AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Strümpell first described hereditary forms of spastic paraplegia in 1883, with Lorrain later providing more extensive detail. The common feature of these syndromes is spasticity in the lower extremities that is progressive and often severe. Hereditary spastic paraplegia (HSP) is also called familial spastic paraparesis and Strümpell-Lorrain syndrome.

Numerous clinical reports have documented that HSP syndromes are heterogeneous. Syndromes are classified as uncomplicated, or pure, when only spinal involvement occurs, and they are classified as complicated when they are associated with neurologic abnormalities, such as ataxia, mental retardation, dementia, extrapyramidal dysfunctions, visual or hearing dysfunctions,¹ adrenal insufficiency, and ichthyosis.

Inheritance may be X-linked, autosomal recessive, or autosomal dominant. The most useful classifications now are based on the mode of inheritance and genetic linkage. Clinical distinctions between pure and complicated forms of HSP have some utility; however, the age of onset often has no clear relation to the HSP genotype.

Pathophysiology

HSP causes degeneration of the ends of the corticospinal tracts within the spinal cord. The ends of the longest fibers, which supply the lower extremities, are affected to a much greater extent than are the fibers to the upper body. Although some degeneration of the fibers supplying the arms commonly takes place, most people with HSP do not have symptoms in the hands or arms.

In most cases of HSP, the primary problem may be disturbance of the ends of the long axons, with little or no loss of myelin and no abnormal myelin. A rare type of X-linked HSP, however, has been associated with a myelin protein gene mutation. Patients with this form of HSP generally show evidence of myelin abnormalities, which are known to affect axon function. Although genes involved with myelination of the central nervous system (CNS) are less likely to be involved with HSP than are those associated with axonal stability, these genes must be considered.

Frequency

International

In Europe, the frequency of HSP is estimated to be 1-9 cases per 100,000 population. Because HSP is rare, it is often misdiagnosed, making the actual frequency rate difficult to determine. A reasonable estimate, however, is that it affects approximately 3 persons per 100,000 population. This represents fewer than 10,000 cases in the United States. Further estimates indicate that about 10% of people with HSP have complicated HSP.

Mortality/Morbidity

In patients with pure HSP, life expectancy typically is unaffected by the condition. Generalizations about the life expectancy of people with complicated HSP are difficult to make, because each patient has unique symptoms.

