Hereditary spastic paraplegia (HSP) is a varied group of disorders, all primarily involving subtly progressing lower extremity muscle weakness and spasticity, or increased muscle reflexes.
Description
There are two primary groups of HSP, known as "uncomplicated" or "pure" HSP and "complicated" HSP. HSP is considered "uncomplicated" or "pure" if the neurological problems only include progressive lower extremity muscle weakness and spasticity, urinary bladder disturbances, a decreased ability to sense vibrations in the lower extremities, and a decreased ability to sense the position of the joints.
HSP is "complicated" if other complex problems are present such as seizures,dementia, loss of muscle mass, mental delays, dry and thick skin (ichthyosis), vision problems or loss, and ataxia.
Problems with gait may progress over years or decades in uncomplicated HSP. This finding may begin at any age, from early childhood through late adulthood. The problems are usually limited to the lower extremities (legs and feet). Occasionally, urinary bladder disturbances may develop over time. People with complicated HSP have other associated health problems including mental delays and dementia.
Alternate names for HSP include hereditary spastic paraparesis, familial spastic paraplegia, familial spastic paralysis, and Stumpell-Lorrain syndrome.
Genetic profile
HSP is a genetically diverse group of disorders. It can be inherited in autosomal dominant or autosomal recessive manners; these are further divided into uncomplicated and complicated groups. An X-linked recessive form also exists for complicated HSP. The genes for HSP are designated "spastic gait" (SPG) genes, and are numbered 1–13 in order of their discovery. Determination of the exact type of HSP in a family is usually done by a detailed family history, rather than genetic testing.
In autosomal recessive HSP, individuals may be carriers, meaning that they carry a copy of an altered gene. However, carriers often do not usually have symptoms of HSP. Those affected with autosomal recessive HSP have two copies of an altered gene, having inherited one copy from their mother, and the other from their father. Thus, only two carrier parents can have an affected child. For each pregnancy that two carriers have together, there is a 25% chance for them to have an affected child, regardless of the child's gender. In families with autosomal recessive HSP, one would not expect to find other affected family members in past generations.
Autosomal recessive uncomplicated HSP is thought to represent about 25% of inherited spastic paraplegia. The SPG5 gene (found on chromosome 8 at 8p11–8q13) and SPG11 gene (on the long arm of chromosome 15 at 15q13–q15) appear to be responsible for this group of HSP. Autosomal recessive complicated HSP has been associated with alterations in the SPG7 gene (on the long arm of chromosome 16 at 16q24.3). Additionally, a gene named the paraplegin gene has been identified at the SPG7 locus. Although its function is not well understood, alterations in this gene appear to be responsible for autosomal recessive complicated HSP.
In autosomal dominant HSP, an affected individual has one copy of a genetic alteration that causes HSP. The individual has a 50% chance to pass the alteration on to each of his or her children, regardless of that child's gender. There are often other affected family members in prior generations, and often a parent is affected.
As of 2000, seven genes have been attributed to autosomal dominant uncomplicated HSP. The uncomplicated form comprises about 80% of families with autosomal dominant HSP. They are: SPG3 (found on the long arm of chromosome 14 at 14q11–q21), SPG4 or spastin (short arm of chromosome 2 at 2p22), SPG6 (long arm of chromosome 15 at 15q11.1), SPG8 (long arm of chromosome 8 at 8q23–q24), SPG10 (long arm of chromosome 12 at 12q13), SPG12 (long arm of chromosome 12 at 19q13), and SPG13 (long arm of chromosome 2 at 2q24–q34). Of this group, about 45% of families have SPG4 or spastin alterations.
Autosomal dominant complicated HSP has been attributed to alterations in the SPG9 gene (on the long arm of chromosome 10 at 10q23.3–q24.2).
In X-linked recessive HSP, only males are affected with the condition, because the genetic alterations are found on the X-chromosome. Males have only one X-chromosome, and females have two. Males with an X-linked condition have the genetic alteration on their single X-chromosome, and they develop symptoms of the condition. Females are carriers, and typically do not have symptoms. However, when carrier females have sons, they have a 50% chance of having an affected son. In families with X-linked HSP, males are affected and it is passed through women in the family.
X-linked forms of HSP are complicated HSP. The SPG1 gene on the long arm of chromosome X at Xq28 (also known as the L1 cell adhesion molecule) and SPG2 gene on Xq28 (also known as the proteolipid protein) have been associated with this form of HSP. Specifically, proteolipid protein alterations cause a condition known as Pelizaeus-Merzbacher disease.
Demographics
HSP is relatively rare; through 1996 more than eighty unrelated families had been studied throughout the world. Hereditary spastic paraplegia appears to affect individuals and various age groups around the world. With the exception of X-linked recessive HSP, it affects men and women equally.
Signs and symptoms
The symptoms of uncomplicated HSP may appear at any age. It may progress very slowly, without any obvious changes to bring symptoms to medical attention, possibly appearing as general "clumsiness." Individuals with uncomplicated HSP often have no problems with strength in their upper extremities and no problems with speech, chewing, or swallowing. They may notice their leg muscles becoming very stiff, and may stumble when climbing stairs or crossing curbs. These symptoms can progress and worsen with time.
