Hereditary Spastic Paraplegia Workup

More than 40 genetic loci have been discovered for autosomal dominant, autosomal recessive, and X-linked types of hereditary spastic paraplegia (HSP), along with 20 genes for the disease. A study by Schlipf et al indicates that since clinical parameters alone are not reliable enough to differentiate between types of HSP, specifically autosomal recessive (AR) HSP, that amplicon-based high-throughput genotyping followed by pooled next-generation sequencing (NGS) is a much more efficient approach.^[22]

SPG4 HSP is the single most common dominantly inherited HSP, representing approximately 40% of such cases. Hazan and colleagues discovered that mutations in a novel gene designated SPG4 (protein, spastin) are the cause of this disorder.^[13] Genetic testing for SPG4/spastin mutations is available commercially, can provide laboratory confirmation of the diagnosis, and can be applied to prenatal testing.

Electrophysiologic studies are useful for assessing peripheral nerve, muscle, dorsal column, and corticospinal tract involvement in patients with HSP.^[23] Because it is uncommon to obtain permission to perform an autopsy, these studies are particularly useful for characterizing the extent of involvement.

Magnetic resonance imaging (MRI) scans may demonstrate atrophy of the spinal cords and occasionally of the cerebral cortex.^[2] The cerebrospinal fluid in HSP is usually normal, although increased protein is noted in some patients.

Although the results of electrophysiologic studies are variable, a number of generalizations can be made. Most studies have found nerve conduction test results to be normal (in contrast to results in Friedrich ataxia and some other spinocerebellar ataxias). One study, however, showed that subclinical sensory impairment was common in patients with HSP, with involvement of peripheral nerves and/or spinal pathways.

Lower extremity somatosensory evoked potentials show a conduction delay in dorsal column fibers. Cortical evoked potentials used to measure neurotransmission in corticospinal tracts show greatly reduced conduction velocity in the corticospinal tract and greatly reduced amplitude of the evoked potential.

Often, no cortical evoked potentials are 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 decreased numbers of corticospinal tract axons are reaching the lumbar spinal cord and that the remaining axons have reduced conduction velocity.

Schady and colleagues emphasized the variable results of cortical evoked potentials.^[23] In their patients, 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. Schady concluded that measurement of central motor conduction velocity may be a useful way of identifying clinical subgroups of HSP.^[24]

The major neuropathologic feature of pure, autosomal dominant HSP is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts (ie, crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis, respectively). Autopsy studies have demonstrated the loss of axons in the ventral and lateral corticospinal tracts.

Spinocerebellar fibers are involved to a lesser extent. Neuronal cell bodies of degenerating fibers are preserved, and no evidence of primary demyelination is noted. Loss of anterior horn cells is observed in some cases. Dorsal root ganglia, posterior roots, and peripheral nerves are normal.

The regional pattern of axonal degeneration in pure HSP is different from that seen in system degeneration diseases, such as amyotrophic lateral sclerosis (ALS). System degeneration in ALS includes cortical (ie, pyramidal) neurons, corticospinal tracts, anterior horn cells innervated by corticospinal tracts, and skeletal muscle. Parkinson disease, characterized by loss of dopaminergic neurons in the substantia nigra pars compacta and secondary changes in brain regions that receive this dopaminergic innervation, may exemplify another system degeneration.

Axonal degeneration in pure, autosomal dominant HSP involves different classes of neurons (eg, corticospinal tract fibers from pyramidal neurons in the motor cortex; fasciculus gracilis; cuneatus to a lesser extent, from dorsal root ganglia neurons). One obvious feature shared by these degenerating axons is their length; these fibers are the longest in the CNS. Degeneration has been found to be maximal in the distal axons of these fibers.