What is paraparesis

Paraparesis means weakness but not total paralysis of the legs. Whereas “paraplegia” means severe weakness in both legs including paralysis.

Tropical spastic paraparesis

Tropical spastic paraparesis also referred to as chronic progressive myelopathy, is used to describe a chronic and slowly progressive disease of the spinal cord seen in some people infected with the human T-cell lymphotrophic virus type 1 (also known as HTLV-1), which results in painful stiffness and weakness of the legs.

Tropical spastic paraparesis is now called HTLV-1 associated myelopathy. The HTLV-1 retrovirus is thought to cause at least 80 percent of the cases of tropical spastic paraparesis by impairing the immune system. In addition to neurological symptoms of weakness and muscle stiffness or spasms, in rare cases individuals with HTLV-1 associated myelopathy or tropical spastic paraparesis also exhibit uveitis (inflammation of the uveal tract of the eye), arthritis (inflammation of one or more joints), pulmonary lymphocytic alveolitis (inflammation of the lung), polymyositis (an inflammatory muscle disease), keratoconjunctivitis sicca (persistent dryness of the cornea and conjunctiva), and infectious dermatitis (inflammation of the skin). The other serious complication of human T-cell lymphotrophic virus type 1 infection is the development of adult T-cell leukemia or lymphoma. Nervous system and blood-related complications occur only in a very small proportion of infected individuals, while most remain largely without symptoms throughout their lives. The human T-cell lymphotrophic virus type 1 is transmitted person-to-person via infected cells: breast-feeding by mothers who are seropositive (in other words, have high levels of virus antibodies in their blood), sharing infected needles during intravenous drug use, or having sexual relations with a seropositive partner. Less than 2 percent of HTLV-1 seropositive carriers will become tropical spastic paraparesis patients.

An estimated 10-20 million people in the world are infected with human T-cell lymphotrophic virus type 1. Although the human T-cell lymphotrophic virus type 1 is present throughout the world, infection with the virus is endemic in some geographical areas — the Caribbean, southern Japan, areas of Africa that are near the equator, and the Seychelles. Other areas that have a high rate of infection include Central and South America, Melanesia, southern Africa and the northwest coast of Canada.

The human T-cell lymphotrophic virus type 1 is transmitted (passed) from an infected person to a non-infected person through bodily secretions and blood.

• It can be transmitted by sexual contact, via the blood through fresh blood transfusions or through re-use of contaminated needles, or passed from mother to child through breast-feeding.
• You cannot spread human T-cell lymphotrophic virus type 1 by casual contact, such as shaking hands, hugging, and sharing homes and workplace, including bathrooms.
• The transmission of the virus can be decreased through safe sex practices (i.e. condoms or abstinence from intercourse) and avoiding needle sharing.
• Women who test positive for the virus should not breast feed.
• Healthcare practitioners should use caution when handling sharp instruments or handling bodily secretions from an infected person.

The great majority people who test positive for the human T-cell lymphotrophic virus type 1 do not go on to get active disease; these individuals are called carriers.

Who gets tropical spastic paraparesis?

Of the 10-20 million people infected with the HTLV-1 virus worldwide, approximately 0.25 to 3 percent of the infected individuals will develop tropical spastic paraparesis (HTLV-1 associated myelopathy). An additional two percent of people infected with the HTLV-1 virus will develop a serious blood cancer (adult T-cell leukemia or lymphoma). The great majority of individuals infected with the HTLV-1 virus will never exhibit signs or symptoms of disease.

However, in some people who are infected with the HTLV-1 virus, inflammation (swelling) occurs in the spinal cord; the immune system’s attack on the virus involves sending cells called lymphocytes to the affected area. These lymphocytes release chemicals called cytokines, which not only kill the infected cells but can also cause damage to the nerves. When the immune system’s response to the virus causes nerve damage in the spinal cord, the legs gradually lose strength and flexibility.

