Hereditary Spastic Paraplegia
Hereditary spastic paraplegia
Hereditary spastic paraplegia (HSP) is not a single entity, but a group of clinically and genetically diverse hereditary degenerative disorders that have in common degeneration of the corticospinal tracts and posterior column tracts in the spinal cord. The corticospinal tracts are made of nerve fibers that convey motor information from the brain to the limbs. The posterior column carries sensory information regarding position sense from the arms and legs to the brain. The fibers that carry motor information to the legs are more often affected than those of the arms, resulting in progressive stiffness and weakness of leg, thigh, calf, and lumbar spinal muscles. The age of onset, extent of degeneration, and severity of symptoms varies among the affected people, even those among the same family. Some families show a pattern of disease called anticipation, with symptoms developing earlier in each new generation. In most individuals, however, the disease onset occurs between the second and the fourth decades of life.
Dr. Adolf von Strumpell described this disease in 1883. Other names of this disorder are hereditary spastic paraparesis, Strumpell-Lorrain syndrome, Strumpell disease, familial spastic paraparesis, spastic spinal familial paralysis, hereditary Charcot disease, silver syndrome, French settlement disease, and Troyer syndrome. When the only manifested symptom is progressive spasticity, HSP is also known as pure hereditary spastic paraplegia.
There are at least 20 different types of HSP, and the mode of inheritance is known for 11 of them. The risk of an individual inheriting the abnormal gene depends on the mode of transmission and whether the mutated gene is present on a sex chromosome or an autosome. Mutations in several different genes can result in a similar phenotype of HSP and this phenomenon is known as genetic heterogeneity. These genes are generically known as spastic paraplegia gene, or SPG. SPGs are thought to contain genetic information regarding proteins that help in microtubule formation and function. Microtubules form the protein framework of a nerve cell and their dysfunction leads to degeneration of the nerve cells. HSP can be complicated when other neurological impairments are seen in addition to spasticity, or can be uncomplicated. Uncomplicated HSP is inherited as an autosomal dominant mutation in about 70% of cases, but the mutated gene varies from one family to another. Three patterns of inheritance are known for HSP: autosomal dominant HSP, autosomal recessive HSP, and X-linked HSP.
Autosomal dominant HSP
This is the most common form of HSP and the mutated gene is present on an autosome (non-sex chromosome). Only one copy of the abnormal gene is required to produce the disease. There is a 50% chance that an affected person will transmit the gene to an offspring. The disease can be present in both males and females, it can be transmitted from either the mother or the father to a son or a daughter, and there is usually an affected family member in each generation. Exceptions to the latter rule are when the disease has been very mild in earlier generations and has been misdiagnosed as arthritis or walking difficulty due to old age. Also, the person might have been deceased prior to manifesting full-blown symptoms. The SPGs for autosomal dominant HSP are identified in chromosomes 2p, 8q, 12q, 14q, 15q, 19q, and 20. In more than 50% of cases, the two most common gene mutations identified are in chromosome 2p and are called spastin and atlastin. In complicated autosomal dominant HSP, the gene is on chromosome 10q. In a rarer form of infantile onset-ascending HSP, there is a deletion mutation in the alsin gene at 2q.
Autosomal recessive HSP
In autosomal recessive HSP, the mutant gene is present on an autosome and two copies of the abnormal gene (one of maternal and one of paternal inheritance) are required for disease expression. Both males and females can express the disease and also transmit the abnormal gene. A mutant HSP gene that is recessive can be passed down silently for generations until someone finally inherits the recessive gene from both parents and develops the disorder. The parents of the affected person are called carriers, as they carry only one copy of the abnormal gene and do not express the disease. If a mother and father are each carriers for a recessive HSP gene mutation, each of their children has a 25% chance of developing HSP, a 50% chance of being a carrier, and a 25% chance of being normal. It is unlikely for individuals with autosomal recessive HSP to have children with the disorder, because their spouse would have to have the disorder or be a carrier. This is possible only in consanguineous marriages (i.e., marriage between cousins). SPGs identified in this inheritance are located on chromosomes 8, 15q, or 16q. The latter is a mutation of the paraplegin gene. One form of autosomal recessive HSP, the Troyer syndrome, is associated with an SPG on chromosome 13. Two different genes associated with autosomal recessive HSP have also been identified on the X chromosome.
