eMedicine Specialties > Physical Medicine and Rehabilitation > Disorders of the Motor Unit

Hereditary Spastic Paraplegia: Differential Diagnoses & Workup

Author: Nam-Jong Paik, MD, PhD, Chief, Associate Professor of Rehabilitation Medicine, Rehabilitation Medicine, Seoul National University Bundang Hospital
Coauthor(s): Jae-Young Lim, MD, Assistant Professor, Department of Rehabilitation Medicine, Division of Musculoskeletal Rehabilitation, Bundang Hospital, Seoul National University College of Medicine
Contributor Information and Disclosures

Updated: Jul 29, 2008

Differential Diagnoses

Other Problems to Be Considered

Hereditary motor-sensory neuropathy type 5
Spondylosis
Atlantoaxial canal stenosis
Arteriovenous malformation compressing spinal cord
Arnold-Chiari syndrome
Tethered cord
Neoplasm
Granuloma
Spinocerebellar ataxias
Adrenomyeloneuropathy
Deficiency of vitamins B-12 and E
Abetalipoproteinemia
Mitochondrial disorders
Human T-cell lymphocytotrophic virus infection
Toxins
Stiff-limb syndrome

Related eMedicine topic:
Vitamin B-12 Associated Neurological Diseases

Workup

Laboratory Studies

• Presently, genetic loci (designated SPG1 through SPG23, in order of their discovery) have been identified for 10 autosomal dominant, 8 autosomal recessive, and 3 X-linked types of HSP. Ten HSP genes have been discovered.^4,5,6,7
• With regard to autosomal dominant pure HSP, SPG4, SPG3A, and SPG6 account for 50-60% of families.
  • 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.⁸ Genetic testing for SPG4/spastin mutations is available commercially, can provide laboratory confirmation of the diagnosis, and can be applied to prenatal testing. Insights into SPG4 phenotype and spastin function can yield useful information relating to hypotheses for axonal degeneration in SPG4 HSP, such as direct cytoskeletal instability, abnormal mitochondrial distribution, and other consequences of abnormal axonal transport.^5,9,10,11
  • A second autosomal dominant HSP (SPG3A) shows a linkage to band 14q11-q21. This is also a pure HSP. Symptoms usually begin in early childhood and are often nonprogressive. Genetic testing for SPG3A is commercially available.
  • A third autosomal dominant HSP, SPG6, shows a linkage to band 15q11.1. Symptoms begin in late teenage years. This kindred contains a number of affected members who have developed more severe disability than is typical in HSP families with other linkages.
• SPG5, SPG7, and FALDH are involved in autosomal recessive HSPs.
  • A family with pure HSP has demonstrated a linkage to band 8q12-q13 (SPG5 HSP).
  • Autosomal recessive SPG7 HSP has been linked to mutations in the gene encoding for paraplegin.^5,12 Mutations in the gene result in impaired oxidative phosphorylation.
  • Another autosomal recessive form of HSP, Sjögren-Larsson syndrome, is a disorder of the fatty aldehyde dehydrogenase gene (FALDH) and is associated with seizures.
• With regard to X-linked HSP, the border between pure and complicated HSP syndromes is blurred.
  • SPG1 HSP is linked to mutations in the gene for the L1 cell adhesion molecule; these mutations are associated with spasticity, ataxia, and mental retardation.
  • SPG2 HSP is linked to a missense mutation in the gene for proteolipid protein, which is located on band Xq21. Mutations in this gene are also related to complicated X-linked HSP and to Pelizaeus-Merzbacher syndrome.
• Preliminary genotype-phenotype correlations are as follows:
  • With the identification of HSP loci on chromosome X and 2p, 8q, 14q, 15q, and 16q, a comparison of phenotypes is possible in families for whom the disorder is linked to one of these loci, as well as in HSP families for whom these loci are excluded.¹³
  • Thus far, genetically diverse types of autosomal dominant HSP (those linked to 2p, 14q, and 15q) appear to be clinically and electrophysiologically similar. This observation suggests that the different abnormal gene products may interact in a common biochemical cascade that results in similar patterns of neuronal degeneration.
  • The disorder may be more severe in the 15q-linked kindred than in kindreds linked with 14q.
  • In a study of the kindred with disease linked to 14q, only 1 patient needed a wheelchair.¹⁴ In contrast, 9 of the patients affected in a kindred HSP linked to 15q required a wheelchair (for some patients, the need began in their 40s).
  • Kindreds with autosomal dominant HSP linked to 2p have exhibited (1) the prototypical adolescent- or adult-onset, progressive form and (2) the less common childhood-onset, relatively nonprogressive form. The significant variations in patients' ages at symptom onset and the degree of progression in these kindreds indicate that the complete phenotype is influenced by different mutations in the same gene or by the effects of modifying genes.

Related eMedicine topics:
Pelizaeus-Merzbacher Disease
Sjogren-Larsson Syndrome

Imaging Studies

• Magnetic resonance imaging (MRI) scans may demonstrate atrophy of the spinal cords and occasionally of the cerebral cortex.²

Other Tests

• Electrophysiologic studies are useful for assessing peripheral nerve, muscle, dorsal column, and corticospinal tract involvement in patients with HSP.¹⁵ Because it is uncommon to obtain permission to perform an autopsy, these studies are particularly useful for characterizing the extent of involvement. Although the results of these 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.¹⁶ 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. Shady concluded that measurement of central motor conduction velocity may be a useful way of identifying clinical subgroups of HSP.¹⁷
• The cerebrospinal fluid is usually normal, although increased protein is noted in some patients.

Histologic Findings

• 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 was maximal in the distal axons of these fibers.

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