The symptoms of tropical spastic paraparesis (HTLV-1 associated myelopathy) usually appear between the ages of 30 and 50 but may occur earlier. The disease has been known to appear in childhood, but this is very rare. The disease may remain undetected for years after infection begins, but can still be transmitted to another person during this time.

How is tropical spastic paraparesis different from multiple sclerosis?

Many of the symptoms of tropical spastic paraparesis are also found in people who have been diagnosed with multiple sclerosis (MS). The clinical course of tropical spastic paraparesis is most similar to the primary-progressive form of MS in that there is a steady worsening of neurologic functioning without any distinct relapses (also called attacks) or periods of remission.

Tropical spastic paraparesis symptoms

In response to the human T-cell lymphotrophic virus type 1 infection, the body’s immune response may injure nerve tissue, causing a variety of symptoms.

More than 90 percent of affected individuals will experience pain, stiffness and/or weakness in the legs, which can result in a tendency to trip or have trouble with stairs or getting out of a low chair.

More than 90 percent of affected individuals will experience urinary symptoms. Possible bladder abnormalities include:

• Increased frequency (the number of visits to the toilet to pass urine)
• Urgency (needing to pass urine with very little warning and often the volume of urine passed is small
• Nocturia (having to get up at night to pass urine more than once)
• Incontinence (not being able to get to the toilet in time
• Urinary retention (the bladder does not fully empty and more than the normal amount of urine remains in the bladder, which can lead to bladder infections and kidney infections)

Bowel function can slow and result in constipation.

About 50 percent of people will have loss of feeling in the feet, tingling sensations, unpleasant sensations when the skin is touched, and low back pain.

As many as 20 percent of people may also experience:

• Deafness
• Double vision
• Tendency to incorrectly estimate the amount of motion necessary to accomplish a specific task (dysmetria)
• Exaggerated reflexes
• Facial paralysis
• Tremor

Inflammation of the nerves can also result in impotence or erectile dysfunction in men.

Tropical spastic paraparesis diagnosis

• Blood test to detect antibodies to HTLV-1. While the presence of antibodies is essential for a diagnosis of tropical spastic paraparesis, it is not enough because most people with antibodies do not have tropical spastic paraparesis.
• Blood smears to detect flower cells (also seen in carriers)
• Spinal tap (lumbar puncture) to detect antibodies to HTLV-1 and to rule out other causes
• Magnetic resonance imaging (MRI) of the brain and spinal cord
• Evoked potentials (EPs) to measure the electrical activity of the brain in response to stimulation of specific sensory nerve pathways. Evoked potentials are able to detect the slowing of electrical conduction caused by demyelination along these pathways even when the change is too subtle to be noticed by the person or to show up on neurologic examination.
• Electromyography (EMG) to measures the electrical impulses of muscles

Tropical spastic paraparesis treatment

There is no no cure for tropical spastic paraparesis (HTLV-1 associated myelopathy). Corticosteroids may relieve some symptoms, but aren’t likely to change the course of the disorder. Clinical studies suggest that interferon alpha provides benefits over short periods and some aspects of disease activity may be improved favorably using interferon beta. Stiff and spastic muscles may be treated with lioresal or tizanidine. Urinary dysfunction may be treated with oxybutynin.

• Spasticity (muscle stiffness) may be treated with medications, including baclofen or tizanidine.
• Urinary symptoms such as frequency, urgency or nocturia (the need to get up at night to urinate) may be treated with any one of a number of bladder medications including oxybutytnin, darifenacin, tamsulosin, terazosin, onabotulintoxinA, and others — which reduce the activity of the bladder muscle.
• Bladder infections are treated with antibiotics.
• Constipation can be treated by increasing the amount of fiber in the diet and, if needed, by laxatives, suppositories and enemas.
• Pain is treated with medications to reduce nerve pain or with non-steroidal anti-inflammatory (NSAIDs) medications.
• Corticosteroids are sometimes used to decrease the inflammation of the spinal cord.

