Hereditary spastic paraplegia
Hereditary spastic paraplegia | |
---|---|
Specialty | Neurology |
Hereditary spastic paraplegia (HSP) is a group of
HSP is caused by defects in transport of proteins, structural proteins, cell-maintaining proteins, lipids, and other substances through the cell. Long nerve fibers (axons) are affected because long distances make nerve cells particularly sensitive to defects in these mentioned mechanisms.[3][4]
The disease was first described in 1880 by the German neurologist
Signs and symptoms
Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive
More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although
In the complex form of the disorder, additional symptoms are present. These include: peripheralAnita Harding[7] classified the HSP in a pure and complicated form. Pure HSP presents with spasticity in the lower limbs, associated with neurogenic bladder disturbance as well as lack of vibration sensitivity (pallhypesthesia). On the other hand, HSP is classified as complex when lower limb spasticity is combined with any additional neurological symptom.[citation needed]
This classification is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia with spasticity, intellectual disability (with spasticity), or leukodystrophy.[7] Some of the genes listed below have been described in other diseases than HSP before. Therefore, some key genes overlap with other disease groups.[citation needed]
Age of onset
In the past, HSP has been classified as early onset beginning in early childhood or later onset in adulthood. The age of onsets has two points of maximum at age 2 and around age 40.[15] New findings propose that an earlier onset leads to a longer disease duration without loss of ambulation or the need for the use of a wheelchair.[15] This was also described earlier, that later onset forms evolve more rapidly.[13]
Cause
HSP is a group of genetic disorders. It follows general
Most altered genes have known function, but for some the function haven't been identified yet. All of them are listed in the gene list below, including their mode of inheritance. Some examples are spastin (SPG4) and paraplegin (SPG7) are both AAA ATPases.[17]
Genotypes
The genes are designated SPG (Spastic gait gene). The gene locations are in the format: chromosome - arm (short or p: long or q) - band number. These designations are for the human genes only. The locations may (and probably will) vary in other organisms. Despite the number of genes known to be involved in this condition ~40% of cases have yet to have their cause identified.[18] In the table below SPG? is used to indicate a gene that has been associated with HSP but has not yet received an official HSP gene designation.
Genotype | OMIM
|
Gene symbol | Gene locus | Inheritance | Age of onset | Other names and characteristics |
---|---|---|---|---|---|---|
SPG1 | 303350 | L1CAM
|
Xq28 | X-linked recessive | Early | MASA syndrome |
SPG2 | 312920 | PLP1
|
Xq22.2 | X-linked recessive | Variable | Pelizaeus–Merzbacher disease |
SPG3A | 182600 | ATL1
|
14q22.1 | Autosomal dominant | Early | Strumpell disease (this Wiki) |
SPG4 | 182601 | SPAST
|
