Hereditary spastic paraplegia

Hereditary Spastic Paraplegia (HSP), also called Familial Spastic Paraplegias or Strumpell-Lorrain disease, is a group of inherited diseases whose main feature is progressive stiffness and contraction (spasticity) in the lower limbs. as a result of damage to dysfunction of the nerves. It sometimes also affects the optic nerve and retina of the eye, causes cataracts, ataxia (lack of muscle coordination), epilepsy, cognitive impairment, peripheral neuropathy, and deafness. HSP is caused by defects in the mechanisms that transport proteins and other substances through the cell. Long nerves are affected because they have to transport cellular material through long distances, and are particularly sensitive to defects of cellular transport.

Hereditary Spastic Paraplegia was first described in 1883 by Adolph Strümpell, a German neurologist, and was later described more extensively in 1888 by Maurice Lorrain, a French physician.

Technically HSP is not spastic diplegia but it usually presents with similar effects and may be helped by similar solutions such as baclofen and orthopedic surgery.

Neuropathology
The major neuropathologic feature of HSP is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating fibers are preserved and there is no evidence of primary demyelination. Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal.

Incidence and Prevalence
Hereditary Spastic Paraplegia is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health. This means that Hereditary Spastic Paraplegia affects less than 200,000 people in the US population. Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people. A Norwegian study of more than 2.5 million people published in March 2009 has found an HSP prevalence rate of 7.4/100,000 of population – a higher rate, but in the same range as previous studies. No differences in rate relating to gender were found. Average age at onset was 24 years old.

Classification
Hereditary Spastic Paraplegias are classified based on the symptoms (pure form versus complicated form); based on their mode of inheritance (autosomal dominant, autosomal recessive or x-linked); and based on the patient’s age at onset.

Based on symptoms
Spasticity in the lower limbs alone is described as pure HSP. On the other hand, HSP is classified as complex or complicated when associated with other neurological signs, including ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction or epilepsy, or with extraneurological signs. Complicated forms are diagnosed as HSPs when pyramidal signs are the predominant neurological characteristic. This classification, however, is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia, mental retardation or leukodystrophy.

Based on mode of inheritance
As mentioned above, HSP is group of genetic disorders, each caused by different genes that cause very similar symptoms. The mode of inheritance of the HSP, hence the particular features of the gene involved, affect the risk of inheriting the disorder. There are four different modes of inheritance: autosomal dominant, autosomal recessive, Mitochondrial inheritance and x-linked recessive. Autosomal dominant represents the most common mode of inheritance. Autosomal means that the HSP gene is located on one of the autosomal chromosomes. The gene can be present in either sex, and it can be passed down from either the mother or the father to a son or a daughter. Dominant means that only one HSP gene is needed to cause the disorder.

Autosomal recessive forms of HSP are also located on one of the autosomes. Therefore, they can be present in males or females and passed to males or females. Since it is recessive, two copies of the gene are needed to result in the disorder, one from each parent. In these forms, neither parent has HSP. Instead, they are carriers. They each have one mutant HSP gene and one normal HSP 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 inherits the disorder. If both parents are carriers for a recessive HSP gene mutation, each of their children has a 25% chance of developing HSP. There is a 50% risk the child will be a carrier like the parents. Finally, there is a 25% chance that the child will receive only the non-mutated forms of the gene. This child would not be affected by HSP, nor would be a carrier.

Finally, some genes responsible for HSP are found on the X chromosome, hence are called X-linked. The inheritance risks and severity of this type of HSP differ depending on the individual’s sex. Women with an X-linked mutant HSP gene are generally not affected by the disorder, or, if they are, usually have less severe symptoms than males.

Based on patient's age at onset
In the past, HSP also has been classified as type I or type II on the basis of the patient's age at the onset of symptoms, which influences the amount of spasticity versus weakness. Type I is characterized by age onset below 35 years, whereas Type II is characterized by onset over 35 years. In the type I cases, delay in walking is not infrequent and spasticity of the lower limbs is more marked than weakness. In the type II muscle weakness, urinary symptoms and sensory loss are more marked. Furthermore, type II form of HSP usually evolves more rapidly.

Symptoms
Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticity in the lower limbs, due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HSP are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia. Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses insidiously over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices. More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles. In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, mental retardation, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.

Diagnosis
Diagnosis of HSPs relies upon family history, the presence or absence of additional signs and the exclusion of other nongenetic causes of spasticity, the latter being particular important in sporadic cases. Specialized genetic testing targeted towards known genetic mutations are available at certain specialized centers. Cerebral and spinal MRI is an important procedure to rule out other frequent neurological conditions, such as multiple sclerosis, but also to detect associated abnormalities such as cerebellar or corpus callosum atrophy as well as white matter abnormalities.

Prognosis
Although HSP is a progressive condition and usually starts in the legs and spreads to other muscles, ultimately leading to confinement to bed, the prognosis for individuals with HSP varies greatly. Some cases are seriously disabling while others are less disabling and are compatible with a productive and full life. The majority of individuals with HSP have a normal life expectancy.

Genetic Causes
The symptoms previously described are the results of a degeneration of the corticospinal tracts. The longest fibers, innervating the lower extremities, are the most affected. This explains why the spasticity and pyramidal signs are often limited to the lower limbs in patients. This neuronal degeneration is thought to be caused by mutations at specific genes. Genetic mapping has identified 20 different HSP loci, designated SPG (SPastic parapleGia) 1 through 21 in order of their discovery. Different genetic types of HSP usually cannot be distinguished by clinical and neuroimaging parameters alone. This reflects both the clinical similarity between different types of HSP and the phenotypic variability within a given genetic type of HSP. Furthermore, there may be significant clinical variability within a given family in which all subjects have the same HSP gene mutation; between families with the same genetic type of HSP; and between families with different genetic types of HSP.

Treatment
There are no specific treatments to prevent, slow, or reverse HSP. Treatment of HSP mainly consists of symptomatic medical management, to promote physical and emotional well-being. Some of the treatments include:
 * Baclofen - a voluntary muscle relaxant to relax muscles and reduce tone
 * Tizanidine - to treat nocturnal or intermittent spasms
 * Diazepam and Clonazepam - to decrease intensity of spasms
 * Oxybutynin chloride - an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
 * Tolterodine tartate - an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
 * Botulinum toxin - to reduce muscle overactivity
 * Antidepressants (such as Selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) - for patients experiencing clinical depression
 * Physical Therapy - to restore and maintain the ability to move; to reduce muscle tone; to maintain or improve range of motion and mobility; to increase strength and coordination; to prevent complications, such as frozen joints, contractures, or bedsores.

Research
The National Institute of Neurological Disorders and Stroke supports research on genetic disorders such as HSP. Genes that are responsible for several forms of HSP have already been identified, and many more will likely be identified in the future. Understanding how these genes cause HSP will lead to ways to prevent, treat, and cure HSP.