  • Oxybutynin chloride – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
  • Tolterodine tartate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
  • Botulinum toxin – to reduce muscle overactivity
  • Antidepressants (such as selective serotonin re-uptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) – for patients experiencing clinical depression
  • Physical Therapy – to restore and maintain the ability to move; to reduce muscle tone; to maintain or improve range of motion and mobility; to increase strength and coordination; to prevent complications, such as frozen joints, contractures, or bedsores.

Incidence and PrevalenceEdit

Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people.[33] A Norwegian study of more than 2.5 million people published in March 2009 has found an HSP prevalence rate of 7.4/100,000 of population – a higher rate, but in the same range as previous studies. No differences in rate relating to gender were found, and average age at onset was 24 years.[34] In the United States, Hereditary Spastic Paraplegia is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health which means that the disorder affects less than 200,000 people in the US population.[33]

ReferencesEdit

  1. Fink JK (August 2003). The hereditary spastic paraplegias: nine genes and counting. Arch. Neurol. 60 (8): 1045–9.
  2. 2.0 2.1 2.2 Depienne C, Stevanin G, Brice A, Durr A (2007). Hereditary Spastic Paraplegia: An Update. Current Opinions in Neurology 20 (6): 674–680.
  3. Classification.
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  5. DOI:10.1056/NEJMra0910494
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  6. Behan W, Maia M (1974). Strümpell's familial spastic paraplegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry 37 (1): 8–20.
  7. Harding AE (1993). Hereditary Spastic Paraplegias. Semin Neurol 13 (4): 333–336.
  8. Schwarz GA, Liu C-N (1956). Hereditary (familial) spastic paraplegia. Further clinical and pathologic observations. AMA Arch Neurol Psychiatry 75 (2): 144–162.
  9. 9.0 9.1 Harding, AE (1983). Classification of the hereditary ataxias and paraplegias, New York: Lancet.
  10. 10.0 10.1 Harding AE (1981). Hereditary "pure" spastic paraplegia: a clinical and genetic study of 22 families. Journal of Neurology, Neurosurgery and Psychiatry. 44 (10): 871–883.
  11. Schüle R, Schöls L. "Genetics of hereditary spastic paraplegias" Semin Neurol. 2011 Nov;31(5):484-93.PMID: 22266886
  12. 12.0 12.1 Fink JK (2003). The Hereditary Spastic Paraplegias. Archives of Neurology 60 (8): 1045–1049.
  13. Dahme M, Bartsch U, Martini R, Anliker B, Schachner M, Mantei N. (1997). Disruption of the mouse L1 gene leads to malformations of the nervous system. Nature Genetics. 17 (3): 346–349.
  14. Cambi F, Tartaglino L, Lubin FD, McCarren D. (1998). X-liked pure familial spastic paraplegia: characterization of a large kindred with magnetic resonance imaging studies. Archives of Neurology 52 (7): 665–669.
  15. Zhao X, Alvarado D, Rainier S, et al. (2001). Mutations in a novel GTPase cause autosomal dominant hereditary spastic paraplegia. Nature Genetics 29 (3): 326–331.
  16. Muglia M, Magariello A, Nicoletti G, et al. (2002). Further evidence that SPG3A mutations cause autosomal dominant hereditary spastic paraplegia. Annuals of Neurology 51: 669–672.
  17. Zhang Y, Moheban DB, Conway BR, Bhattacharyya A, Segal RA. (2000). Cell surface Trk receptors mediate NGF-survival while internalized receptors regulate NGF-induced differentiation. Journal of Neuroscience. 20 (15): 5671–5678.
  18. Carroll RC, Beattie EC, Xia H, et al. (1999). Dynamin-dependent endocytosis of ionotropic glutamate receptors. Proceedings of National Academy of Sciences of the United States. 96 (24): 14112–14117.
  19. Pitts KR, Yoon Y, Krueger EW, McNiven MA. (1999). The Dynamin-like Protein DLP1 Is Essential for Normal Distribution and Morphology of the Endoplasmic Reticulum and Mitochondria in Mammalian Cells. Molecular Biology of the Cell. 10 (12): 4403–4417.
  20. Ochoa GC, Slepnev VI, Neff L, et al. (2000). A Functional Link between Dynamin and the Actin Cytoskeleton at Podosomes. Journal of Cellular Biology. 150 (2): 377–389.
  21. Hentati A, Deng H-X, Zhai BA, et al. (2000). Novel mutations in spastin gene and absence of correlation with age at onset of symptoms. Neurology 55 (9): 1388–1390.
  22. Rainier S, Jones SM, Esposito C, Otterud B, Leppert M, Fink JK. (1998). Analysis of microtubule-associated protein 1a gene in hereditary spastic paraplegia. Neurology 51 (5): 1509–1510.
  23. De Michele G, De Fusco M, Cavalcanti F, et al. (1998). A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. American Journal of Human Genetics. 63 (1): 135–139.
  24. Ferreirinha F, Quattrini A, Valsecchi V, Errico A, Ballabio A, Rugarli EI. (2001). Mice lacking Paraplegin, a mitochondrial AAA protease involved in hereditary spastic paraplegia, show axonal degeneration and abnormal mitochondria. American Journal of Human Genetics. 69: 196.
  25. DOI:10.1086/341234
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  26. Hansen JJ, Durr A, Cournu-Rebeix I, et al. (2002). Hereditary Spastic Paraplegia SPG13 Is Associated with a Mutation in the Gene Encoding the Mitochondrial Chaperonin Hsp60. American Journal of Human Genetics. 70 (5): 1328–1332.
  27. Hereditary spastic paraplegia 15.
  28. Patel H, Cross H, Proukakis C, et al. (2002). SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nature Genetics. 31 (4): 347–348.
  29. DOI:10.1093/brain/awn328
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  30. DOI:10.1007/s10048-010-0249-2
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  31. DOI:10.1016/j.ajhg.2009.06.004
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  32. McAndrew CR, Harms P. (2003). Paraesthesias during needle-through-needle combined spinal epidural versus single-shot spinal for elective caesarean section. Anaesthesia and Intensive Care. 31 (5): 514–517.
  33. 33.0 33.1 National Institute of Health (2008). Hereditary Spastic Paraplegia Information Page. URL accessed on 2008-04-30.
  34. Brain. 2009 Mar 31. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Erichsen AK, Koht J, Stray–pedersen A, Abdelnoor M, Tallaksen CM. Department of Neurology, Ullevål University Hospital, Oslo, Norway.

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