NORD gratefully acknowledges Martha A. Nance, MD, Medical Director, Struthers Parkinson’s Center, Chair, Scientific Advisory Board, Spastic Paraplegia Foundation, for assistance in the preparation of this report.
SummaryHereditary spastic paraplegia (HSP) is a general term for an expanding group of rare genetic disorders characterized by slowly progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. The age of onset, rate of progression, associated symptoms, degree of muscle weakness and spasticity, and overall severity of HSP can vary greatly from one person to another, even among individuals with the same subtype or among individuals within the same family. HSP is classified as "pure" or "uncomplicated" if the symptoms are primarily confined to the aforementioned lower limb weakness and spasticity. Other symptoms can occur in the pure subtypes including bladder dysfunction or abnormal sensations in the lower legs or feet. HSP is classified as "complex" or "complicated" if additional symptoms are present such as an inability to coordinate voluntary movements (ataxia), seizures, intellectual disability, skin disease, dementia, and hearing and vision abnormalities. Individual forms of HSP are caused by a mutation to a specific gene. HSP can be inherited as autosomal dominant, autosomal recessive or X-linked condition.
IntroductionHSP was first reported in the medical literature in the 1880s by a German doctor named Adolph Strumpell. A French doctor named Maurice Lorrain provided further detailed descriptions of the disorder shortly thereafter. More than 50 different forms of HSP have been identified in the ensuing years. Several different names have been used to describe these disorders. Recently, researchers have proposed a classification system that names each subtype by the official abbreviation SPG and a number (e.g. SPG1). The subtypes a numbered in the order they were identified in the medical literature. HSPs are a rapidly growing disease family and information about these disorders is constantly changing.
HSP encompass a wide variety of disorders. As mentioned above, they are highly variable even among members of the same family. In addition, many subtypes of HSP have only been reported in a handful of individuals or single family, which prevents physicians from developing an accurate picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The primary symptom of all HSPs is slowly progressive weakness and spasticity of the muscles of the legs. HSP can begin at any age and in most cases weakness and spasticity are slowly progressive throughout life without remission or abrupt or rapid worsening of the condition.
The initial symptoms of pure HSP typically include stiffness, weakness and spasms of the leg muscles. Some affected individuals may experience muscle cramps. “Spasticity” refers to an abnormal increase in muscle tone or stiffness of affected muscles. Spasticity can be associated with muscle spasms, deep tendon reflexes, and fixed joints (contractures). Some individuals may experience involuntary crossing or bending of the legs (spasms). Affected individuals may have difficulties with balance, frequently stub their toes, or experience unexplained stumbling or falling. Affected individuals have a distinctive “clumsy” manner of walking (abnormal or spastic gait). Affected individuals will experience progressive difficulty walking and may eventually require an assistive device such as a cane or walker. In severe cases, affected individuals may ultimately require a wheelchair or motorized device. Some individuals with mild forms of HSP will not require any assistive device.
If pure HSP begins in early childhood, a delay in walking may be seen. However, when pure HSP begins in infancy or childhood, there is usually little or no worsening of associated weakness and spasticity even over many years. When the onset of HSP is during the teen-age years or later, the disorder is usually slowly progressive.
Individuals with pure HSP may also have abnormal sensations (paresthesiae) affecting the lower legs and feet, exaggerated reflexes (hyperreflexia) of the lower and/or upper limbs, and highly-arched feet (pes cavus). As the disease progresses, affected individuals may also experience a sudden compelling urge to urinate (urinary bladder urgency).
Generally individuals with pure HSP have normal strength and dexterity of the upper limbs. Life expectancy in pure HSP is unaffected by the disorder.
Individuals with complex HSP have all of the symptoms discussed above. However, these individuals may have a variety of additional symptoms. They are several different forms of complicated HSP and the associated symptoms can be highly variable. In some cases, some of these symptoms may result from another inherited disorder. Symptoms that can occur with certain forms of complicated HSP include additional neurological findings including seizures, intellectual disability, progressive wasting of muscle tissue (amyotrophy), dementia, ataxia, dystonia, and extrapyramidal signs. Cerebellar signs including difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and atrophy may also occur. Some individuals may develop nerve disease affecting the nerves outside of the central nervous system (peripheral neuropathy).