Each family with HSP is unique, with varying symptoms. Additionally, affected individuals within the same family may have varying presentations of the disease. In 1999, a family was reported in which individuals in successive generations had increasingly severe symptoms of pure HSP, a phenomenon known as "genetic anticipation." People with pure HSP may experience difficulty walking and often eventually require canes, walkers, or wheelchairs. As a later symptom, people may experience an urgency to urinate, or may have problems with urinary control. Generally, the lower extremities experience increased reflexes, and may become stiff.
Individuals with complicated HSP still have spastic paraplegia of the lower extremities as a common finding, but may also experience other associated health problems. These may include seizures, mental delays, vision loss, and loss of muscle mass. Cataracts, gastric reflux, abnormal eye movements, severe general muscle weakness, and ataxia can also be present.
For some forms of complicated HSP, specific syndromes have been identified. Silver syndrome is an autosomal dominant condition involving progressive spastic paraplegia and loss of muscle mass, particularly in the hands. Pelizaeus-Merzbacher disease is an X-linked recessive form of complicated HSP. It usually develops in infancy or early childhood with abnormal eye movements, severe muscle weakness, feeding problems, and developmental delays. These findings can progress to include severe muscle spasticity and ataxia.
Diagnosis
HSP has classically been diagnosed by a careful physical examination, as well as obtaining a detailed personal and family medical history. Other similar disorders often need to be ruled out before considering HSP. Uncomplicated HSP is diagnosed by four clinical criteria:
Clinical symptoms: Progressive spastic muscle weakness of both lower extremities, often with urinary urgency or lower extremity paresthesia.
Neurologic examination: Increased muscle tone/reflexes at the hamstrings, quadriceps, and ankles; muscle weakness at hamstrings and lower limbs; decreased ability to sense vibrations in the lower limbs; abnormal gait with an uneven drop of the foot. (Mental delays or dementia are not expected in pure HSP.)
Family history: Similar to an autosomal dominant pattern (several affected family members in different generations), autosomal recessive pattern (siblings may be affected but little or no history of affected family members in prior generations), or X-linked recessive pattern (primarily affected males who are related to each other through their mothers).
Exclusion of other conditions.
Magnetic resonance imaging (MRI) of the brain and spinal cord are usually normal in people with uncomplicated HSP. It is a difficult task to eliminate other neurologic disorders with symptoms similar to HSP, such as structural abnormalities of the brain or spinal cord. Multiple sclerosis often includes gait incoordination, but it does not always progress or worsen with time. Some other genetic conditions involving muscle weakness include various forms of leukodystrophy; however, these neurological problems may progress rapidly, and may even result in death. Some infectious diseases may in some ways mimic HSP, such as AIDS or syphilis.
Genetic testing for some forms of both pure and complicated HSP is available on a research basis. In these cases, testing is usually performed on a blood sample, and the genes are analyzed. Because the testing is considered experimental research, testing may be cost-free but results may not always be available to the family.
For Pelizaeus-Merzbacher disease, genetic testing is available on a clinical basis at a limited number of laboratories, and families receive their results. In this case, results would be considered abnormal if alterations in the proteolipid gene were identified. Because Pelizaeus-Merzbacher disease is an X-linked recessive disorder, any male with the alteration would always have carrier daughters and unaffected sons. The affected person's mother would then be a carrier, and risks to her family members could be predicted by the same form of testing. An exception to this would be in the case of some mothers of boys with PLP mutations who are not carriers because their sons have new mutations.
Prenatal testing for Pelizaeus-Merzbacher disease can be performed on DNA extracted from fetal cells obtained through amniocentesis or chorionic villus sampling (CVS).
Treatment and management
There is no specific treatment to prevent, slow, or reverse the progressive symptoms in HSP. Some treatment approaches for other patients with paraplegia have been useful. This includes oral and muscle injections of a medication known as Baclofen, which can be used in early stages of muscle weakness. A medication known as Oxybutynin has been helpful for the urinary disturbances. Physical therapy and exercise are considered important elements in maintaining muscle strength and range of motion. However, it is still unclear whether physical therapy promotes muscle improvement or reduces the rate of muscle weakness and decline.
Prognosis
Complicated HSP may be associated with a shortened lifespan, because involvement of other health problems can worsen an individual's prognosis. For example, in Pelizaeus-Merzbacher disease, lifespan is shortened because the associated severe muscle weakness and feeding problems for a young child may lead to early death. Though it is usually very physically disabling, uncomplicated or pure HSP does not typically shorten lifespan.
PERIODICALS
Fink, J.K., et al. "Hereditary Spastic Paraplegia: Advances in Genetic Research." Neurology 46 (1996): 1507–14.
ORGANIZATIONS
HSPinfo.org. 2107 Worchester Drive, Salt Lake City, UT 84121. Phone: (801) 944-6295. Fax: (801) 328-7348. info@hspinfo.org. <http://www.hspinfo.org>.
National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. Phone: (763) 553-0020. Fax: (763) 553-0167. naf@mr.net. <http://www.ataxia.org>.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (800) 999-6673 or (203) 746-6518. Fax: (203) 746-6481. <http://www.rarediseases.org>.
