Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of inherited disorders characterized by insidiously progressive, often severe, lower extremity weakness and spasticity.¹ Symptom severity, age of onset and rate of disease progression may vary widely among patients.^1-2 It is estimated that three in every 100,000 people are affected with HSP in the U.S.³

HSPs are classified by clinical presentation, as either uncomplicated or complicated, and by inheritance pattern. Uncomplicated (or pure) HSP 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.⁴ Uncomplicated HSP can be disabling, but it does not shorten life span.¹ HSP 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.¹ Researchers estimate that uncomplicated HSP represents 90% of all HSP cases, while complicated HSP accounts for 10%.³

HSP's inheritance pattern may be autosomal dominant (the most common), autosomal recessive or X-linked. Recent advances in molecular genetic testing now enable the identification of at least 50% of uncomplicated autosomal dominant hereditary spastic paraplegia (ADHSP) cases.^5-6 The diagnosis of HSP in individuals with positive family histories may be relatively evident, but often the pattern of inheritance is difficult to discern, making the diagnosis more complex.

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 associated with 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 Spastic Paraplegia*

*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 SPG4⁹ and the recently identified SPG3A.⁶ Together, these forms of HSP are estimated to comprise more than 50% of uncomplicated ADHSP.^5-6

SPG4 gene mutations are thought to cause the most common form, an estimated 40-45%, of uncomplicated ADHSP.^4,7 SPG4 encodes for an amino acid protein, spastin, a member of the highly conserved ATPase domain.⁹ The function of the gene is not understood. The types of mutations in the SPG4 gene suggest that this form of HSP results from a loss of function of the protein. The loss of function implies that a threshold level of spastin is essential in axonal preservation, which may explain the variable expressivity and incomplete penetrance of SPG4 HSP.⁶

The SPG3A gene is thought to account for an estimated 9% of uncomplicated ADHSP⁶ and 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 HSP 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:

• Primary axonal degeneration that is more severe in the distal portions of the corticospinal tracts in the thoracic spinal cord and less severe at the distal ends of dorsal column fibers (particularly the fasciculus gracilus fibers) in the cervico-medullary region
• Possible mild loss of anterior horn cells
• Demyelination, if present, that is consistent with the degree of axonal degeneration.¹

Gait disturbance (stumbling and tripping), because of bilateral lower extremity weakness and/or spasticity, is the primary symptom of uncomplicated HSP.⁴ The age of symptom onset is highly variable. The first symptoms of HSP have been reported as early as late-infancy to early childhood; and as late as the eighth decade.¹⁰ Urinary urgency and lower extremity parasthesia often occur.¹ Upper-extremity function is preserved among individuals with uncomplicated HSP.

In general, HSP is thought to be caused by mutations in the SPG3A gene is characterized by early onset (before the age of 11) ⁷ 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 SPG4 mutations 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, HSP was generally diagnosed clinically based on family history, neurological signs and the exclusion of other disorders.⁷

According to Fink¹, the differential diagnosis of uncomplicated HSP includes:

• Structural spinal cord abnormalities: Arnold-Chiari malformations; cervical or lumbar spondylosis; tethered cord syndrome; neoplasm involving spinal cord; spinal cord arteriovenous malformation.
• Degenerative diseases: familial cerebral palsy; multiple sclerosis; amyotrophic lateral sclerosis; primary lateral sclerosis and spinocerebellar ataxias, including Machado-Joseph disease, and Friedreich's ataxia.
• Leukodystrophy: adrenoleukodystrophy (ALD); adrenomyeloneuropathy (AMN); metachromatic leukodystrophy (MLD) and Krabbe (globoid cell) leukodystrophy
• Metabolic disorders: subacute combined degeneration (B12 deficiency); mitochondrial encephalomyopathy; abetalipoproteinemia (Bassen-Kornzweig disease) and vitamin E deficiency
• Infectious diseases: tertiary syphilis (hypertrophic pachymeningitis); tropical spastic paraparesis and acquired immunodeficiency syndrome (AIDS)
• DOPA-responsive dystonia

There are no effective treatments for the underlying distal axonal degeneration of HSP.¹ Currently, only symptomatic treatments are available.⁴ However, 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.¹

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 appear present in more than 50% of ADHSP cases.^5-6 A definitive molecular determination helps the physician in their overall diagnosis of the condition, possibly reducting the anxiety in affected individuals who have been living with symptoms of an undiagnosed disorder. 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.² While the risk of inheriting 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.

	A woman with no previous medical history of HSP consulted a physician at the age of 40 years because of difficulty walking, due to "stiffness of both legs" that had begun insidiously several months earlier and appeared to be progressively increasing. Examination revealed increased muscle tone and a mild proximal motor deficit in the lower limbs, hyperreflexia in lower and upper limbs, with clonus of the ankles and a positive Hoffmann sign and extensor plantar reflex, and slightly impaired vibration sense in the ankles. She had no sphincter disturbances. Her parents were alive and healthy and so were her three children, but she mentioned a 79-year-old aunt with increasing walking difficulties that had worsened since the age of 63, who was now unable to walk at all. Thorough investigations excluded structural, inflammatory, metabolic and infectious etiologies. Because of the possibility of HSP, the asymptomatic family members were then examined. Brisk reflexes and an extensor plantar response were found in her 74-year-old mother and in her eldest sister, aged 54. Her other sister, aged 49, had no abnormal neurologic signs on examination. Two of her children were also examined. The eldest, a 24-year-old man, had a normal neurologic examination, whereas the daughter aged 20, had brisk reflexes and extensor plantar reflexes. Molecular analysis revealed a mutation in the SPG4 gene in the patient, her mother, her two sisters, and the two children who had been examined. Further family studies revealed the presence of the mutation in the aunt and three of her six children, who already had mild walking difficulties with onset at 9, 30 and 45 years, respectively.

	A healthy female was born following uncomplicated full-term gestation and normal spontaneous vaginal delivery. There were no perinatal complications. Early infantile milestones were attained normally. When the child began to walk, it was noted that she was walking on her toes, and that her feet were turned inward. Medical and orthopedic evaluations revealed lower extremity spasticity. Serial casting procedures followed by gastroc-soleus tendon lengthening procedures were performed. Lower extremity spastic gait continued through childhood with very little change. Despite having markedly abnormal gait, this individual played actively with other children. Gait disturbance continued through adolescence and adulthood with very little change. As an adult, the patient often would use a cane, and for long distances and while shopping, would intermittently use a wheel chair. The patient's brother, father, aunt, and cousins had similar early childhood onset spastic gait disturbance. Genetic testing of this individual revealed a SPG3A mutation.

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