Hereditary spastic paraplegia
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2008-06-19T14:55:01Z
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{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = |
ICD10 = {{ICD10|G|11|4|g|10}} |
ICD9 = {{ICD9|334.1}} |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = pmr |
eMedicineTopic = 45 |
MeshID = D015419 |
}}
'''Hereditary Spastic Paraplegia''' (HSP), also called '''Familial Spastic Paraplegias''' or '''Strumpell-Lorrain disease''', is not a single disease but is a heterogeneous group of genetic disorders in which the main feature is progressive [[spasticity]] in the lower limbs due to [[pyramidal tract]] dysfunction.<ref>{{cite journal |author=Depienne C, Stevanin G, Brice A, Durr A |title=Hereditary Spastic Paraplegia: An Update |journal=Current Opinions in Neurology |volume=20 |pages=674–680 |year=2007}}</ref>
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.
==Neuropathology==
The major neuropathologic feature of HPS 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]].<ref>{{cite journal |author=Behan W, Maia M |title=Strumpell's familial spastic paraplegia: genetics and neuropathology. |journal=J Neurol Neurosurg Psychiatry |volume=37 |pages=8–20 |year=1974}}</ref> 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]]. <ref>{{cite journal |author=Harding AE |title=Hereditary Spastic Paraplegias |journal=Semin Neurol |volume=13 |pages=333–336 |year=1993}}</ref> Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal.<ref>{{cite journal |author=Schwarz GA, Liu C-N |title=Hereditary (familial) spastic paraplegia. Further clinical and pathologic observations |journal=AMA Arch Neurol Psychiatry |volume=75 |pages=144–162 |year=1956}}</ref>
==Incidence and Prevalence==
Hereditary Spastic Paraplegia is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the [[National Institutes of Health]]. This means that Hereditary Spastic Paraplegia affects less than 200,000 people in the US population.<ref>{{Citation |last = National Institute of Health |title = Hereditary Spastic Paraplegia Information Page | year = 2008 | url = http://www.ninds.nih.gov/disorders/hereditary_spastic_paraplegia/hereditary_spastic_paraplegia.htm |accessdate = 2008-04-30}}</ref> Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people.<ref>{{Citation |last = National Institute of Health |title = Hereditary Spastic Paraplegia Information Page | year = 2008 | url = http://www.ninds.nih.gov/disorders/hereditary_spastic_paraplegia/hereditary_spastic_paraplegia.htm |accessdate = 2008-04-30}}</ref>
==Classification==
Hereditary Spastic Paraplegias are classified based on the symptoms (pure form versus complicated form); based on their mode of inheritance ([[autosomal dominant]], [[autosomal recessive]] or [[x-linked]]); and based on the patient’s age at onset.
===Based on symptoms===
[[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]].<ref>{{cite book |last = Harding |first = AE | title = Classification of the hereditary ataxias and paraplegias | publisher = Lancet | date = 1983 | location = New York}}</ref>
===Based on mode of inheritance===
As mentioned above, HSP is group of genetic disorders, each caused by different genes that cause very similar symptoms. The mode of inheritance of the HSP, hence the particular features of the gene involved, affect the risk of inheriting the disorder. There are three different modes of inheritance: [[autosomal dominant]], [[autosomal recessive]] and [[x-linked]].