Tropical spastic paraparesis prognosis

Tropical spastic paraparesis (HTLV-1 associated myelopathy) is a progressive neurological disease, but it is rarely fatal. Most individuals live for several decades after the diagnosis. Their prognosis improves if they take steps to prevent urinary tract infection and skin sores, and if they participate in physical and occupational therapy programs.

Complications of tropical spastic paraparesis (HTLV-1 associated myelopathy) — such as severe urinary tract infections and/or pressure sores on the skin — can lead to a poorer prognosis. Adequate bladder management, good skin care and rehabilitation strategies (including physical and occupational therapy) can improve a person’s prognosis.

The course of tropical spastic paraparesis (HTLV-1 associated myelopathy) is variable but most change occurs during the first couple of years following the appearance of the first symptoms. After this, the condition is more stable and worsens more slowly. Some individuals have mild disability that does not interfere greatly with their lives. Up to half of all people with tropical spastic paraparesis (HTLV-1 associated myelopathy) may eventually need to use a wheelchair after many years with the disease.

Familial spastic paraparesis

Familial spastic paraparesis also known as hereditary spastic paraplegias, are a large group of inherited neurologic disorders that share the primary symptom of difficulty walking due to muscle weakness and muscle tightness (spasticity) in the legs. There are more than 80 different genetic types of familial spastic paraparesis.

There may be significant variation in the severity of leg weakness (varying from none to marked), the degree of spasticity (varying from minimal to severe), and the occurrence of other neurologic symptoms between different genetic types of familial spastic paraparesis; as well differences in the nature and severity of symptoms between individuals who have exactly the same genetic type of familial spastic paraparesis.

Familial spastic paraparesis affects males and females of all ethnic groups from around the world.

Familial spastic paraparesis classification

Various types of familial spastic paraparesis are classified according to:

• A) the mode of inheritance (dominant, recessive, X-linked, maternal);
• B) the gene in which the mutation occurs; and
• C) the clinical syndrome (pattern of symptoms and neurologic findings).

Familial spastic paraparesis syndromes are classified as “uncomplicated” when symptoms are confined to leg weakness and tightness and urinary urgency. familial spastic paraparesis syndromes are classified as “complicated” when leg weakness and tightness (spasticity) are accompanied by other neurologic disturbance such as peripheral nerve impairment, muscle atrophy, or intellectual impairment.

There are more than 80 genetic types of familial spastic paraparesis. The chromosome locations (“loci”) of familial spastic paraparesis genes are designated “SPastic parapleGia, loci (“SPG”) and numbered in order of their discovery (for example, SPG1 through SPG80).

Familial spastic paraparesis causes

As with all inherited disorders, the familial spastic paraparesiss are due to gene mutations. Each genetic type of familial spastic paraparesis is due to a mutation in a specific “familial spastic paraparesis gene”. For example, mutations in SPG3A/atlastin, SPG4/spastin, and SPG7/paraplegin genes cause SPG3A, SPG4, and SPG7 familial spastic paraparesis, respectively.

Depending on the genetic type of familial spastic paraparesis, familial spastic paraparesis may be transmitted to offspring (and inherited from parents) as dominant, recessive, X-linked, and “maternal” traits. The various genetic types of familial spastic paraparesis and their inheritance patterns are summarized in the table below.

• Genetic types of familial spastic paraparesis can be found here: https://rarediseases.org/wp-content/uploads/2015/02/Genetic-Types-of-HSP.pdf

The following discussion of inheritance patterns is intended as an overview. Individuals seeking genetic counseling for familial spastic paraparesis are recommended to consult a genetic counselor or medical geneticist for specific information. In general, dominantly inherited forms of familial spastic paraparesis can be transmitted by (or inherited from) an individual who has the disorder. In general, each child of an individual who has a dominantly inherited form of familial spastic paraparesis has a 50% chance of inheriting the gene mutation and a similar (approximately 50% chance) of developing the condition. Occasionally, dominantly inherited familial spastic paraparesis “skips” a generation. (i.e. genetic penetrance is very high, exceeding 90%, but is occasionally incomplete). Although the chance of inheriting the condition can be estimated, it is difficult to predict with certainty the age at which symptoms would begin or their severity. There may be significant differences in the severity of the disorder between family members.