This is a rare form in which the mutant gene is located on the X chromosome at Xq28 or Xq22. Transmission is usually by the mother and the risk of inheriting this mutated gene and expressing the disease depends on the patient's gender. Women with an X-linked mutant HSP gene are generally not affected by the disorder, or, if they are affected, usually have less severe symptoms than males. Each son of a woman who is a carrier for X-linked HSP has a 50% chance of developing HSP. Each daughter of a woman who is a carrier for X-linked HSP has a 50% chance of being a carrier (female carriers of X-linked disorders often have no symptoms).
In some instances, a definite mode of inheritance cannot be recognized when there is no other affected family member. This can occur if the inheritance has been autosomal recessive or X linked, where it can skip generations and remain silent and suddenly appear in the present generation. Also, the disease could have been milder (incomplete penetrance) and therefore undiagnosed in prior generations or the affected persons could have passed away prior to full symptom onset. Due to the phenomenon of anticipation, a child may exhibit symptoms even before the parent. Truly sporadic HSP is rare and is due to a new mutation occurring only in the affected individual.
As usually happens with other rare neurological diseases, HSP symptoms may overlap or be mistaken with other neurodegenerative disorders. Consequently, HSP incidence is only estimated and is approximately three cases out of 100,000 individuals in the United States and Europe. About 10,000–20,000 people in the United States are estimated to suffer from this disease, of which about 10% have the complicated form of HSP. Ninety percent of HSP cases are uncomplicated and life expectancy is unaffected.
Signs and symptoms
Previously, HSP was classified into early-onset (type I) HSP and late-onset (type II) HSP. In type I, symptoms of spasticity occurred prior to age 35, but progressed slowly. In type II HSP, symptom onset was after age 35 with weakness, spasticity, mild sensory loss, and bladder problems, and the disease progressed faster. This classification is confusing as both early and late onset disease can occur in the same family due to the phenomenon of anticipation. Therefore categorization into uncomplicated (pure) and complicated HSP is considered a more specific and useful distinction.
This is usually the autosomal dominant form and may start at any age, mostly in the second to fourth decades but can also occur in infancy, early childhood, or old age. Atlastin causes childhood onset autosomal dominant HSP and spastin causes the adult onset form. In children, the disease progresses until adolescence and then stabilizes, resulting in partial walking disability. Complete paralysis of the legs is rare in uncomplicated HSP, regardless of age of onset. Progressive difficulty walking is the main problem and occurs due to taut and weak muscles. This manifests initially as stumbling, stubbing the toe, catching of the feet on uneven surfaces and sidewalks, clumsy gait, or difficulty with balance. The muscles that are most commonly affected include those on the inner side, front and back of the thighs and calves, leading to difficulty with hip and ankle flexion. This can lead to uncontrollable shaking (clonus) of the feet and scissoring of the legs while walking. Often the changes are so slowly progressive that patients do not notice subtle symptoms for several years. Arms are affected to a much lesser degree. Spasticity is worsened by cold, high humidity, emotional stress, and infections. Other common symptoms include urinary urgency and frequency, hyperactive tendon reflexes, diminished vibration and position sense in the feet, leg paresthesias, muscle spasms, cramps, and pain. Muscles can atrophy at a late stage. High arched feet (pes cavus) and bunions can occur due to imbalance in the strength and tone of muscles that maintain proper alignment of bones in the feet.