[[Autosomal dominant]] represents the most common mode of inheritance. Autosomal means that the HSP gene is located on one of the autosomal chromosomes. The [[gene]] can be present in either sex, and it can be passed down from either the mother or the father to a son or a daughter. Dominant means that only one HSP [[gene]] is needed to cause the disorder. Since there is a 50% chance a child will receive the dominant HSP [[gene]] mutation from the affected parent, there is a 50% chance the child will inherit the [[gene]], hence the disorder. This is the same risk for every birth, independent of every other birth.<ref>{{cite book |last = Pagon R., Cassidy S., Bird T., Dinulos M., Feldman G., Smith R., Dolan C. | title = Gene Review. | publisher = University of Washington | date = 2008| location = Seatlle (WA)}}</ref>
[[Autosomal recessive]] forms of HSP are also located on one of the [[autosomes]]. Therefore, they can be present in males or females and passed to males or females. Since it is [[recessive]], two copies of the [[gene]] are needed to result in the disorder, one from each parent. In these forms, neither parent has HSP. Instead, they are [[carriers]]. They each have one mutant HSP [[gene]] and one normal HSP gene. A mutant HSP gene that is recessive can be passed down silently for generations until someone finally inherits the recessive gene from both parents and inherits the disorder. If both parents are [[carriers]] for a recessive HSP gene mutation, each of their children has a 25% chance of developing HSP. There is a 50% risk the child will be a [[carrier]] like the parents. Finally, there is a 25% chance that the child will receive only the non-mutated forms of the gene. This child would not be affected by HSP, nor would be a carrier.<ref>{{cite book |last = Pagon R., Cassidy S., Bird T., Dinulos M., Feldman G., Smith R., Dolan C. | title = Gene Review. | publisher = University of Washington | date = 2008| location = Seatlle (WA)}}</ref>
Finally, some [[genes]] responsible for HSP are found on the [[X chromosome]], hence are called X-linked. The inheritance risks and severity of this type of HSP differ depending on the individual’s sex. Women with an X-linked mutant HSP gene are generally not affected by the disorder, or, if they are, usually have less severe symptoms than males.<ref>{{cite book |last = Pagon R., Cassidy S., Bird T., Dinulos M., Feldman G., Smith R., Dolan C. | title = Gene Review. | publisher = University of Washington | date = 2008| location = Seatlle (WA)}}</ref>
===Based on patient's age at onset===
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.<ref>{{cite journal |author=Harding AE |title=Hereditary “pure” spastic paraplegia: a clinical and genetic study of 22 families. |journal=Journal of Neurology, Neurosurgery and Psychiatry. |volume=44 | issue=10 |pages=871–883 |year=1981}}</ref>
==Symptoms==
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 HPS are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and [[paresthesia]].<ref>{{cite journal |author= McAndrew CR, Harms P. |title= Paraesthesias during needle-through-needle combined spinal epidural versus single-shot spinal for elective caesarean section. |journal=Anaesthesia and Intensive Care. |volume=31 | issue=5 |pages=514–517 |year=2003}}</ref>
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.<ref>{{cite journal |author= Fink JK |title= The Hereditary Spastic Paraplegias. |journal=Archives of Neurology. |volume=60 |pages=1045–1049 |year=2003}}</ref>
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.<ref>{{cite journal |author=Harding AE |title=Hereditary “pure” spastic paraplegia: a clinical and genetic study of 22 families. |journal=Journal of Neurology, Neurosurgery and Psychiatry. |volume=44 | issue=10 |pages=871–883 |year=1981}}</ref>
In the complex form of the disorder, additional symptoms are present. These include: peripheral [[neuropathy]], [[amyotrophy]], [[ataxia]], [[mental retardation]], [[ichtyosis]], [[epilepsy]], optic [[neuropathy]], [[dementia]], [[deafness]], or problems with speech, swallowing or breathing.<ref>{{cite journal |author=Depienne C, Stevanin G, Brice A, Durr A |title=Hereditary Spastic Paraplegia: An Update |journal=Current Opinions in Neurology |volume=20 |pages=674–680 |year=2007}}</ref>