The involvement of other systems of the body can also occur in complex HSP. Such symptoms can include gastroesophageal reflux, abnormal side-to-side curvature of the spine (scoliosis), hip dislocation, and skin disease such as ichthyosis, a general term for a group of scaly skin disorders. Hearing and vision abnormalities may also occur including rapid, involuntary eye movements (nystagmus), degeneration of the optic nerve (optic atrophy), cataracts, retinal disease, and hearing loss.
By definition all subtypes of HSP are characterized by spastic paraplegia. Below is a list of several of the better known subtypes of HSP. Next to the subtypes name is the inheritance pattern; whether it is pure, complex or both; genetic locus (location of the disease gene whether known or unknown): the gene name (if known): and a brief description of symptoms. Many of the subtypes of HSP have been identified have only been seen in individual families (kindreds) or only a few individuals; most of those disorders are not discussed here.
SPG1: X-linked – Complicated – Xp28 – L1CAM. This form of HSP affects males and is associated with developmental delays, moderate to severe intellectual disability, adducted thumbs, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain. The L1CAM gene mutation that causes SPG1 also causes MASA syndrome, X-linked corpus callosum agenesis, and X-linked hydrocephalus with stenosis of the aqueduct of Sylvius. Collectively, these disorders are known as L1 syndrome. NORD has a separate report on L1 syndrome.
SPG2: X-linked – Pure/Complicated – Xp22 – PLP1. The gene that causes this form of HSP also causes Pelizaeus-Merzbacher disease (allelic disorder). SPG2 represents the mild end of this disease spectrum; Pelizaeus-Merzbacher disease represents the severe end. SPG2 primarily affects males. Affected individuals may have a pure form of HSP associated with slowly progressive spastic paraplegia and urinary abnormalities. In some cases, a complex form may occur with additional symptoms including ataxia, delays in reaching developmental milestones, nystagmus, and intellectual disability. Affected individuals may also exhibit peripheral neuropathy. In some cases, female carriers of these disorders can develop mild symptoms. Onset is usually during infancy or early childhood. NORD has a separate report on Pelizaeus-Merzbacher disease.
SPG3A: Autosomal dominant – Pure/Complex – 14q21 – ATL1. This subtype of HSP is associated with lower limb weakness and spasticity that is generally non-progressive or extremely slow. The need for an assistive device such as a cane or wheelchair is relatively rare in individuals with SPG3A. This subtype usually develops in early childhood with more than 80% of affected individuals developing spastic gait before 10 years of age. Later-onset cases are associated with slowly progressive disease. Urinary bladder hyperactivity also occurs. Some individuals may develop axonal neuropathy and/or distal muscle wasting.
SPG4: Autosomal dominant – Pure/Complex – 2p22.3 – SPAST. Accounting for approximately 45% of cases, this is the most common form of autosomal dominant HSP. Affected individuals have slowly progressive muscle weakness and spasticity. In rare cases, some individuals may have a complex form associated with seizures, ataxia, memory impairment, cognitive decline and dementia. Hand tremor and upper limb spasticity have also been reported. Onset can range from infancy to older adulthood.
SPG5A: Autosomal recessive – Pure – 8q12-q13 – CYP7B1. This form of HSP is characterized by progressive muscle weakness and paraplegia. Approximately 50% of individual ultimately require a wheelchair. In rare cases, the upper limbs may become involved. Onset is anywhere between infancy to middle age.
SPG6: Autosomal dominant – Pure/Complex – 15q11.2 – NIPA1. Most cases represent a pure form of HSP. Spastic paraplegia is usually rapidly progressive and severe. Pes cavus is common. In some cases, affected individuals may develop a complex form of HSP with memory deficits or epilepsy. This form usually has adult-onset.
SPG7: Autosomal recessive – Pure/Complex – 16q24.3 – SPG7. Individuals with SPG7 can exhibit a pure form of the disorder. However, a variety of additional symptoms have been associated with complex forms of SPG7 including ataxia originating in the cerebellum (cerebellar ataxia), dysarthria and, in rare cases, dysphagia. Eye abnormalities including optic atrophy, nystagmus, and crossed eyes (strabismus) may also occur. Hearing loss has also been reported. Scoliosis, distal muscle wasting, and pes cavus may be present as well. Onset is usually in adulthood.