For recessively inherited forms of familial spastic paraparesis, both parents are usually carriers of the gene mutation and usually do not have symptoms (there are exceptions to this generalization: occasionally, parents who are carriers of some forms of recessively inherited familial spastic paraparesis have had symptoms of familial spastic paraparesis). In general, if one individual in a family has a recessively inherited disorder, each of this individual’s full siblings (for example, another child in this family) has approximately a 25% chance of having the same disorder. In general, individuals who have recessively inherited disorders do not transmit the disorder to their children. There have been some reported exceptions to this however.

X-linked disorders are transmitted from women to their sons. Daughters may carry X-linked gene mutations, but like their mothers, usually do not have symptoms although they may have mild symptoms and rarely, may have more significant symptoms of the disorder.

Maternally transmitted disorders are those in which the gene mutation involves a mitochondrial gene, are transmitted from mothers to sons or daughters (not transmitted from males).

Underlying causes of familial spastic paraparesis: Each of the more than 80 genetic types of familial spastic paraparesis is due to mutations in a different gene. These genes encode proteins that have diverse molecular functions including movement of chemicals from one part of the cell to another (“axon transport”), energy production (“mitochondrial disturbance”), and disorders of specific lipid metabolism, among others ¹.

Disturbance in some of these functions appears to lead to altered nerve cell (neuron) development. For these types of familial spastic paraparesis, the disorder is not a degenerative process, but rather a developmental disturbance in which the formation of selected nerve pathways during intra-uterine development was abnormal.

For other genetic types, familial spastic paraparesis gene mutations cause the ends of very long nerve processes (axons) to slowly degenerate within the spinal cord. This impairs nerve transmission from the brain through the spinal cord. To be clear, the entire spinal cord is not degenerating. Rather, the abnormalities in familial spastic paraparesis appear to selectively affect only specific nerve pathways, particularly the very long nerve processes (axons) that carry signals from the brain motor cortex to the lower part of the thoracic spinal cord. In some types, this disturbance is not limited to the spinal cord but also affects nerves in the legs (and arms, to a lesser extent). This latter process is termed “peripheral neuropathy”.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Familial spastic paraparesis symptoms

Symptoms describe an individual’s experience of a medical disorder. Signs are the objective evidence of the disorder, documented, for example by physician examination, laboratory studies, or magnetic resonance images (MRI). The primary symptom of familial spastic paraparesis is difficulty walking due to weakness and tightness (spasticity) in the legs. Both legs are affected, usually to a relatively similar degree.

The term “paraplegia” means severe weakness in both legs including paralysis. “Paraparesis” indicates weakness in both legs of lesser severity than paraplegia. Although the disorder is typically referred to as hereditary spastic paraplegia the degree of weakness is variable and ranges from no weakness (full strength) to marked weakness (paraplegia).

When present, weakness does not affect all leg muscles, but rather is most obvious in muscles of hip flexion (iliopsoas), hip abduction (gluteus medius), knee flexion (hamstrings), and foot dorsiflexsion (bending the foot back toward the shin via tibialis anterior muscle). In contrast, muscles of leg extension (quadriceps) and foot extension (gastrocnemius-soleus) usually are not affected in uncomplicated familial spastic paraparesis.

Spasticity primarily affects muscles of leg extension (quadriceps), knee flexion (hamstrings), hip adduction (bringing the knees together, thigh adductor muscles), and muscles that extend the feet (gastrocnemius-soleus [Achilles tendon]).