2p22.3 | Autosomal dominant | Variable | |
SPG5A | 270800 | CYP7B1 | 8q12.3 | Autosomal recessive | Variable | |
SPG6 | 600363 | NIPA1 | 15q11.2 | Autosomal dominant | Variable | |
SPG7 | 607259 | SPG7
|
16q24.3 | Autosomal recessive | Variable | |
SPG8 | 603563 | KIAA0196 | 8q24.13 | Autosomal dominant | Adult | |
SPG9A | 601162 | ALDH18A1
|
10q24.1 | Autosomal dominant | Teenage | Cataracts with motor neuronopathy, short stature and skeletal abnormalities |
SPG9B | 616586 | ALDH18A1
|
10q24.1 | Autosomal recessive | Early | |
SPG10 | 604187 | KIF5A | 12q13.3 | Autosomal dominant | Early | |
SPG11 | 604360 | SPG11 | 15q21.1 | Autosomal recessive | Variable | |
SPG12 | 604805 | RTN2 | 19q13.32 | Autosomal dominant | Early | |
SPG13 | 605280 | HSP60
|
2q33.1 | Autosomal dominant | Variable | |
SPG14 | 605229 | ? | 3q27–q28 | Autosomal recessive | Adult | |
SPG15 | 270700 | ZFYVE26 | 14q24.1 | Autosomal recessive | Early | |
SPG16 | 300266 | ? | Xq11.2 | X-linked recessive | Early | |
SPG17 | 270685 | BSCL2 | 11q12.3 | Autosomal dominant | Teenage | |
SPG18 | 611225 | ERLIN2 | 8p11.23 | Autosomal recessive | Early | |
SPG19 | 607152 | ? | 9q | Autosomal dominant | Adult onset | |
SPG20 | 275900 | SPG20 | 13q13.3 | Autosomal recessive | Early onset | Troyer syndrome
|
SPG21 | 248900 | ACP33
|
15q22.31 | Autosomal recessive | Early onset | MAST syndrome |
SPG22 | 300523 | SLC16A2
|
Xq13.2 | X-linked recessive | Early onset | Allan–Herndon–Dudley syndrome |
SPG23 | 270750 | RIPK5 | 1q32.1 | Autosomal recessive | Early onset | Lison syndrome
|
SPG24 | 607584 | ? | 13q14 | Autosomal recessive | Early onset | |
SPG25 | 608220 | ? | 6q23–q24.1 | Autosomal recessive | Adult | |
SPG26 | 609195 | B4GALNT1 | 12q13.3 | Autosomal recessive | Early onset | |
SPG27 | 609041 | ? | 10q22.1–q24.1 | Autosomal recessive | Variable | |
SPG28 | 609340 | DDHD1 | 14q22.1 | Autosomal recessive | Early onset | |
SPG29 | 609727 | ? | 1p31.1–p21.1 | Autosomal dominant | Teenage | |
SPG30 | 610357 | KIF1A | 2q37.3 | Autosomal recessive | Teenage | |
SPG31 | 610250 | REEP1 | 2p11.2 | Autosomal dominant | Early onset | |
SPG32 | 611252 | ? | 14q12–q21 | Autosomal recessive | Childhood | |
SPG33 | 610244 | ZFYVE27 | 10q24.2 | Autosomal dominant | Adult | |
SPG34 | 300750 | ? | Xq24–q25 | X-linked recessive | Teenage/Adult | |
SPG35 | 612319 | FA2H | 16q23.1 | Autosomal recessive | Childhood | |
SPG36 | 613096 | ? | 12q23–q24 | Autosomal dominant | Teenage/Adult | |
SPG37 | 611945 | ? | 8p21.1–q13.3 | Autosomal dominant | Variable | |
SPG38 | 612335 | ? | 4p16–p15 | Autosomal dominant | Teenage/Adult | |
SPG39 | 612020 | PNPLA6
|
19p13.2 | Autosomal recessive | Childhood | |
SPG41 | 613364 | ? | 11p14.1–p11.2 | Autosomal dominant | Adolescence | |
SPG42 | 612539 | SLC33A1
|
3q25.31 | Autosomal dominant | Variable | |
SPG43 | 615043 | C19orf12 | 19q12 | Autosomal recessive | Childhood | |
SPG44 | 613206 | GJC2 | 1q42.13 | Autosomal recessive | Childhood/teenage | |
SPG45 | 613162 | NT5C2 | 10q24.32–q24.33 | Autosomal recessive | Infancy | |
SPG46 | 614409 | GBA2 | 9p13.3 | Autosomal recessive | Variable | |
SPG47 | 614066 | AP4B1 | 1p13.2 | Autosomal recessive | Childhood | |
