Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. HSP is also sometimes referred to as familial spastic paraplegia (FSP) or Strumpell-Lorraine syndrome. The age at symptom onset and the degree of muscle weakness and spasticity may be extremely variable from case to case, including among individuals within the same family (kindred). According to reports in the medical literature, symptom onset may occur as early as infancy or as late as the eighth or ninth decade of life; however, symptoms may most often develop during early to mid-adulthood. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, unexplained tripping and falls, and an unusually "clumsy" manner of walking (gait). As the disorder progresses, walking may become increasingly difficult. However, complete loss of the ability to walk is relatively rare.
HSP may be classified into two major subtypes: "uncomplicated" or "complicated" HSP. In individuals with uncomplicated (or "pure") HSP, progressive spastic paraplegia occurs as an isolated, primary finding. In those with complicated HSP, additional neurologic abnormalities are present. Some individuals with uncomplicated HSP may develop muscle spasms and difficulties with bladder control. In those with complicated HSP, associated symptoms and findings may include visual and/or hearing impairment, mental retardation, impaired control of voluntary movements (ataxia), and/or other abnormalities.
According to researchers, changes (mutations) of many different genes may cause HSP. In most cases, such mutations appear to be transmitted as an autosomal dominant trait. More rarely, mutations for HSP may be inherited as an autosomal recessive or X-linked recessive trait. The basic underlying defect or defects in HSP are unknown. However, associated symptoms appear to result from progressive degenerative changes of regions of the spinal cord (corticospinal tracts) that convey motor impulses from the brain to muscles involved in controlling certain voluntary movements .
The primary finding associated with hereditary spastic paraplegia (HSP) is the development of progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of the leg muscles. The degree of associated muscle weakness and spasticity and the age at symptom onset may be extremely variable, differing among affected families (kindreds) as well as members of the same kindred.
Researchers classify HSP into two major subtypes. The occurrence of progressive spastic paraplegia as an isolated, primary finding is known as "uncomplicated" or "pure" HSP. "Complicated" HSP is characterized by spasticity and muscle weakness in association with other neurologic symptoms and findings, such as impaired control of voluntary movements (ataxia), mental retardation, visual and/or hearing impairment, and/or other abnormalities.
One researcher further subdivided HSP into types I and II based upon the age at symptom onset and the varying degrees of muscle weakness and spasticity. Type I designated symptom onset before age 35 and more severe spasticity as compared to muscle weakness, whereas type II designated an onset of symptoms after 35 years of age and more severe muscle weakness. However, many researchers now suggest that such classification is less useful since later studies have revealed an extreme variability in symptom onset and the presence of types I and II among members of the same family.
Initial symptoms and findings associated with HSP may include stiffness, weakness, and spasms of the leg muscles; difficulties with balance; unexplained stumbling and falls; and a distinctive, "clumsy" manner of walking (gait). In addition, certain reflexes may become exaggerated (hyperreflexia); the arches of the feet may become abnormally increased in height (pes cavus deformities); and the gait may be characterized by a tendency to "catch" the toes, an abnormally shortened stride, and distinctive circular movement of the legs (circumduction). As the disease progresses, affected individuals may develop difficulties with bladder control, potentially experiencing a sudden compelling urge to urinate (urinary bladder urgency) and/or other symptoms. Over time, individuals with HSP may also have increasing difficulties walking, potentially requiring the use of assistive devices, such as a cane, walker, or other mobility equipment. In some severe cases, affected individuals may require the use of a wheelchair.