Walking pattern described as “spastic gait” occurs in which the following elements are present, each to variable degree in different individuals: a) heel strike is shifted forward (landing on the mid-foot or even further forward on the balls of the feet); b) there is reduced foot dorsiflexion (not bending the toes up, but instead tending to drag the toes, often catching them on carpet or when stepping over curbs, and causing the toes of the shoes to be worn out); c) stride length may become shorter; d) there may be “circumduction” or “scissoring”, with one leg crossing into the path of the other; e) there is a tendency for the knees to be maintained flexed (not fully extended in mid-stride), f) for thighs to be close together (adductor tightness), and g) hip flexion (knee lifting) to be reduced. Balance difficulty, often worse when walking in the dark or on uneven surfaces is not uncommon in individuals with familial spastic paraparesis.

Tightness in the legs and leg muscle spasm (often at night) are not uncommon.
The consequences of abnormal walking pattern cause strain on the ankles, knees, hips, and back and often cause pain in these areas.

Urinary urgency, the symptom of experiencing a very short interval between the sensation of need to urinate and difficulty remaining continent, is very common in familial spastic paraparesis and occasionally may be an early symptom. Bowel urgency is less common but may occur. Medications such as oxybutynin may reduce urinary urgency. If urinary urgency is severe or accompanied by difficulty initiating urination, consultation with a urologist is recommended.

Additional symptoms

Some genetic types of familial spastic paraparesis tend to cause only spastic weakness in the legs and urinary urgency. These syndromes are referred to as “uncomplicated familial spastic paraparesis”. Other genetic types of familial spastic paraparesis tend to be associated with additional symptoms (“complicated familial spastic paraparesis”) including difficulty with coordination (“ataxia”), impaired vision, seizures (epilepsy), muscle atrophy, disturbance of the nerves in the arms and legs (neuropathy), and disturbance cognitive ability (intellectual impairment and dementia). Previously, it was considered that familial spastic paraparesis caused symptoms only in the legs, and therefore, did not affect the strength or coordination of the arms and hands, or speech or swallowing. As the number of familial spastic paraparesis types has grown, it is now recognized that the arms, hands, and speech and swallowing may be affected in some genetic types of complicated familial spastic paraparesis

Pattern of symptom progression (course of the disorder)

When familial spastic paraparesis begins in very early childhood (before age two years, for example), symptoms may not worsen even over many years or decades. Individuals with this “non-progressive” (non-worsening) pattern may resemble subjects with spastic cerebral palsy, a life-long disorder that also remains relatively stable. One caveat however: although early childhood-onset forms of familial spastic paraparesis may be “non-progressive”, the degree of spasticity may increase slowly if adequate range-of-motion is not maintained through stretching exercises and muscle spasticity reduction.

In contrast, when familial spastic paraparesis symptoms begin after early childhood (in adolescence or adulthood), symptoms usually worsen very slowly over a number of years. Sudden onset or rapid worsening over weeks or months is not typical of familial spastic paraparesis and suggests an alternate disorder or co-existing condition. After a number of years of very gradual worsening, the rate of worsening appears to slow down for many (not all) subjects. These subjects seem to reach a “functional plateau” beyond which the degree of worsening seems to be similar to that expected for age and similar degrees of physical exercise. Nonetheless, not all patients reach an apparent “leveling off” or functional plateau but instead experience continuous worsening of walking ability due to very slowly progressive muscle weakness and tightness .

Variability:

There may be significant variability in the type of symptoms and their severity. For example, symptoms may remain mild in some patients or become quite severe in others patients. This variability may occur between different genetic types of familial spastic paraparesis as well as in between individuals with the same genetic type of familial spastic paraparesis including family members who share not only the same genetic type of familial spastic paraparesis but also precisely the same genetic mutation.

