Hereditary spastic paraplegia (HSP) (also known as Familial Spastic Paraparesis and Strumpell-Lorrain syndrome) is not a single disease entity but rather a group of clinically and genetically diverse disorders that share the primary feature of progressive, generally severe, lower extremity spasticity. HSP is classified as “uncomplicated” (symptoms confined to lower extremity weakness, bladder disturbance, and to a lesser extent impaired position sense in the legs); and “complicated” when additional neurologic deficits are present.
Following normal gestation, delivery, and early childhood development, subjects with uncomplicated autosomal dominant HSP develop leg stiffness and gait disturbance (e.g., stumbling and tripping) due to difficulty dorsiflexing the foot and weakness of hip flexion. Although the majority of patients experience symptom onset in the second through fourth decades, there is a wide range of age of symptom onset (from infancy through age 85) (Cooley et al, Clin Gen 38:57-68 (1990); Durr et al, Neurology 44:1274-7 (1994); Hazan et al, Nat Genet. 5:163-7 (1993)). Gait disturbance progresses insidiously without exacerbations, remissions, or step-wise worsening. Paresthesiae below the knees are not uncommon. Urinary urgency progressing to urinary incontinence is a frequent, although variable, late manifestation.
Neurologic examination of subjects with uncomplicated HSP reveals normal facial and extraocular movements and normal fundi. Although jaw jerk may be brisk in older subjects, there is no speech disturbance, difficulty swallowing or evidence of frank corticobulbar tract dysfunction. 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. Muscle wasting may occur in uncomplicated HSP (Harding A E, J Neurol Neurosurg Psychiatry 44:871-83 (1981); Silver J R, J Neurol Neurosurg Psychiatry 29:135-44 (1996); Cross et al, Arch Neurol 16:473-85 (1967); Refsum and Skillicorn, Neurology 4:40-7 (1954)). Peripheral nerves are normal in uncomplicated HSP although decreased perception of sharp stimuli below the knees is noted occasionally. Vibratory sense is often diminished mildly in the distal lower extremities. When present, this is a useful diagnostic sign that helps distinguish HSP from other disorders. Slight terminal dysmetria is observed occasionally on finger-to-nose testing in older affected subjects. Deep tendon reflexes may be brisk in the upper extremities but are pathologically increased in the lower extremities. Gait demonstrates circumduction owing to difficulty with hip flexion and ankle dorsiflexion. Crossed adductor reflexes, ankle clonus, and extensor plantar responses are present uniformly. Hoffman's and Tromner's signs may be observed. High arched feet (pes cavus) are generally present and usually prominent in older affected subjects.
The age of symptom onset, rate of symptom progression, and extent of disability are variable both within and between HSP kindreds (Durr et al, Neurology 44:1274-7 (1994); Schady and Scheard, Brain 113:709-20 (1990); Polo et al, J Neurol Neurosurg Psychiatry 56:175-81 (1993); Holmes and Shaywitz, J Neurol Neurosurg Psychiatry 40:1003-8 (1977)). In contrast to variable age of symptom onset and extent of disability, the distribution of neurologic deficits in uncomplicated HSP is invariant and consist of spastic weakness in the legs; variable impairment of vibratory sense in the feet; and variable urinary bladder disturbance. Additional deficits such as visual disturbance, marked muscle wasting, fasciculations, dementia, seizures, or peripheral neuropathy in subjects from uncomplicated HSP kindreds should not be attributed to variant presentations of uncomplicated HSP. Rather, such subjects should be evaluated thoroughly for concurrent or alternative neurologic disorders. Some autosomal dominant uncomplicated HSP kindreds that exhibit onset of progressive spastic paraplegia in childhood (before age 6 years) and relatively little progression of symptoms beyond adolescence. These patients often do not experience urinary bladder disturbances and generally remain ambulatory (with assistance).
Electrophysiologic studies are useful for assessing peripheral nerve, muscle, dorsal column, and corticospinal tract involvement in HSP (Harding A E, Semin Neurol 13:333-6 (1993)). These studies are particularly useful for characterizing the extent of involvement since autopsies are obtained infrequently. Although results of these studies are variable, a number of generalizations can be made. Most studies found nerve conduction studies to be normal (in contrast to Friedrich's ataxia and some other spinocerebellar ataxias) (Rosenberg R N, Arch Neurol 50:1123-8 (1993)). One study however, showed that subclinical sensory impairment was common in HSP, with involvement of peripheral nerves, spinal pathways, or both (Schady and Scheard, Brain 113:709-20 (1990)). Lower extremity somatosensory evoked potentials (SSEP) show conduction delay in dorsal column fibers (Pelosi et al, J Neurol Neurosurg Psychiatry 54:1099-102 (1991)). Cortical evoked potentials used to measure neurotransmission in corticospinal tracts show greatly reduced corticospinal tract conduction velocity and amplitude of evoked potential (Claus et al, Ann Neurol 28:43-9 (1990); Polo et al, J Neurol Neurosurg Psychiatry 56:175-81 (1993); Schady et al, J Neurol Neurosurg Psychiatry 54:775-9 (1991); Pelosi et al, J Neurol Neurosurg Psychiatry 54:1099-102 (1991)). Often, there is no cortical evoked potential elicited in muscles innervated by lumbar spinal segments, but cortical evoked potentials of the arms are normal or show only mildly reduced conduction velocity. These findings indicate that there are decreased numbers of corticospinal tract axons reaching the lumbar spinal cord and that the remaining axons have reduced conduction velocity. Central motor conduction velocity in the upper extremities was normal except for all 5 (affected) members of one HSP kindred for whom responses were considerably delayed. Measurement of central motor conduction velocity may be a useful way of identifying clinical subgroups of HSP.
Currently, there is no specific treatment to prevent, retard, or reverse HSP's progressive disability. Treatments aimed at reducing and preventing HSP symptoms are needed. In addition, the molecular pathogenesis of HSP is poorly understood. As such, an understanding of the molecular pathogenesis surrounding HSP and similar disorders is also needed
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