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.<ref>{{cite journal |author=Depienne C, Stevanin G, Brice A, Durr A |title=Hereditary Spastic Paraplegia: An Update |journal=Current Opinions in Neurology |volume=20 |pages=674–680 |year=2007}}</ref>
==Diagnosis==
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. Specialized genetic testing targeted towards known genetic [[mutations]] are available at certain specialized centers. Cerebral and spinal [[MRI]] is an important procedure 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.<ref>{{cite book |last = Harding |first = AE | title = Classification of the hereditary ataxias and paraplegias | publisher = Lancet | date = 1983 | location = New York}}</ref>
==Prognosis==
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]].<ref>{{cite journal |author=Depienne C, Stevanin G, Brice A, Durr A |title=Hereditary Spastic Paraplegia: An Update |journal=Current Opinions in Neurology |volume=20 |pages=674–680 |year=2007}}</ref>
==Genetic Causes==
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 20 different HSP [[loci]], designated SPG (SPastic parapleGia) 1 through 21 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.<ref>{{cite journal |author= Fink JK |title= The Hereditary Spastic Paraplegias. |journal=Archives of Neurology. |volume=60 |pages=1045–1049 |year=2003}}</ref>
{| class="wikitable"
| '''Type ''' || '''Gene''' || '''Description'''
|-
| Autosomal dominant || SPG4 ([[spastin]] protein) || SPG4 mutations are pathogenic because of [[haploinsufficiency]] (that is, decreased abundance of functionally normal [[spastin]]) rather that a dominant negative mechanism.<ref>{{cite journal |author= Hentati A, Deng H-X, Zhai BA, et al. |title= Novel mutations in spastin gene and absence of correlation with age at onset of symptoms |journal=Neurology |volume=55 |pages=1388–1390 |year=2000}}</ref> 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.<ref>{{cite journal |author= Rainier S, Jones SM, Esposito C, Otterud B, Leppert M, Fink JK. |title= Analysis of microtubule-associated protein 1a gene in hereditary spastic paraplegia |journal=Neurology |volume=51 |pages=1509–1510 |year=1998}}</ref>
|-
| Autosomal dominant || [[SPG3A]] (atlastin protein) || 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]]). <ref>{{cite journal |author= Zhao X, Alvarado D, Rainier S, et al. |title= Mutations in a novel GTPase cause autosomal dominant hereditary spastic paraplegia. |journal=Nature Genetics |volume=29 |pages=326–331 |year=2001 |doi= 10.1038/ng758}}</ref> 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. <ref>{{cite journal |author= Muglia M, Magariello A, Nicoletti G, et al. |title= Further evidence that SPG3A mutations cause autosomal dominant hereditary spastic paraplegia. |journal=Annuals of Neurology |volume=51 |pages=669–672 |year=2002}}</ref> [[Dynamins]] play essential roles in a wide variety of [[vesicle trafficking]] events: regulation of [[neurotrophic factors]]<ref>{{cite journal |author= Zhang Y, Moheban DB, Conway BR, Bhattacharyya A, Segal RA. |title= Cell surface Trk receptors mediate NGF-survival while internalized receptors regulate NGF-induced differentiation. |journal=Journal of Neuroscience. |volume=20 |pages=5671–5678 |year=2000}}</ref>; recycling of [[synaptic vesicles]] <ref>{{cite journal |author= Carroll RC, Beattie EC, Xia H, et al. |title= Dynamin-dependent endocytosis of ionotropic glutamate receptors. |journal=Proceedings of National Academy of Sciences of the United States. |volume=96 |pages=14112–14117 |year=1999 |doi= 10.1073/pnas.96.24.14112 |pmid= 10570207}}</ref>; maintenance and distribution of [[mitochondria]]<ref>{{cite journal |author= Pitts KR, Yoon Y, Krueger EW, McNiven MA. |title= The dynamin-like protein DSP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. |journal=Molecular Biology of the Cell. |volume=10 |pages=4403–4417 |year=1999}}</ref>; maintenance of the [[cytoskeleton]] via association to [[actin]] and [[microtubules]] <ref>{{cite journal |author= Ochoa GC, Slepnev VI, Neff L, et al. |title= A functional link between dynamin and the actin-cytoskeleton at podosomes. |journal=Journal of Cellular Biology. |volume=150 |pages=377–389 |year=2000 |doi= 10.1083/jcb.150.2.377 |pmid= 10908579}}</ref>. 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.