As mentioned above, individuals with "complicated" HSP may have additional symptoms and findings in association with progressive spastic paraplegia. Complicated HSP may be associated with certain eye abnormalities, such as degenerative changes of the nerve-rich membrane at the back of the eyes (retinopathy) and/or the pair of nerves that transmit impulses from the retinas to the brain (optic neuropathy). The degree of visual impairment depends upon the severity and combination of eye abnormalities present. Some individuals with complicated HSP may also have a condition in which there is abnormal dryness, thickening, and scaling of the skin (ichthyosis). In addition, complicated HSP may be characterized by impaired control of voluntary movements (ataxia); progressive deterioration of cognitive progresses and memory (dementia); abnormal, involuntary, abrupt or writhing movements (extrapyramidal disease); mental retardation; deafness; and/or other abnormalities.
Researchers indicate that changes (mutations) of several different genes may be associated with hereditary spastic paraplegia (HSP). In most affected families (kindreds), the pattern of inheritance is autosomal dominant. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.
Less commonly, HSP may be transmitted as an autosomal recessive or X-linked trait.
In autosomal recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
X-linked recessive disorders are conditions that result from mutations of a gene on the X chromosome. Females have two X chromosomes, while males have one X chromosome from the mother and one Y chromosome from the father. In females, certain disease traits on the X chromosome may be "masked" by the normal gene on the other X chromosome. However, since males have only one X chromosome, if they inherit a gene for a disease present on the X, it is more likely to be fully expressed. Men with a disease gene for an X-linked disorder transmit the gene to their daughters, who are carriers, but not to their sons. Women with a copy of the disease gene have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons.
A number of disease genes responsible for autosomal dominant forms of HSP have been mapped to specific chromosomal locations (genetic loci). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. Therefore, for example, 2p21 refers to band 21 on the short arm of chromosome 2.
Genetic loci for autosomal dominant HSP have been mapped to chromosome 2 (2p22-p21), chromosome 8 (8q23-q24), chromosome 12 (12q13), chromosome 14 (14q11.2-q24.3), chromosome 15 (15q11.1), and chromosome 19 (19q13). Using the designation "SPG," researchers have classified these genetic loci as SPG4, SPG8, SPG10, SPG3, SPG6, and SPG12, respectively. Autosomal dominant HSP most frequently is associated with the SPG4 gene among affected families in which linkage has been established. Evidence suggests that the SPG4 gene, also called the SPAST gene, regulates the production of a protein known as spastin.
At least three genetic loci for autosomal recessive forms of HSP have also been mapped: i.e., to chromosome 8 (8p12-q13) (SPG5A); chromosome 15 (15q13-q15) (SPG11); and chromosome 16 (16q24.3) (SPG7). The gene mapped to chromosome 16 appears to regulate a mitochondrial protein (known as paraplegin). (Mitochondria are the tiny, rodlike structures [organelles] outside the nuclei of cells that provide the primary source of cellular energy.)
In addition, at least two disease genes are known to be responsible for X-linked recessive forms of HSP. One form (SPG2) appears to result from mutations of a gene known as PLP (myelin proteolipid protein gene) located on the long arm (q) of chromosome X (Xq22). Another form of X-linked HSP (SPG1) is thought to be caused by mutations of the gene called L1CAM (L1 cell adhesion molecule) on the long arm at band 28 (Xq28).
Some affected families may not demonstrate linkage to the chromosomal locations discussed above, indicating that there may be other genetic loci for HSP that remain unknown. Research is ongoing to map other HSP loci and to identify mutations of specific genes responsible for the disorder.
The basic underlying defect or defects in HSP are not yet understood. However, associated symptoms and findings are thought to result from progressive degeneration of nerve fibers (axons) of certain spinal tracts, which are the bundles of nerve fibers within the outer region of the spinal cord. Such degenerative changes appear to particularly affect the spinal tracts that convey motor impulses from the brain to certain muscles involved in controlling voluntary movements (corticospinal tracts). In addition, there may be degenerative changes of the pathways that convey sensory impulses from certain regions of the spinal cord to the brain. .
Since HSP was initially described in Germany and France, it has been reported in nearly every geographic region worldwide. However, due to the variability of associated symptoms and the fact that some affected individuals may remain undiagnosed, it is difficult to determine the true frequency of the disorder in the general population. HSP appears to affect males and females relatively equally.