There is not a perfect correlation between the genetic type of familial spastic paraparesis and the pattern of symptoms. For example, while some genetic types of familial spastic paraparesis (e.g. dominantly inherited familial spastic paraparesis due to SPG4/spastin mutation) usually are associated with “uncomplicated” familial spastic paraparesis syndromes, some patients with these types of familial spastic paraparesis develop additional neurologic symptoms. As another example, although SPG7 and SPG11 typically are associated with additional neurologic symptoms (ataxia, neuropathy, cognitive impairment, for example), some subjects with mutations in these genes have uncomplicated familial spastic paraparesis (only spastic weakness in the legs). There also may be variation in severity and the nature of symptoms between affected family members. Therefore, it is generally not possible to predict with certainty the severity or exact nature of symptoms associated with given genetic type of familial spastic paraparesis. A cautious, “wait and see” approach, combined with pro-active, individualized physical therapy is recommended.

Familial spastic paraparesis diagnosis

Familial spastic paraparesis is diagnosed by the following:

1. Typical symptoms (lower extremity spastic weakness that may be non-worsening (early childhood onset) or slowly progressive over many years;
2. Findings on neurologic examination (lower extremity hyperreflexia usually accompanied by some degree of spasticity and sometimes a specific pattern of muscle weakness); and
3. By the exclusion of alternate disorders (by history, examination, neuroimaging, and laboratory studies as needed).

The occurrence of similarly affected family members is helpful in recognizing familial spastic paraparesis but is not required for the diagnosis of familial spastic paraparesis. Many individuals with familial spastic paraparesis do not have similarly affected family members. Such individuals could represent the first occurrence of a genetic mutation (“de novo mutation”). Depending on the genetic type of familial spastic paraparesis (dominant, recessive, X-linked, or maternal transmission), there may be a possibility that the disorder could be transmitted to the offspring of these individuals. Genetic testing is often helpful in confirming the clinical diagnosis of familial spastic paraparesis and in determining the genetic type of familial spastic paraparesis. Results of genetic testing can be used, together with clinical information, to provide genetic counseling.

Diagnostic evaluation

Neurologic examination is important for patients with symptoms of familial spastic paraparesis. First, this establishes the diagnosis and excludes alternative and co-existing disorders, some of which may have specific treatments. Second, neurologic examination helps identify the specific features of an individual’s walking disturbance. Knowing which specific muscles need strengthening, which specific muscles need spasticity-reduction (through medication, Botox injection, and stretching), and the degree of impairment of balance, speed, and precision of movement helps neurologists and physiatrists develop a proactive therapy approach to improve and maintain the ability to walk; and limit the cumulative impact of abnormal walking patterns on ankles, knees, hips, and spine.

Laboratory tests, neurophysiologic testing, and neuroimaging

Routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions) including analysis of cerebrospinal fluid (obtained by “spinal tap”) are normal in most types of familial spastic paraparesis. The primary role of such testing is to help exclude alternate and co-existing diagnoses.

MRI scans of the brain and spinal cord are important in diagnosing familial spastic paraparesis because they help exclude other disorders such as multiple sclerosis and structural abnormalities of the brain and spinal cord. Routine magnetic resonance imaging (MRI) of the brain is usually normal in uncomplicated familial spastic paraparesis, and, depending on the genetic type and its neurologic features, in many forms of complicated familial spastic paraparesis. In contrast to routine brain MRI, which is usually normal in uncomplicated familial spastic paraparesis, special MRI techniques such as diffusion tensor imaging, reserved primarily for research purposes often show more widespread nerve pathway abnormalities in uncomplicated and complicated familial spastic paraparesis.

In contrast to the typically normal brain MRI in subjects with uncomplicated familial spastic paraparesis, there are many types of complicated familial spastic paraparesis in which brain MRI demonstrates specific abnormalities including reduced size of the corpus callosum (a structure containing nerve fibers that transit from one brain hemisphere to the other).Thin corpus callosum is a frequent (but not constant) feature of SPG11 and SPG15 and has also been present in many other types of familial spastic paraparesis (including SPG3A, SPG4, SPG7, SPG15, SPG21, SPG32, SPG47, PG49, SPG54, and SPG56). (2,5) In addition to thin corpus callosum, many genetic types of familial spastic paraparesis have abnormal appearing brain white matter (e.g. due SPG5/CYPB7, SPG7/paraplegin, SPG21/maspardin, and SPG35/FA2H gene mutations) ².