SPG8: Autosomal dominant – Pure – 8q24.13 – KIAA0196. This form of HSP is associated with slowly progressive onset, usually between 18-60 years of age. Spasticity in SPG8 is generally more severe than many other types of HSP and some affected individuals ultimately require a wheelchair. Urinary urgency and abnormal sensations affecting the feet may also occur.
SPG9: Autosomal dominant – Complex – 10q23.3-q24.1 – N/A. Affected individuals may have cataracts, gastroesophageal reflux and progressive wasting of muscle tissue (generalized amyotrophy). Skeletal abnormalities such as a malformed (dysplastic) hip may also occur.
SPG10: Autosomal dominant – Pure/Complex – 12.13.3 – KIF5A. Most cases represent a pure form of HSP with late onset. Complex forms may occur with additional symptoms including upper limb amyotrophy, intellectual disability, hearing loss and retinitis pigmentosa, a general term for a group of vision disorders that cause progressive degeneration of the membrane lining the eyes (retina) resulting in visual impairment. Parkinsonism, a general term for when individuals have symptoms that resemble Parkinson’s disease, may also occur. Such symptoms may include tremor, abnormal slowness of movement and an inability to remain in a stable or balanced position. Onset can range from infancy to mid-adulthood.
SPG11: Autosomal Recessive – Pure/Complex – 15q21.1 – KIAA1840. In addition to the pure subtype, affected individuals may develop intellectual disability, learning disabilities, dysarthria, dysphagia, amyotrophy, and an abnormally thin corpus callosum, the area of the brain that connects the two cerebral hemispheres. In some cases, the corpus callosum may be absent (agenesis of the corpus callosum). Peripheral neuropathy and the involvement of the upper limbs may also occur. This form of HSP often leads to loss of the ability to walk unassisted within 10 years of onset. Onset can occur during childhood or adulthood. Some affected individuals develop abnormalities of the eyes including nystagmus during childhood and macular degeneration, pigmented retinal degeneration and decreased clarity of vision (visual acuity) during adulthood. Parkinsonism has been reported as well.
SPG12: Autosomal dominant – Pure – 19q13.32 – RNT2. Onset is usually between 7-14 years of age, but can occur earlier and has been report to occur well into adulthood. This form of HSP is rapidly progressive and affected individuals often ultimately require a wheelchair.
SPG13: Autosomal dominant – Pure/Complex – 2q24-q31 – SPGD1. This subtype of HSP is typically characterized by a pure form of the disease with late onset. Weakness and spasticity may be severe. Upper limbs may be affected in some cases. One kindred with SPG13 also had dystonia.
SPG15: Autosomal recessive – Complex – 14q21.1 – ZFYVE26. In addition to the characteristic findings of HSP, affected individuals may have hearing and vision abnormalities, an abnormally thin corpus callosum and variable degrees of intellectual disability. Affected individuals may also develop retinal degeneration, macular degeneration and decreased clarity of vision (visual acuity). Amyotrophy, especially of the hands and feet, may also occur. Onset is usually between 5 and 19 years of age. This disorder is also known as Kjellin syndrome.
SPG17: Autosomal dominant – Complex – 11q12.3 – BSCL2. This subtype of SPG is associated with amyotrophy of the upper extremities, and is also known as Silver syndrome. Weakness of the upper extremities may be greater than weakness associated with the lower extremities. Affected individuals may also have hand and foot deformities. The age of onset varies and progression of the disorder is generally slow. This form of SPG is one of the BSCL2-related disorders, a group of clinically distinct disorders caused by mutations of the same gene (the BSCL2 gene). This group of disorders includes Silver syndrome, Charcot-Marie-Tooth disease type 2, Berardinelli-Seip syndrome, and distal hereditary motor neuropathy type V. NORD has separate reports on some of these disorders.