According to reports in the medical literature, the age at symptom onset and symptom severity may differ between families (kindreds) with HSP linked to different chromosomal locations (genetic loci), between kindreds linked to the same genetic loci, as well as among members of the same family. In those with HSP, symptoms may become apparent as early as infancy or as late as the eighth or ninth decade of life. However, they most often appear to develop during early to mid-adulthood.
Symptoms of the following disorders may be similar to those associated with hereditary spastic paraplegia (HSP). Comparisons may be useful for a differential diagnosis:
HTLV-1-associated familial spastic paraparesis is a progressive disorder characterized by stiffness (spasticity) and weakness or paralysis of leg muscles (paraparesis) in association with the presence of antibodies directed against the HTLV-1 virus (anti-HTLV-1 antibodies) in the blood (HTLV-1 seropositive). HTLV-1, an acronym for "human T-cell lymphotrophic virus type 1," is a virus that has been associated with certain cancers (adult T-cell leukemia/lymphoma). The virus is present worldwide yet most prevalent in Japan, Africa, and the Caribbean. Infection with the HTLV-1 virus may occur via transfusion with contaminated blood, from mother to child (e.g., during breastfeeding or via the placenta during pregnancy), or during sexual contact. HTLV-1 associated familial spastic paraparesis has been described among a parent and one or more children within several affected families. Researchers suspect mother-to-child transmission in most cases. In addition, some speculate that genetic factors may play some causative role in the disorder's development.
Primary lateral sclerosis (PLS) is a rare, neuromuscular disorder that affects the central motor neurons and is characterized by painless but progressive weakness and stiffness of the muscles of the legs. Such weakness may progress to affect the arms and the muscles at the base of the brain (bulbar muscles). Less frequently, the muscles of the face are affected. In most cases, the disorder affects adults during midlife. The exact cause of primary lateral sclerosis is unknown. (For more information on this disorder, choose "Primary lateral sclerosis" as your search term on the Rare Disease Database.)
There are a number of other disorders that may be characterized by progressive weakness and stiffness of leg muscles (spastic paraplegia) and other abnormalities similar to those associated with uncomplicated or complicated HSP. Many such disorders may be characterized by additional symptoms and findings that may differentiate them from HSP. (For more information on these disorders, choose the exact disease name as your search term in the Rare Disease Database.)
Diagnosis Hereditary spastic paraplegia (HSP) is typically diagnosed based upon careful evaluation of family history and exclusion of other disorders with similar symptoms and findings. In individuals with suspected HSP, diagnostic assessment includes a thorough clinical evaluation to detect characteristic physical findings; a complete patient and family history; and specialized tests, such as blood tests, certain advanced imaging techniques, studies that record electrical activity of nerves and muscles, and/or other tests. Advanced imaging studies may include computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain and spinal cord. During CT scanning, a computer and x-rays are used to create cross-sectional images of certain tissue structures. During MRI, a magnetic field and radio waves create cross-sectional images of particular organs and bodily tissues. In addition, in some individuals with suspected HSP, electromyograms (EMGs) and nerve conduction velocity (NCV) testing may also be conducted. EMGs record electrical activity in skeletal muscles at rest and during muscle contraction. During NCV testing, an electrical stimulator placed in the skin over a particular nerve evaluates the time that it takes for a nerve impulse to travel over a certain, measured portion of the nerve. The results of such tests may help physicians to rule out other disorders that may be responsible for symptoms similar to those associated with HSP, potentially leading to a diagnosis of hereditary spastic paraplegia, particularly for those with a positive family history of the disorder.
If available, genetic testing may assist in diagnosing particular forms of HSP in selected cases. However, such testing may only be available through certain research laboratories with a special interest in the disease.
