Hereditary spastic paraplegia
|Hereditary spastic paraplegia|
|Classification and external resources|
Hereditary Spastic Paraplegia (HSP), also called Familial Spastic Paraplegias, French Settlement Disease, or Strumpell-Lorrain disease, is a group of inherited diseases whose main feature is progressive stiffness and contraction (spasticity) in the lower limbs, as a result of damage to or dysfunction of the nerves.
HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as, for example, spastic diplegia. The origins of HSP are entirely separate phenomena from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to try to treat HSP symptomatology.
The condition 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. 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.
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.
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. 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. Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal.
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 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.
Based on mode of inheritance
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 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.
Based on associated gene
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  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.
|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.|
|SPG2||312920||PLP1||Xq22||X-linked||Mutations in the proteolipid protein cause progressive leukodystrophy and dysmyelination, resulting in axonal degeneration.|
|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). 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. Dynamins play essential roles in a wide variety of vesicle trafficking events: regulation of neurotrophic factors; recycling of synaptic vesicles; maintenance and distribution of mitochondria; maintenance of the cytoskeleton via association to actin and microtubules. 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. 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.|
|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.|
|SPG7||607259||SPG7||16q24.3||Autosomal recessive||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.|
|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. Results obtained in a Drosophila model suggest that SPG10 is caused by the loss of endogenous kinesin-1 function due to the dominant-negative action of mutant KIF5A on kinesin-1 complexes.|
|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.|
|270700||ZFYVE26||14q24.1||Autosomal recessive||Characterized by progressive stiffness and increased reflexes in the leg muscles as well as retinal degeneration.|
|270685||BSCL2||11q13||Autosomal dominant||Phenotype overlapping with distal spinal muscular atrophy type VA.|
|SPG18||611225||ERLIN2||8p11.23||Autosomal recessive||Characterised by joint contractures and intellectual disability.|
|275900||SPG20||13q12.3||Autosomal recessive||Mutations in this gene have shown to cause distal muscle wasting.|
NTE-related motor neuron disorder
|SPG44||613206||GJC2||1q42.13||Autosomal recessive||Described in one family.|
|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.|
|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.|
|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|
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. 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. 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. 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.
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.
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).
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 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.
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. 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.
Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people. 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. 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.
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- GeneReviews/NCBI/NIH/UW entry on Spastic Paraplegia 3A
- Hereditary spastic paraplegia on the Open Directory Project
- GeneReviews/NCBI/NIH/UW entry on Hereditary Spastic Paraplegia Overview
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- Hereditary Spastic Paraplegia Support Group
- Hereditary Spastic Paraplegia multi-language communication platform