SPG48 | 613647 | AP5Z1 | 7p22.1 | Autosomal recessive | 6th decade | |
SPG49 | 615041 | TECPR2 | 14q32.31 | Autosomal recessive | Infancy | |
SPG50 | 612936 | AP4M1 | 7q22.1 | Autosomal recessive | Infancy | |
SPG51 | 613744 | AP4E1 | 15q21.2 | Autosomal recessive | Infancy | |
SPG52 | 614067 | AP4S1 | 14q12 | Autosomal recessive | Infancy | |
SPG53 | 614898 | VPS37A | 8p22 | Autosomal recessive | Childhood | |
SPG54 | 615033 | DDHD2 | 8p11.23 | Autosomal recessive | Childhood | |
SPG55 | 615035 | C12orf65 | 12q24.31 | Autosomal recessive | Childhood | |
SPG56 | 615030 | CYP2U1 | 4q25 | Autosomal recessive | Childhood | |
SPG57 | 615658 | TFG | 3q12.2 | Autosomal recessive | Early | |
SPG58 | 611302 | KIF1C | 17p13.2 | Autosomal recessive | Within first two decades | Spastic ataxia 2 |
SPG59 | 603158 | USP8 | 15q21.2 | ?Autosomal recessive | Childhood | |
SPG60 | 612167 | WDR48 | 3p22.2 | ?Autosomal recessive | Infancy | |
SPG61 | 615685 | ARL6IP1 | 16p12.3 | Autosomal recessive | Infancy | |
SPG62 | 615681 | ERLIN1 | 10q24.31 | Autosomal recessive | Childhood | |
SPG63 | 615686 | AMPD2
|
1p13.3 | Autosomal recessive | Infancy | |
SPG64 | 615683 | ENTPD1 | 10q24.1 | Autosomal recessive | Childhood | |
SPG66 | 610009 | ARSI | 5q32 | ?Autosomal dominant | Infancy | |
SPG67 | 615802 | PGAP1 | 2q33.1 | Autosomal recessive | Infancy | |
SPG68 | 609541 | KLC2 | 11q13.1 | Autosomal recessive | Childhood | SPOAN syndrome |
SPG69 | 609275 | RAB3GAP2 | 1q41 | Autosomal recessive | Infancy | Martsolf syndrome, Warburg Micro syndrome |
SPG70 | 156560 | MARS | 12q13 | ?Autosomal dominant | Infancy | |
SPG71 | 615635 | ZFR | 5p13.3 | ?Autosomal recessive | Childhood | |
SPG72 | 615625 | REEP2 | 5q31 | Autosomal recessive; autosomal dominant |
Infancy | |
SPG73 | 616282 | CPT1C
|
19q13.33 | Autosomal dominant | Adult | |
SPG74 | 616451 | IBA57 | 1q42.13 | Autosomal recessive | Childhood | |
SPG75 | 616680 | MAG
|
19q13.12 | Autosomal recessive | Childhood | |
SPG76 | 616907 | CAPN1
|
11q13 | Autosomal recessive | Adult | |
SPG77 | 617046 | FARS2 | 6p25 | Autosomal recessive | Childhood | |
SPG78 | 617225 | ATP13A2 | 1p36 | Autosomal recessive | Adult | Kufor–Rakeb syndrome |
SPG79 | 615491 | UCHL1
|
4p13 | Autosomal recessive | Childhood | |
HSNSP | 256840 | CCT5 | 5p15.2 | Autosomal recessive | Childhood | Hereditary sensory neuropathy with spastic paraplegia
|
SPG? | SERAC1 | 6q25.3 | Juvenile | MEGDEL syndrome | ||
SPG? | 605739 | KY | 3q22.2 | Autosomal recessive | Infancy | |
SPG? | PLA2G6 | 22q13.1 | Autosomal recessive | Childhood | ||
SPG? | ATAD3A | 1p36.33 | Autosomal dominant | Childhood | Harel-Yoon syndrome | |
SPG? | KCNA2 | 1p13.3 | Autosomal dominant | Childhood | ||
SPG? | Granulin | 17q21.31 | ||||
SPG? | POLR3A | 10q22.3 | Autosomal recessive |
Pathophysiology
The major feature of HSP is a length-dependent axonal degeneration.
HSP affects several pathways in motor neurons. Many genes were identified and linked to HSP. It remains a challenge to accurately define the key players in each of the affected pathways, mainly because many genes have multiple functions and are involved in more than one pathway[citation needed].