Treatment Specific therapies for the treatment of individuals with HSP are symptomatic and supportive. In some cases, the administration of certain drugs by mouth (orally) may help to reduce spasticity, such as baclofen, tizanidine, dantrolene, diazepam, or clonazepam. For some patients, recommended treatment may include administration of the drug baclofen by means of a surgically implanted pump (intrathecal baclofen therapy) that delivers the drug directly into the spinal canal. Evidence suggests that intrathecal baclofen may be an appropriate alternative for those who are unable to tolerate or have an inadequate response to oral baclofen, potentially improving gait in some patients.
In addition, physical therapy may be recommended for some individuals with HSP. As the disease progresses, affected individuals may benefit from the use of particular assistive devices, such as a cane, crutches, or a walker. In some severe cases, the use of a motorized cart, a wheelchair, or other mobility equipment may be required.
Other treatment is symptomatic and supportive. Genetic counseling will be of benefit for affected individuals and family members. .
The Food and Drug Administration (FDA) awarded an orphan drug research grant to John H. Growdon, M.D., Massachusetts General Hospital, Boston, MA, for studies on administration of L-threonine as treatment for spasticity associated with hereditary spastic paraplegia (HSP). L-threonine is an essential amino acid that is a biologic forerunner (precursor) of glycine. (Amino acids are chemical compounds that form the basic structural units of proteins.) Evidence suggests that L-threonine may enhance the activity of glycine, which functions as an inhibitory neurotransmitter. Such neurotransmitters serve to inhibit the transmission of nerve signals from nerve cells (neurons) upon which they are released. Further studies are needed to determine the long-term safety and effectiveness of this agent as a treatment for HSP.
Research is currently underway to study the clinical spectrum associated with HSP, including age at symptom onset, severity of symptoms, etc., and to analyze blood samples to help identify HSP genes. For information on participating in HSP research, affected individuals and family members may contact:
Dr. John Fink Professor, Department of Neurology Director, Neurogenetic Disorders Clinic University of Michigan Room 5214 CCGCB Box 0940 1500 E Medical Center Drive Ann Arbor, MI 48109-0940 Phone: (734) 936-3087 E-mail: jkfink@umich.edu Web site: http://www.med.umich.edu/hsp/help.htm
Ongoing HSP research is being conducted at the Duke University Medical Center (DUMC), Center for Human Genetics (CHG), to link affected families (kindreds) with known gene locations for HSP and to help identify possible new locations. To date, most participants involved in the study have uncomplicated HSP. The long-term goal of such research efforts is to help improve the diagnosis and treatment of HSP. Families with a history of HSP who are interested in participating may contact:
P.C. Gaskell, Jr., PA-C Center for Human Genetics Duke University Medical Center Durham, NC 27710 Phone: (800) 283-4316 E-mail: pete@chg.mc.duke.edu Web site: http://www.chg.duke.edu/patients/fsp.html#research
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WE MOVE (Worldwide Education and Awareness for Movement Disorders) 204 West 84th Street New York, NY 10024 USA Tel: (212)875-8312 Fax: (212)875-8389 Email: wemove@wemove.org Internet: http://www.wemove.org
National Institute of Neurological Disorders and Stroke (NINDS) 31 Center Drive 8A07 Bethesda, MD 20892-2540 Tel: (301)496-5751 Fax: (301)402-2186 Tel: (800)352-9424 Email: braininfo@ninds.nih.gov Internet: http://www.ninds.nih.gov/
Spastic Paraplegia Foundation 11 Douglass Green Woburn, MA 01801 USA Tel: (877)773-4483 Email: info@sp-foundation.org Internet: http://sp-foundation.org
MUMS (Mothers United for Moral Support, Inc) National Parent-to-Parent Network 150 Custer Court Green Bay, WI 54301-1243 USA Tel: (920)336-5333 Fax: (920)339-0995 Tel: (877)336-5333 Email: mums@netnet.net Internet: http://www.netnet.net/mums/
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