Hereditary spastic paraplegia
|Hereditary spastic paraplegia|
|Classification and external resources|
Hereditary spastic paraplegia (HSP), also known as hereditary spastic paraparesis, 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. Over 70 genotypes have been described.
Over 50 genetic loci have been linked to this condition. Ten genes have been identified with autosomal dominant inheritance. One of these SPG4 accounts for ~50% of all cases. Twelve genes are known to be inherited in an autosomal recessive fashion. Collectively this latter group account for ~1/3 cases.
The functions of a number of these genes are known: spastin (SPG4) and paraplegin (SPG7) are both AAA ATPases. Spastizin (ZFYVE26) is zinc finger transcription factor: mutations in this gene cause SPG15. The inheritance of SPG15 is autosomal recessive.
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.
Summary of 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.
|Genotype||Gene name||Gene function||Inheritance||Age of onset||Gene location|
|SPG1||L1 cell adhesion molecule||Glycoprotein||X linked recessive||Early||Xq28|
|SPG2||Myelin protein||Transmembrane protein||X linked recessive||Variable||Xq22.2|
|SPG3A||Atlastin||Membrane anchored GTPase||Autosomal dominant||Early||14q22.1|
|SPG4||Spastin||AAA ATPase||Autosomal dominant||Variable||2p22.3|
|SPG5||25-hydroxycholesterol 7-alpha-hydroxylase||Cytochrome P45||Autosomal recessive||Variable||8q12.3|
|SPG6||Non-imprinted in Prader-Willi/Angelman syndrome region protein 1||Transmembrane protein||Autosomal dominant||Teenage||15q11.2|
|SPG7||Paraplegin||AAA ATPase||Autosomal dominant||Variable||16q24.3|
|SPG8||Strumpellin||Valosin containing endoplasmic reticulum protein||Autosomal dominant||Adult||8q24.13|
|SPG9||Not currently known||Autosomal dominant||Teenage||10q23.3–24.2|
|SPG10||Kinesin heavy chain isoform 5A||Kinesin chain||Autosomal dominant||Early||12q13.3|
|SPG11||Spatacsin||Lysosomal protein||Autosomal recessive||Variable||15q21.1|
|SPG12||Reticulon 2||Endoplasmic reticulum protein||Autosomal dominant||Early||19q13.32|
|SPG13||Chaperonin 60/Heat shock protein 60||Heat shock protein||Autosomal dominant||Variable||2q33.1|
|SPG14||Not currently known||Autosomal recessive||Adult||3q27–q28|
|SPG15||Spastizin||Zinc finger containing protein||Autosomal recessive||Early||14q24.1|
|SPG16||Not currently known||X linked recessive||Early||Xq11.2|
|SPG17||Seipin||Integral membrane protein of the endoplasmic reticulum||Autosomal dominant||Teenage||11q12.3|
|SPG18||ERLIN2||Endoplasmic reticulum protein||Autosomal recessive||Early||8p11.23|
|SPG19||Not currently known||Autosomal dominant||Adult onset||9q|
|SPG20||Spartin||FK506-binding protein||Autosomal recessive||Early onset||13q13.3|
|SPG21||Acidic cluster protein 33/Maspardin||Membrane protein||Autosomal recessive||Early onset||15q22.31|
|SPG22||Monocarboxylate transporter 8||Transmembrane transport protein||X linked recessive||Early onset||Xq13.2|
|SPG23||Not currently known||Autosomal recessive||Early onset||1q24–q32|
|SPG24||Not currently known||Autosomal recessive||Early onset||13q14|
|SPG25||Not currently known||Autosomal recessive||Adult||6q23–q24.1|
|SPG26||Beta-1,4 N-acetylgalactosaminyltransferase 1||Autosomal recessive||Early onset||12p11.1–q14|
|SPG27||Not currently known||Autosomal recessive||Variable||10q22.1–q24.1|
|SPG28||DDHD1/Phosphatidic acid phospholipase A1||Autosomal recessive||Early onset||14q22.1|
|SPG29||Not currently known||Autosomal dominant||Teenage||1p31.1–p21.1|
|SPG30||Kinesin 3||Kinesin protein||Autosomal recessive||Teenage||2q37.3|
|SPG31||Receptor expression-enhancing protein 1||Endoplasmic reticulum protein||Autosomal dominant||Early onset||2p11.2|
|SPG33||Protrudin||Membrane protein||Autosomal dominant||Adult||10q24.2|
|SPG34||Unknown||X linked recessive||Teenage/Adult||Xq24-q25|
|SPG35||Fatty acid 2-hydroxylase||Autosomal recessive||Childhood||16q23.1|
|SPG39||Neuropathy target esterase||Endoplasmic reticulum protein||Autosomal recessive||Childhood||19p13.2|
|SPG42||Acetylcoenzyme A transporter 1||Autosomal dominant||Variable||3q25.31|
|SPG44||Gap junction protein GJA12/GJC2, Connexin 47||Autosomal recessive||Childhood/teenage||1q42.13|
|SPG45||5'-nucleotidase, cytosolic II (NT5C2)||Autosomal recessive||Infancy||10q24.32-q24.33|
|SPG46||Non lysosomal glucosylceramidase||Autosomal recessive||Variable||9p13.3|
|SPG47||Adaptor protein 4 complex subunit beta 1||Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system||Autosomal recessive||Childhood||1p13.2|
|SPG48||Adaptor protein 5 complex subunit zeta 1||Puative helicase||Autosomal recessive||6th decade||7p22.1|
|SPG49||Tectonin beta propeller repeat containing protein 2||Involved in autophagy||Autosomal recessive||Infancy||14q32.31|
|SPG50||Adaptor protein 4 complex subunit mu 1||Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system||Autosomal recessive||Infancy||7q22.1|
|SPG51||Adaptor protein 4 complex subunit epsilon 1||Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system||Autosomal recessive||Infancy||15q21.2|
|SPG52||Adaptor protein 4 complex subunit sigma 1||Autosomal recessive||Infancy||14q12|
|SPG53||Vacuolar protein sorting-associated protein 37A||Component of the ESCRT-I complex, a regulator of vesicular trafficking process||Autosomal recessive||Childhood||8p22|
|SPG54||Phospholipase DDHD2||Autosomal recessive||Childhood||8p11.23|
|SPG55||C12orf65||Mitochondrial protein||Autosomal recessive||Childhhod||12q24.31|
|SPG56||CYP2U1 (Cytochrome P450 2U1)||Long chain fatty acid ω-hydroxylase; metabolizes arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) and 19-HETE||Autosomal recessive||Childhhod||4q25|
|SPG not assigned||Glutamate decarboxylase 1||Autosomal recessive||Infancy|
|SPG not assigned (SPOAN syndrome)||Unknown||Autosomal recessive||Early onset|
|SPG not assigned||Cytosolic chaperonin containing T complex peptide 1 episilon subunit||Autosomal recessive|
|SPG not assigned||Mitochondrial ATPase 6||Mitochondrial protein||Mitochondrial inheritance||Adult||Mitochondrial DNA|
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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