Spinal cord MRI scan in familial spastic paraparesis is usually normal although may show somewhat smaller diameter of the thoracic spinal cord ³.

Genetic testing

Testing for familial spastic paraparesis genes is available and performed for individual familial spastic paraparesis genes, for panels containing dozens of familial spastic paraparesis genes, and by analysis of all genes (whole exome and whole genome analysis). Genetic testing is often helpful to confirm the clinical diagnosis of familial spastic paraparesis. Genetic testing is most often able to find causative gene mutations for subjects with familial spastic paraparesis who have a family history of a similarly affected first-degree relative.

Despite discovery of more than 60 genes in which mutations cause various types of familial spastic paraparesis, many individuals with familial spastic paraparesis do not have an identified gene mutation. This is because: a) genes for all types of familial spastic paraparesis have not been discovered and furthermore, some discovered genes are not yet included in clinical testing panels; b) methods of gene sequencing typically used to analyze large panels of genes do not analyze all regions of genes. Furthermore, while sensitively detecting gene sequence changes, these “next generation sequencing” methods are less sensitive in detecting gene insertions and deletions that do not change the sequence of the remaining portion of the gene.

Genetic testing is expensive and not all insurance companies provide reimbursement for this analysis. Identifying a causative gene mutation can bring closure to a diagnostic odyssey, contribute insight into the prognosis and can be applied to genetic counseling and prenatal diagnosis. Nonetheless at present, genetic testing results very rarely influence treatment which is largely directed toward reducing symptoms.

Interpreting familial spastic paraparesis genetic test results may be straightforward. Genetic testing may identify a gene mutation that is known to be associated with familial spastic paraparesis in other subjects, absent in unaffected subjects, and known or predicted to change the protein function. These mutations are termed “likely pathogenic” (likely to be disease causing). On the other hand, genetic testing may also identify gene variations that are considered normal variations (for example, they may be present in subjects who do not have familial spastic paraparesis and may be predicted to not change the protein function). Such mutations are considered “benign” variations and are not likely to cause familial spastic paraparesis.

In addition to “likely pathogenic” and “likely benign” mutations”, it is not uncommon for genetic testing to identify gene variations that are “of uncertain significance”. Such mutations may not have been reported to be associated with the disorder or may not be predicted to disturb the function of the protein. By definition, it is not known if gene variations of uncertain significance cause familial spastic paraparesis (i.e. are pathogenic) or are actually normal variations that are of no medical consequence. Individuals seeking more information regarding results of genetic testing are recommended to consult a medical geneticist or genetic counselor.

Familial spastic paraparesis treatment

Management of symptoms

Despite encouraging progress in many research laboratories ⁴, treatment for familial spastic paraparesis is presently limited to reducing symptoms of muscle weakness, spasticity, and urinary urgency.

Exercise

A pro-active regimen of daily physical exercise, guided by physical therapist or personal trainer and developed for each patient’s unique constellation of symptoms is recommended. This recommendation is based not on peer-reviewed scientific publications but rather on the reports of large numbers of familial spastic paraparesis subjects who state that exercise helps and that periods of reduced exercise are associated with increased symptoms. familial spastic paraparesis symptoms are variable. One type of exercise may not benefit all individuals. Exercise programs should be developed by a neurologist, physiatrist, physical therapist or personal trainer who is experienced with familial spastic paraparesis or similar disorders and should focus on the specific factors that make walking difficult for the specific individual. Individuals are advised to consult their primary care physician before beginning exercise programs, to begin with low intensity, increase slowly, set small goals, keep records of their progress, add variety, and be creative.