This is usually an autosomal recessive form with symptom onset between two and 16 years of age. Symptoms are progressive and may be associated with other neurological conditions, such as epilepsy , mental retardation, peripheral neuropathy, ocular degeneration such as retinopathy, and/or the destruction of optic nerve. Other clinical complications are ataxia (incoordination), dysarthria (difficulty speaking), deafness, nystagmus (involuntary eye movements), decreased functioning of the adrenal glands, and ichthyosis (abnormal dryness, scaling, and thickening of the skin). However, these neurological symptoms may be caused by other disorders present at the same time. For instance, a person with uncomplicated HSP may have peripheral neuropathy due to diabetes .
A detailed personal and family history along with physical and neurological examinations are the first tools in HSP diagnosis. The physician will conduct comparative examination of muscle tone and strength between arms and legs and look for signs of weakness in specific muscle groups of the thigh, presence of abnormal increase of deep tendon reflexes in the legs, loss of ankle flexibility, and decrease of sensation in the legs. A thorough clinical examination is vital to avoid misdiagnosing other conditions like vitamin B12 deficiency, vitamin E deficiency, amyotrophic lateral sclerosis (ALS), and tropical spastic paraparesis, which mimic HSP. Genetic screening for SPG is the definitive test to avoid misdiagnosis and is commercially available. The University of Michigan Neurogenetic Disorders Clinic is the largest clinical and research program for HSP in the United States, and one of the few that offers comprehensive evaluation, including genetic testing . Other ancillary tests like nerve conduction studies, spinal tap, magnetic resonance imaging (MRI), and blood tests will help exclude some of the other mimickers of the disease.
There is no curable or preventive treatment for HSP. Symptomatic treatment for muscle spasm and spasticity includes oral medications like baclofen, tizanidine, and benzodiazepines like valium. Major side effects from these include confusion, dry mouth, drowsiness, and sedation. Symptomatic treatment for painful neuropathy includes medications like gabapentin and tricyclic antidepressants. Medications like oxybutynin can help in treating an overactive bladder. Baclofen can also be administered through a mechanical pump implanted in the space around the spinal cord to minimize systemic adverse effects. Newer approaches involve the local injection of botulinum toxin into the spastic muscles and the effect tends to last 3–6 months after an injection. Surgery may be necessary to relieve tendon contractures and to lengthen spastic muscles. An electrical stimulator device implanted in the nerves near the tailbone can help in stimulating the bladder for complete urinary evacuation.
Supportive care includes physical therapy, which helps to improve muscle strength, range of motion, prevent contractures of joints, and bedsores. Therapies may include stretching, strengthening and aerobic exercises, balance and coordination training, gait training, and appropriate use of assistive devices such as canes, braces, and walkers. They can also include techniques such as massage, ultrasound, electrical stimulation, or whirlpool. Exercise also enhances a sense of well-being, and reduces stress and depression .
This varies widely, but most often HSP is compatible with a normal life expectancy. The rate of progression varies considerably and is influenced by the mode of inheritance. Some patients have serious disability not only from the spasticity but also from associated neurological problems. Others however have very mild disability and can lead a very productive and almost normal life. Complications arising from falls and immobility may inadvertently shorten a person's life.
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National Institutes of Health/National Institute of Neurological Disorders and Stroke Brain Resources and Information Network. 9000 Rockville Pike, Bethesda, MD 20892. (301) 496 5751. (April 4, 2005.) <http://www.ninds.nih.gov>.
National Organization for Rare Disorders Inc. 55 Kenosia Ave, PO Box 1968, Danbury, CT 06813-1968. (800) 999 6673. (April 4, 2005.) <http://www.rarediseases.org>.
Spastic Paraplegia Foundation. 209 Park Road, Chelmsford, MA 01824. (703) 495 9261. (April 4, 2005.) <http://www.sp-foundation.org>.
Association Strumpell-Lorrain. 7 D rue des Granges, Besancon, Intl 25000, France. (038) 150 2391. (April 4, 2005.) <http://www.perso.wanadoo.fr/asl.spastic>.
Athena Diagnostics Inc. Four Biotech Park, 377 Plantation Street, Worcester, MA 01605. (800) 394 4493. (April 4, 2005.) <http://www.athenadiagnostics.com>.
Chitra Venkatasubramanian, MBBS, MD