Axon pathfinding
Pathfinding is important for axon growth to the right destination (e.g. another nerve cell or a muscle). Significant for this mechanism is the L1CAM gene, a cell surface glycoprotein of the immunoglobulin superfamily. Mutations leading to a loss-of-function in L1CAM are also found in other X-linked syndromes. All of these disorders display corticospinal tract impairment (a hallmark feature of HSP). L1CAM participates in a set of interactions, binding other L1CAM molecules as well as extracellular cell adhesion molecules, integrins, and proteoglycans or intracellular proteins like ankyrins.[citation needed]
The pathfinding defect occurs via the association of L1CAM with
Lipid metabolism
Axons in the central and peripheral nervous system are coated with an insulation, the myelin layer, to increase the speed of action potential propagation. Abnormal myelination in the CNS is detected in some forms of hsp HSP.[20] Several genes were linked to myelin malformation, namely PLP1, GFC2 and FA2H.[3] The mutations alter myelin composition, thickness and integrity.[citation needed]
Endoplasmic reticulum (ER) is the main organelle for lipid synthesis. Mutations in genes encoding proteins that have a role in shaping ER morphology and lipid metabolism were linked to HSP. Mutations in
Endosomal trafficking
Neurons take in substances from their surrounding by endocytosis. Endocytic vesicles fuse to endosomes in order to release their content. There are three main compartments that have endosome trafficking: Golgi to/from endosomes; plasma membrane to/from early endosomes (via recycling endosomes) and late endosomes to lysosomes. Dysfunction of endosomal trafficking can have severe consequences in motor neurons with long axons, as reported in HSP. Mutations in AP4B1 and KIAA0415 are linked to disturbance in vesicle formation and membrane trafficking including selective uptake of proteins into vesicles. Both genes encode proteins that interact with several other proteins and disrupt the secretory and endocytic pathways.[20]
Mitochondrial function
Mitochondrial dysfunctions have been connected with developmental and degenerative neurological disorders. Only a few HSP genes encode mitochondrial proteins. Two mitochondrial resident proteins are mutated in HSP: paraplegin and chaperonin 60. Paraplegin is a m-AAA metalloprotease of the inner mitochondrial membrane. It functions in ribosomal assembly and protein quality control. The impaired chaperonin 60 activity leads to impaired mitochondrial quality control. Two genes DDHD1 and CYP2U1 have shown alteration of mitochondrial architecture in patient fibroblasts. These genes encode enzymes involved in fatty-acid metabolism.[citation needed]
Diagnosis
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.[7]
Cerebral and spinal
Ultimate confirmation of HSP diagnosis can only be provided by carrying out
Classification
Hereditary spastic paraplegias can be classified based on the symptoms; mode of inheritance; the patient's age at onset; the affected genes; and biochemical pathways involved.[citation needed]
Treatment
No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being.[citation needed] Therapeutics offered to HSP patients include:
- Baclofen – a voluntary muscle relaxant to relax muscles and reduce tone. This can be administered orally or intrathecally. (Studies in HSP [22][23][24])
- Tizanidine – to treat nocturnal or intermittent spasms (studies available [25][26])
- Diazepam and clonazepam – to decrease intensity of spasms[citation needed]
- Oxybutynin chloride – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems[citation needed]
- Tolterodine tartrate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems[citation needed]
- Cro System – to reduce muscle overactivity (existing studies for spasticity [27][28][29])
- Botulinum toxin – to reduce muscle overactivity (existing studies for HSP patients[30][31])
- Antidepressants (such as selective serotonin re-uptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) – for patients experiencing clinical depression[citation needed]
- 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.[citation needed]
Prognosis
Although HSP is a progressive condition, the prognosis for individuals with HSP varies greatly. It primarily affects the legs although there can be some upperbody involvement in some individuals. Some cases are seriously disabling whilst others leave people able to do most ordinary activities to an ordinary extent without needing adjustments. The majority of individuals with HSP have a normal life expectancy.[14]
Epidemiology
Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people.[32] 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.[33] 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.[32]
References
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- ^ Lorrain, Maurice. Contribution à l'étude de la paraplégie spasmodique familiale: travail de la clinique des maladies du système nerveux à la Salpêtrière. G. Steinheil, 1898.
- ^ S2CID 6780732.
- PMID 14601273.
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- ^ "Hereditary spastic paraplegia". nhs.uk. 2017-10-18. Retrieved 2018-01-28.
- PMID 12925358.
- ^ PMID 7310405.
- ^ S2CID 35343501.
- ^ S2CID 10558032.