SPG20: Autosomal recessive – Complex – 13q13.3 – SPG20. This form of HSP has been reported to occur in two large kindreds, an Amish kindred in the United States and an Arab kindred in Oman. Affected individuals have exhibited short stature, developmental delays, dysarthria, learning disabilities, and distal muscle wasting. Slow deterioration of walking and speech may occur. Behavioral issues such as inappropriate euphoria have been reported. In severe cases, choreoathetosis, a condition characterized by involuntary, rapid, jerky movements (chorea) occurring with relatively slow, writhing motions (athetosis), may develop. Mild cerebellar signs are common. Onset is usually during infancy. This form of HSP is also known as Troyer syndrome.
SPG21: Autosomal recessive – Pure/Complex – 15q22.31 – ACP33. This form of HSP is characterized by a variety of symptoms including walking difficulties that usually are noted during adolescence through adulthood and intellectual disability that may be noted during childhood. Affected individuals may have a thin corpus callosum. At an advanced age, affected individuals may display cerebellar signs, extra-pyramidal signs and dementia. SPG21 is highly prevalent among the Amish. This form of HSP is also known as Mast syndrome.
SPG22: X-linked – Pure/Complex – Xq21 – SLC16A2. This form of HSP affects males. Common symptoms include diminished muscle tone (hypotonia), intellectual disability, joint contractures, dystonic and/or athetoid movements and severe delays in psychomotor development. Some individuals may never sit or walk or may lose these skills once acquired. Some affected individuals may never talk or have difficulty speaking. Additional symptoms can include seizures, scoliosis, and ataxia. This disorder is also known as MCT8-specific thyroid hormone cell transporter deficiency or Allan-Herndon-Dudley syndrome. NORD has a separate report on this disorder, titled MCT8-specific thyroid hormone cell transporter deficiency.
SPG31: Autosomal dominant – Pure – 2p11.2 – REEP1. This form of HSP has been described in approximately 40 families mainly in Europe. The severity may vary from one individual to another. Amyotrophy may occur. The upper extremities may also be affected by weakness and spasticity. Less often, dysphagia, dysarthria, urinary urgency has been reported. Most cases occur in the first two decades of life, but some individuals experience onset after the age of 30.
SPG35: Autosomal recessive – Pure/Complex – 16q21-q23 – FA2H. In addition to a pure form of HSP, some affected individuals developed intellectual disability, seizures, dystonia, ataxia and dysarthria. In some cases, the disease can progress so that an affected individual requires a wheelchair. Ear abnormalities including optic atrophy and nystagmus have also been reported. Onset is generally in childhood. SPG35 is considered part of a spectrum of disease known as fatty acid hydroxylase-associated neurodegeneration.
SPG39: Autosomal recessive – Complex – 19p13.2 – NTE. In addition to the characteristic findings of HSP, affected individuals may develop distal muscle wasting of the legs and certain hand muscles. Some individuals have shown atrophy of the spinal cord.
There are several disorders that are considered unclassified forms of HSP. These disorders may be included in the classification of HSP in the future. An example of an unclassified form of HSP is SPOAN, which is an acronym for (s)pastic paraplegia, (o)ptic (a)trophy and (n)europathy. SPOAN syndrome is a neurodegenerative disorder characterized by spastic paraplegia with onset during infancy. During late adolescence sensorimotor neuropathy may develop. Additional symptoms include optic atrophy, dysarthria, joint contractures and spinal deformities. Affected individuals ultimately require a wheelchair.
Individual forms of HSP are caused by a mutation to a specific gene. Some forms are inherited as autosomal dominant conditions. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
HSP can also be inherited as an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits the same abnormal 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 for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receiver normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Finally, some forms of HSP are inherited as an X-linked condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Females from families where females have a milder phenotype, such as SPG2, should be more cautiously counseled. In some of these families the disorder behaves more like an X-linked dominant disorder with reduced penetrance. Males with X-linked disorders pass the disease gene to all of their daughters, who will all be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
More than 50 different loci and almost 20 mutated genes that cause HSP have been identified (see symptoms section above).
