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Hereditary spastic paraparesis (HSP)"Hereditary spastic paraparesis (HSP) is a clinically and genetically heterogeneous group of inherited disorders characterized by insidiously progressive,often severe, lower extremity weakness and spasticity" Symptom severity, age of onset and rate of disease progression may vary widely among patients. It is estimated that three in every 100,000 people are affected with hereditary spastic paraparesis in the U.S. HSPs are classified by clinical presentation, as either uncomplicated or complicated, and by inheritance pattern. Uncomplicated (or pure) hereditary spastic paraparesis is the most common form and is characterized by progressive lower extremity spastic weakness, accompanied by hypertonic urinary bladder disturbances, and often, mildly impaired vibration sensation.4Uncomplicated hereditary spastic paraparesis can be disabling, but it does not shorten life span.1hereditary spastic paraparesis is classified as complicated if the impairments of the uncomplicated form are accompanied by additional neurologic abnormalities that are not attributable to other co-existing disorders.Researchers estimate that uncomplicated hereditary spastic paraparesis represents 90% of all hereditary spastic paraparesis cases, while complicated HSP accounts for 10%. Twenty-one loci have been linked to various forms of HSP; 10 loci have been mapped for autosomal dominant forms of HSP, seven loci for autosomal recessive forms and three loci for X-linked forms (Table 1). Six genes associatedwith HSP have been identified: SPG3A (atlastin), SPG4(spastin), SPG7 (paraplegin), SPG20(spartin), L1CAM (L1 cell adhesion molecule) and PLP(proteolipid protein).7-8 Table 1: Genetic types of Hereditary SpasticParaplegia*
*Adapted from: Fink, J. Hereditary Spastic Paraplegia:The Pace Quickens. Ann Neurol 2002; 51:669-72.
The two most common causative genes associated with uncomplicated autosomal dominant hereditary spastic paraplegia (ADHSP) that have been identified to date are SPG49and the recently identified SPG3A.6Together, these forms of HSP are estimated to comprise more than 50% of uncomplicated ADHSP. SPG4 gene mutations are thought to cause the most common form, an estimated 40-45%, of uncomplicated ADHSP. SPG4 encodes for an amino acid protein,spastin, a member of the highly conserved ATPase domain.9The function of the gene is not understood. The types of mutations inthe SPG4gene suggest that this form of HSP results from a loss of function ofthe protein. The loss of function implies that a threshold level ofspastin is essential in axonal preservation, which may explain thevariable expressivity and incomplete penetrance of SPG4HSP. The SPG3A gene is thought to account for an estimated 9% of uncomplicated ADHSP6and encodes a protein of the dynamin family of GTPases, atlastin.Dynamins are believed to play an important role in vesicle trafficking events (such as rapid and efficient recycling of synaptic vesicles), are associated with cytoskeletal elements such as actin and microtubules, and are possibly associated with the maintenance and distribution of mitochondria. Different genetic types of uncomplicated Hereditary Spastic Paraparesis may cause very similar symptoms. On the other hand, symptom severity and the age at which symptoms begin may be quite variable both between SPG3A and SPG4 families, as well as within a given family. Neuropathological studies of uncomplicated HSP have shown:
Gait disturbance (stumbling and tripping), because of bilateral lower extremity weakness and/or spasticity, is the primary symptom of uncomplicated HSP.The age of symptom onset ishighly variable. The first symptoms of HSP have been reported as early as late-infancy to early childhood; and as late as the eighth decade.Urinary urgency and lower extremity parasthesia often occur.Upper-extremity function is preserved among individuals withuncomplicated HSP. In general, HSP is thought to be caused by mutations inthe SPG3A gene is characterized by early onset(before the age of 11) and is often non-progressive: individuals with this form of HSP may not show significant worsening even over several decades. In contrast, subjects with HSP are thought to be due to SPG4mutations have symptoms onset over a much broader age-range (from infancy to the eighth decade); and usually experience insidiously progressive gait disturbance over many years. Until the recent availability of genetic testing, Hereditary Spastic Paraparesis was generally diagnosed clinically based on family history, neurological signs and the exclusion of other disorders. According to Fink, the differential diagnosis of uncomplicated HSP includes:
There are no effective treatments for the underlying distal axonal degeneration of HSP.Currently, only symptomatic treatments are available.4However, oral or intrathecal baclofen or oral dantrolene or tizanidine may reduce spasticity. Urinary urgency may be reduced by oxybutynin. Physical therapy is recommended for affected individuals, which can improve range of motion, maintain and increase lower extremity strength and increase cardiovascular conditioning (which can increase endurance and reduce fatigue). Canes, walkers and wheelchairs can aid individuals with impaired gait. The genetic characterization of SPG4(spastin) and SPG3A(atlastin) has allowed the development of molecular assays. These assays permit laboratory detection of SPG4 and SPG3A which appearpresent in more than 50% of ADHSP cases. A definitive molecular determination helps the physician in their overall diagnosis of the condition, possibly reducing the anxiety in affected individuals who have been living with symptoms of an undiagnoseddisorder. Molecular detection of HSP helps distinguish it from other disorders (such as amyotrophic lateral sclerosis and primary lateral sclerosis) that have significantly different prognoses. HSP genetic counseling must be individualized for each family. Genetic penetrance in ADHSP is age-dependent and though high, may be incomplete. Genetic counseling must consider that the age at which symptoms begin and the degree of disability may be variable within a given kindred, between kindreds linked to the same gene and between genetic types of HSP. While the risk ofinheriting an HSP gene mutation can be estimated from pedigree analysis or detected by mutation analysis (in the case of SPG3A and SPG4), it is not possible to accurately predict the age of symptom onset or degree of disability for a given individual.
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