- ^ a b Schüle R, Schöls L (2011) Genetics of hereditary spastic paraplegias. Semin Neurol 31(5):484-493
- ^ Wang YG, Shen L (2009) AAA ATPases and hereditary spastic paraplegia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 26(3):298-301
- ^ Helbig KL, Hedrich UB, Shinde DN, Krey I, Teichmann AC, Hentschel J, Schubert J, Chamberlin AC, Huether R, Lu HM4, Alcaraz WA, Tang S, Jungbluth C, Dugan SL, Vainionpää L, Karle KN, Synofzik M, Schöls L, Schüle R, Lehesjoki AE, Helbig I, Lerche H, Lemke JR (2016) A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia. Ann Neurol 80(4)
- ^ Wharton SB, McDermott CJ, Grierson AJ, Wood JD, Gelsthorpe C, Ince PG, Shaw PJ (2003) The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. J Neuropathol Exp Neurol 62:1166–1177
- ^ a b c Noreau, A., Dion, P.A. & Rouleau, G.A., 2014. Molecular aspects of hereditary spastic paraplegia. Experimental Cell Research, 325(1), pp.18–26
- ^ Lo Giudice, T. et al., 2014. Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms. Experimental Neurology, 261, pp.518–539.
- ^ Margetis K, Korfias S, Boutos N, Gatzonis S, Themistocleous M, Siatouni A, et al. Intrathecal baclofen therapy for the symptomatic treatment of hereditary spastic paraplegia. Clinical Neurology and Neurosurgery. 2014;123:142-5.
- ^ Heetla HW, Halbertsma JP, Dekker R, Staal MJ, van Laar T. Improved Gait Performance in a Patient With Hereditary Spastic Paraplegia After a Continuous Intrathecal Baclofen Test Infusion and Subsequent Pump Implantation: A Case Report. Archives of Physical Medicine and Rehabilitation. 2015;96(6):1166-9.
- ^ Klebe S, Stolze H, Kopper F, Lorenz D, Wenzelburger R, Deuschl G, et al. Objective assessment of gait after intrathecal baclofen in hereditary spastic paraplegia. Journal of Neurology. 2005;252(8):991-3.
- ^ Knutsson E, Mårtensson A, Gransberg L. Antiparetic and antispastic effects induced by tizanidine in patients with spastic paresis. Journal of the Neurological Sciences. 1982;53(2):187-204.
- ^ Bes A, Eyssette M, Pierrot-Deseilligny E, Rohmer F, Warter JM. A multi-centre, double-blind trial of tizanidine, a new antispastic agent, in spasticity associated with hemiplegia. Current Medical Research and Opinion. 1988;10(10):709-18.
- ^ Celletti C, Camerota F. Preliminary evidence of focal muscle vibration effects on spasticity due to cerebral palsy in a small sample of Italian children. Clin Ter. 162(5): 125–8. 2011
- ^ Caliandro P, Celletti C, Padua L, Minciotti I, Russo G, Granata G, La Torre G, Granieri E, Camerota F. Focal muscle vibration in the treatment of upper limb spasticity: a pilot randomized controlled trial in patients with chronic stroke. Arch Phys Med Rehabil. 93(9):1656-61. 2012.
- ^ . Casale R1, Damiani C, Maestri R, Fundarò C, Chimento P, Foti C. Focalized 100 Hz vibration improves function and reduces upper limb spasticity: a double-blind controlled study. Eur J Phys Rehabil Med. 2014 Oct;50(5):495-504. 2014.
- ^ Hecht MJ, Stolze H, Auf Dem Brinke M, Giess R, Treig T, Winterholler M, et al. Botulinum neurotoxin type A injections reduce spasticity in mild to moderate hereditary spastic paraplegia— Report of 19 cases. Movement Disorders. 2008;23(2):228-33.
- ^ de Niet M, de Bot ST, van de Warrenburg BP, Weerdesteyn V, Geurts AC. Functional effects of botulinum toxin type-A treatment and subsequent stretching of spastic calf muscles: A study in patients with hereditary spastic paraplegia. Journal of rehabilitation medicine. 2015;47(2):147-53.
- ^ a b National Institute of Health (2008). "Hereditary Spastic Paraplegia Information Page". Archived from the original on 2014-02-21. Retrieved 2008-04-30.
- PMID 19339254.
Further reading
- GeneReviews/NCBI/NIH/UW entry on Spastic Paraplegia 3A
- GeneReviews/NCBI/NIH/UW entry on Hereditary Spastic Paraplegia Overview
- Warner, Tom (January–February 2007). "Hereditary Spastic Paraplegia" (PDF). Advances in Clinical Neuroscience and Rehabilitation. 6 (6): 16–17. Archived from the original (PDF) on 2020-11-27. Retrieved 2013-05-20.