The exact underlying mechanisms that cause HSP are not fully understood. These disorders are associated with the degeneration of the upper motor neurons of the brain and spinal cord. Motor neurons are basic nerve cells that form part of the pathway that relays signals from the brain and spinal cord to muscles and nerves. Motor neurons directly or indirectly control muscles movements by initiating contraction or relaxation of muscles. In HSP, the upper motor neurons are affected. These cells carry signals from the brain to the brainstem and spinal cord. In turn, these signals are carried by lower motor neurons to the muscles. In HSP, these signals are not conducted to the lower motor neurons, usually due to progressive degeneration of certain nerve fibers (axons) of certain spinal tracts. Spinal tracts are the bundles of nerve fibers within the outer region of the spinal cord that carry motor commands from the brain to the spinal cord. The characteristic degenerative changes of HSP appear to particularly affect the 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. More research is necessary to understand the complex, underlying mechanisms that cause HSP.
Since HSP was initially described in Germany and France, it has been reported in nearly every geographic region worldwide. It is estimated to affect 10,000-20,000 individuals in the United States. The prevalence of HSP is estimated to be between 4.3-9.98 individuals per 100,000 in the general population. The largest population study conducted established a prevalence of 7.4 per 100,000 in Norway. However, due to the variability of associated symptoms and lack of overall knowledge of these disorders, many individuals go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of HSP in the general population. Most forms of HSP affect males and females in equal numbers, except for X-linked forms which predominantly affect males.
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.
A diagnosis of HSP is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. The diagnosis of HSP is clinical and is made by ruling out other potential conditions. A variety of specialized tests such as neuroimaging and neurophysiologic studies may be required to rule out other conditions. Routine lab tests, cerebrospinal fluid analysis, electromyography and nerve conduction studies are normal in individuals with HSP.
Molecular genetic testing is available for some subtypes of HSP on a clinical basis.
There is no specific therapy for HSP. Treatment is directed toward the specific symptoms that are apparent in each individual. Regular physical therapy may be beneficial in maintaining and improving muscle tone and strength. Physical therapists can also recommend exercises to help a person maintain flexibility and range of motion and reduce spasticity.
Medications may help to reduce muscle spasticity and improve gait. The drug, baclofen, is often used to treat spasticity. It relaxes and muscles and helps to reduce muscle tone. Baclofen is usually taken orally. For some patients, treatment may include administration of baclofen by means of a surgically implanted pump (intrathecal baclofen therapy) that delivers the drug directly to the spinal canal. Evidence suggests that intrathecal baclofen may be an appropriate alternative for individuals with severe spasticity who are unable to tolerate or have an inadequate response to oral baclofen. Intrathecal baclofen can be associated with significant side effects in some cases.
Additional medications that have been used to treat spasticity include tizanidine, dantrolene, diazepam and clonazepam. Tizanidine is effective for an intermittent reduction of spasticity in some individuals. Dantrolene helps to reduce muscle contraction. Diazepam and clonazepam are sedatives that slow the activity of the central nervous system.
Anticholinergic drugs such as oxybutynin, tolterodine tartrate, and hyoscyamine can be used to treat bladder control problems caused by HSP. The antidepressant duloxetine and botulinum toxin injections into the bladder are less commonly used treatments. However, it is important first to make sure that the bladder symptoms are no due to some other problem such as bladder infection, prostate enlargement, or stress incontinence. Referral to an urologist can be helpful.
Orthotic devices designed for ankle-foot problems such as braces may be of benefit to some affected individuals. Occupational therapy may also be recommended. As the disease progresses, affected individuals may benefit from the use of particular assistive devices such as a cane, crutches, or a walker. In severe cases, the use of a wheelchair or motorized cart or other mobility equipment may be required.
Genetic counseling is important for affected individuals and their families.
Other treatments depend on the symptoms that a specific individual experiences. For example, antiepileptic drugs may be used to prevent seizures, L-DOPA may be used to treat tremors, dystonia, or rigidity, and antidepressants can be used for depression.
Botulinum toxin injections have been used to treat some individuals with HSP in whom other medications were ineffective. Botulinum toxin is a neurotoxin that is injected into muscles in very small doses. After injection into a muscle, the action of botulinum toxin is to interrupt nerve messages to the muscles. Temporary muscle weakness is a side effect of this treatment. Botulinum toxin injections may also be used to treat dystonia in individuals with HSP. More research is necessary to determine the long-term safety and effectiveness of botulinum toxin in the treat of individuals with HSP.
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