|-
| Autosomal dominant || SPG10 ([[KIF5A]] protein) || 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.<ref>{{cite journal |author= Pericak-Vance MA, Kloss MT, Reid E, et al. |title= A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). |journal=American Journal of Human Genetics. |volume=71 |pages=165 |year=2002}}</ref>
|-
| Autosomal dominant || SPG13 (chaperonin 60, or heat shock protein 60 - [[HSP60]]) || Although chaperonin 60 is known to encode mitochondrial proteins, the specific mechanisms by which mutations in that protein cause HSP are not yet known.<ref>{{cite journal |author= Hansen JJ, Durr A, Cournu-Rebeix I, et al. |title= Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondria chaperonin His60. |journal=American Journal of Human Genetics. |volume=70 |pages=1328–1332 |year=2002 |doi= 10.1086/339935}}</ref>
|-
| Autosomal dominant || SPG6 ([[NIPA1]]) || 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.<ref>{{cite journal |author= De Michele G, De Fusco M, Cavalcanti F, et al. |title= A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3 |journal=American Journal of Human Genetics. |volume=63 |pages=135–139 |year=1998 |doi= 10.1086/301930}}</ref>
|-
| Autosomal recessive HSP || [[SPG7]] (paraplegin protein) || 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.<ref>{{cite journal |author= Ferreirinha F, Quattrini A, Valsecchi V, Errico A, Ballabio A, Rugarli EI. |title= Mice lacking Paraplegin, a mitochondrial AAA protease involved in hereditary spastic paraplegia, show axonal degeneration and abnormal mitochondria. |journal=American Journal of Human Genetics. |volume=69 |pages=196 |year=2001}}</ref>
|-
| Autosomal recessive HSP || [[SPG20]] (spartin protein) || Mutations in this gene have shown to cause distal [[muscle wasting]].<ref>{{cite journal |author= Patel H, Cross H, Proukakis C, et al. |title= SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. |journal=Nature Genetics. |volume=31 |pages=347–348 |year=2002}}</ref>
|-
| Autosomal recessive || [[SPG11]] || -
|-
| Autosomal recessive || [[SPG21]] || -
|-
| X-linked || SPG2 ([[Proteolipid protein]]) || Mutations in the [[proteolipid protein]] cause progressive [[leukodystrophy]] and dysmyelination, resulting in axonal degeneration.<ref>{{cite journal |author= Cambi F, Tartaglino L, Lubin FD, McCarren D. |title= X-liked pure familial spastic paraplegia: characterization of a large kindred with magnetic resonance imaging studies. |journal=Archives of Neurology. |volume=52 |pages=665–669 |year=1998}}</ref>
|-
| X-linked || SPG1, Neuronal Cell Adhesion Molecule L1 ([[L1CAM]]) || Mutations in this protein interfere with its role in [[neurite]] outgrowth guidance, neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts.<ref>{{cite journal |author= Dahme M, Bartsch U, Martini R, Anliker B, Schachner M, Mantei N. |title= Disruption of the mouse L1 gene leads to malformations of the nervous system. |journal=Nature Genetics. |volume=17 |pages=346–349 |year=1997 |doi= 10.1038/ng1197-346}}</ref>
|}
==Treatment==
There are no specific treatments to prevent, slow, or reverse HSP. Treatment of HSP mainly consists of symptomatic medical management, to promote physical and emotional well-being. Some of the treatments 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 reuptake 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.
==Research==
The [[NINDS|National Institute of Neurological Disorders and Stroke]] supports research on genetic disorders such as HSP. Genes that are responsible for several forms of HSP have already been identified, and many more will likely be identified in the future. Understanding how these genes cause HSP will lead to ways to prevent, treat, and cure HSP.
== External links ==
* {{DMOZ|Health/Conditions_and_Diseases/Genetic_Disorders/Hereditary_Spastic_Paraplegia/}}
==References==
{{Reflist|2}}
{{Diseases of the nervous system}}
[[Category:Neurology]]
[[Category:Genetic disorders]]
[[de:Spastische Spinalparalyse]]
[[es:Síndrome de Strumpell Lorrain]]
[[fr:Paraplégie spastique familiale]]
[[nl:Ziekte van Strümpell]]