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Hereditary spastic paraplegia
Classification and external resources
ICD-10 G11.4
ICD-9 334.1
DiseasesDB 33207
eMedicine pmr/45
MeSH 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[1] due to pyramidal tract dysfunction.[2] It is sometimes described as not affecting the sensory tracts,[3] and sometimes described as affecting the sensory tracts late in the course.[4] Conditions other than progressive spasticity may be present, but these are considered complications of the hereditary spastic paraplegia,[5] and only the spastic paraplegia is inherently intrinsic to the condition.

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.

Contents

Neuropathology

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]

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.[9] Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people.[10]

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.[11]

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 recessive.

Autosomal Dominant Pedigree Chart

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.

Relationship between two carrier parents and probabilities of children being unaffected, carriers, or affected

Autosomal recessive is less common. The HSP gene is still located on one of the autosomal chromosomes, but it is recessive. This means that it can only be passed to a child if both mother and father have the HSP gene. They may be affected or carriers. 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.[12]

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.[13]

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.[14]

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.[15]

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.[16] 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.[17] 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.[18] 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.[19]

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.[20]

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.[21]

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.[22]

Type Gene Locus OMIM Description
Autosomal dominant SPG4 (spastin protein) 2p22-p21 182601 SPG4 mutations are pathogenic because of haploinsufficiency (that is, decreased abundance of functionally normal spastin) rather that a dominant negative mechanism.[23] 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.[24]
Autosomal dominant SPG3A (atlastin protein) 14q11-q21 182600 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).[25] 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.[26] Dynamins play essential roles in a wide variety of vesicle trafficking events: regulation of neurotrophic factors;[27] recycling of synaptic vesicles;[28] maintenance and distribution of mitochondria;[29] maintenance of the cytoskeleton via association to actin and microtubules.[30] 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.
Autosomal dominant SPG10 (KIF5A protein) 12q13 604187 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.[31]
Autosomal dominant SPG13 (chaperonin 60, or heat shock protein 60 - HSP60) 2q33.1 605280 Although chaperonin 60 is known to encode mitochondrial proteins, the specific mechanisms by which mutations in that protein cause HSP are not yet known.[32]
Autosomal dominant SPG6 (NIPA1) 15q11.1 600363 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.[33]
Autosomal recessive HSP SPG7 (paraplegin protein) 16q24.3 607259 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.[34]
Autosomal recessive HSP SPG20 (spartin protein) 13q12.3 275900 Mutations in this gene have shown to cause distal muscle wasting.[35]
Autosomal recessive SPG11 15q21.1 604360 -
Autosomal recessive SPG21 [1] -
X-linked SPG2 (Proteolipid protein) Xq22 312920 Mutations in the proteolipid protein cause progressive leukodystrophy and dysmyelination, resulting in axonal degeneration.[36]
X-linked SPG1, Neuronal Cell Adhesion Molecule L1 (L1CAM) [2] Mutations in this protein interfere with its role in neurite outgrowth guidance, neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts.[37]
Autosomal dominant SPG17 11q13 270685 Silver syndrome.
Autosomal recessive SPG23 1q24-q32 270750 Lison syndrome.
Autosomal recessive SPG15 14q24.1 270700 Kjellin syndrome.
Autosomal recessive SPG25 6q23-q24.1 608220
 ?  ?  ? 308750 Kallmann syndrome with Spastic paraplegia.
 ?  ?  ? 182820 Precocious puberty with Spastic paraplegia.
Autosomal dominant SPG9 10q23.3-q24.1 601162
X-linked SPG1 Xq28 303350 Masa syndrome. Also known as Gareis-Mason syndrome and Crash syndrome.
Autosomal recessive SPG5A 8q21.3 270800
X-linked SPG34 Xq24-q25 300750
Autosomal recessive  ? 11q13 609541 SPOAN (Spastic paraplegia, optic atrophy and neuropathy).
X-linked SPG16 Xq11.2 300266
Autosomal dominant SPG29 1p31.1-p21.1 609727
Autosomal dominant SPG8 8q24.13 603563
Autosomal dominant SPG31 2p11.2 610250
Autosomal dominant SPG12 19q13 604805
Autosomal dominant SPG33 10q24.2 610244
Autosomal dominant SPG42 3q25.31 612539
Autosomal dominant SPG37 8p21.1-q13.3 611945
Autosomal recessive SPG26 12p11.1-q14 609195
Autosomal dominant SPG19 9q 607152
Autosomal recessive SPG14 3q27-q28 605229
 ?  ?  ? 600302 Fryns macrocephaly with spastic paraplagia
Autosomal recessive SPG27 10q22.1-q24.1 609041
 ?  ?  ? 607565 SPAR (Spastic paraplagia, ataxia and mental retardation).
Autosomal recessive SPG35 16q21-q23.1 612319
Autosomal recessive SPG5B  ? 600146
Autosomal recessive SPG28 14q21.3-q22.3 609340

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 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

References

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  3. ^ hereditary spastic paraplegia at Dorland's Medical Dictionary
  4. ^ MeSH Spastic+Paraplegia,+Hereditary
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  20. ^ Harding, AE (1983). Classification of the hereditary ataxias and paraplegias. New York: Lancet.  
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  23. ^ 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: 1388–1390.  
  24. ^ 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: 1509–1510.  
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  28. ^ 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: 14112–14117. doi:10.1073/pnas.96.24.14112. PMID 10570207.  
  29. ^ Pitts KR, Yoon Y, Krueger EW, McNiven MA. (1999). "The dynamin-like protein DSP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells.". Molecular Biology of the Cell. 10: 4403–4417.  
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