Exercise goals are to 1) improve and maintain cardiovascular fitness; 2) reverse the reduced functional capacity, stiffness, and weakness due to relatively sedentary lifestyle that often accompanies chronic gait disorders and which are superimposed on walking disturbance due to familial spastic paraparesis; 3) improve the mechanics of walking, facilitate neurologic circuits underlying walking reflexes, reduce falling, and maintain bone and joint fitness; and 4) maximize an individual’s independence and sense of control.

For some patients, weakness in certain muscles is the most significant factor making walking difficult. For these patients, daily exercise programs should focus on resistance exercises designed to maintain and very gradually increase the strength of these weak muscles. For others, spasticity is a more significant factor than weakness in limiting the ability to walk. For these patients, stretching exercises and muscle relaxant medication may be more beneficial than muscle strengthening exercises alone. A variety of exercises is recommended including walking, for example in shallow swimming pool, water aerobics, swimming, bicycling (including pedaling in reverse to exercise the strength and speed of hip flexion), yoga, dance, core exercises, balance exercises, and therapeutic horseback riding.

Muscle relaxing medication

Patients with significant degrees of spasticity may benefit from medications such as Lioresal. In general, reducing spasticity through medication improves walking primarily when spasticity, not weakness is the primary factor limiting the ability to walk. When weakness is the major factor, markedly reducing spasticity (e.g. through intrathecal Lioresal pump) may make the legs very relaxed (even hypotonic or “floppy”) but actually make walking and standing more difficult. Patients considering intrathecal baclofen pumps should undergo at least one trial in which the important criteria is not simply if spasticity reduction occurred, but rather if spasticity reduction resulted in improved walking ability. Botulinum toxin (“Botox”) injection may be helpful when muscle tightness particular affects a limited number of muscles (e.g. adductors or ankles). Oxybutynin and related medications may reduce urinary urgency. Individuals with more advanced bladder or bowel symptoms are recommended to consult urology or gastroenterology specialists, respectively.

Orthotics

Ankle-foot orthotics may be useful to reduce the tendency for the feet to be extended (toes down) causing toe dragging and tripping. Ankle-foot orthotics are often used in combination with medications (e.g. Lioresal or Botox) that reduce muscle spasticity.

Future directions

There have been rapid advances in our knowledge of the causes of familial spastic paraparesis. Discovery of dozens of genes implicated in familial spastic paraparesis is providing insight into molecular pathways involved. Gene discoveries have permitted development of diverse animal models (in mice, rats, fruit flies, zebrafish, C. elegans) in which to explore disease mechanisms and potential treatments. Parallel advances in gene transfer (gene therapy) and gene modification (e.g. utilizing CRISPR/Cas9 methods) approaches offer additional treatment strategies. Nonetheless, the process of drug discovery, development, and testing takes many years. Until (and even after) specific treatments become widely available, individuals with familial spastic paraparesis are recommended to pursue active lifestyles including physical rehabilitation in order to maintain and improve functional abilities and cardiovascular fitness.

Familial spastic paraparesis prognosis

As noted above, there is significant variation in familial spastic paraparesis symptoms and their severity. This limits the certainty of making predictions. In general however, some genetic types of familial spastic paraparesis are usually associated with only leg weakness, spasticity, and urinary urgency (“uncomplicated familial spastic paraparesis”). Other types of familial spastic paraparesis are usually associated with other neurologic disturbances in addition to these symptoms (“complicated familial spastic paraparesis”). Although there are exceptions (discussed above), an individual with a genetic type of familial spastic paraparesis usually associated with “uncomplicated” syndrome would be expected to have only spastic weakness and urinary urgency.

Symptoms of familial spastic paraparesis vary from mild to severe. Individuals with severe symptoms may be unable to walk independently. In general, however, familial spastic paraparesis does not shorten lifespan.

References

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