Age

Pure HSP may occur at any age, from infancy through late adulthood (eg, 85 y). Most patients experience the onset of symptoms between the second and fourth decades of life.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Clinical features
• • HSP is not a single disease entity; it is a group of clinically and genetically diverse disorders that share a primary feature, which is the causation of progressive and generally severe lower extremity weakness and spasticity.
  • Pure, autosomal dominant HSP has been reviewed. After normal gestation, delivery, and early childhood development, subjects develop leg stiffness and gait disturbance (eg, stumbling, tripping) because of difficulty in dorsiflexing the foot and as a result of weakness in hip flexion.
• Classification
• • HSP is generally classified as pure or complicated.
  • In pure HSP, symptoms are generally limited to gradual weakening in the legs; urinary bladder disturbance; and, sometimes, impaired sensation in the feet.²
  • In complicated HSP, additional symptoms may include peripheral neuropathy, epilepsy, ataxia, optic neuropathy, retinopathy, dementia, ichthyosis, mental retardation, deafness, and problems with speech, swallowing, or breathing. Complicated HSP is rare.
  • Some of these additional symptoms may be related to a separate disorder, rather than being directly caused by HSP. Patients may actually have pure HSP plus 1 or more other disorders. For example, a person with pure HSP may have peripheral neuropathy caused by diabetes, or they may have unrelated epilepsy.
  • HSP may also be classified by the mode of inheritance (X-linked, autosomal dominant, or autosomal recessive); each type has several subtypes, which are based on the location of the gene. The mode of inheritance cannot be used to predict the severity of the disorder, because symptoms can vary greatly within each type.
  • In the past, HSP was also classified as type I or type II, based on the patient's age at the onset of symptoms and on the amount of spasticity versus weakness. Because both types can appear in the same family, this method of classification is no longer in general use.²
  • To date, the locations of several genes have been identified. Ten types of dominantly inherited pure or complicated HSP are known, along with 7 types of recessively inherited HSP and 3 types of X-linked HSP.
• Symptoms²
• • The classic symptom of HSP is progressive difficulty in walking, but the severity varies. Some patients eventually may require the use of a wheelchair, while others may never need any type of assistive device. Patients usually have difficulty lifting their toes; as a result, they drag their toes when walking and catch them on stairs or on uneven sidewalks or curbs.
  • In later stages, patients experience difficulty flexing the thigh muscle to raise the leg when walking. A reduced sense of balance is noted. Muscles weaken but also experience increased muscle tone. Some patients complain of reduced sensation in the distal regions of the legs.
  • Some people also experience urinary problems (eg, incontinence, sense of urgency even when bladder is not full). People with HSP also experience hyperactive reflexes. Many symptoms that are common in people with HSP are not directly caused by HSP but are instead caused indirectly by muscle spasticity, weakness, or hyperactive reflexes.
  • Spasticity
  • • Spasticity is an increase in muscle tone with resulting stiffness. Muscle tone refers to the mild contraction that muscles continue to have even when at rest (ie, resting muscle tone). A reflex between nerve endings in the muscle and spinal cord regulates muscle tone. Normally, the corticospinal nerves control and reduce sensitivity of this reflex. Because HSP causes deterioration of the corticospinal nerves, the reflex is not reduced as it should be, the result being an exaggerated (ie, hyperactive) reflex and increased muscle tone.
    • Depending on the circumstances, the amount of spasticity experienced is likely to change a good deal. Stiffening of the leg muscles is normal after long periods of sitting, because the muscles have been contracted and then are stretched upon standing. Many people also notice that their muscles seem tighter when they are emotionally stressed or upset. Other factors that can affect spasticity are cold temperature, poor posture, high humidity, and illness.
  • Abnormal gait
  • • Increasing stiffness in the legs is associated with frequent tripping, particularly when the patient is walking on uneven terrain.
    • Uncontrollable shaking of the legs may be noted when the patient ambulates. Dragging of the feet, scissoring of the legs during ambulation, weakness and giving way at the ankles, flexor spasms of the legs during the night, and a sense of unsteadiness during walking also are common.
  • Decreased sense of balance
  • • A common symptom of HSP is a decreased sense of balance. For many people, this is the first symptom that they notice.
    • Many people with HSP have an impaired sense of position in their feet. If the brain does not receive accurate signals about the body's position, it may not be able to respond properly to those signals, and loss of balance occurs.
  • The age of symptom onset, the rate of symptom progression, and the extent of disability are variable within and between HSP kindreds. In contrast to the extent of disability and to the variable age of patients at symptom onset, the distribution of neurologic deficits in pure HSP is consistent; it consists of spastic weakness in the legs, variable impairment of vibratory sense in the feet, and variable urinary bladder disturbance.
  • In patients with pure HSP kindreds, the presence of additional deficits, such as visual disturbance, marked muscle wasting, fasciculations, dementia, seizures, and peripheral neuropathy, should not be attributed to variant presentations of pure HSP. Therefore, these patients should be thoroughly evaluated for concurrent or alternative neurologic disorders.
  • Some pure, autosomal dominant HSP kindreds exhibit an onset of progressive spastic paraplegia in childhood (ie, <6 y) and relatively little progression of symptoms beyond adolescence.³ These patients often do not experience urinary bladder disturbances and generally remain ambulatory with assistance.

Physical

• Neurologic examination reveals no evidence of cranial nerve dysfunction or reduced mentation. Although the jaw jerk may be brisk in older subjects, no speech disturbance, difficulty swallowing, or evidence of frank corticobulbar tract dysfunction is noted.
• Upper extremity muscle tone and strength are normal.
• • In the lower extremities, muscle tone is increased at the hamstrings, quadriceps, and ankles.
  • Results of manual muscle testing are difficult to assess because of increased tone; however, weakness is occasionally demonstrated in the legs.
  • Weakness is most notable at the iliopsoas muscles, the tibialis anterior muscles, and, to a lesser extent, the hamstring muscles.
  • Muscle wasting may occur in patients with pure HSP, but it is mild and is limited to atrophy of the shins in elderly, wheelchair-dependent patients.
• Peripheral nerves are normal in patients with pure HSP, although decreased perception of sharp stimuli below the knees is occasionally noted.
• • Vibratory sensation is often mildly diminished in the distal lower extremities. When it occurs, this deficit provides a diagnostic sign that helps to distinguish HSP from other disorders.
  • Slight terminal dysmetria is occasionally observed on finger-to-nose testing in older affected individuals.
  • Deep tendon reflexes may be brisk (2+ to 3+) in the upper extremities but are pathologically increased (3+ to 4+) in the lower extremities.
• The patient's gait demonstrates circumduction owing to a difficulty with hip flexion and ankle dorsiflexion.
• • Crossed adductor reflexes, ankle clonus, and extensor plantar responses are uniformly present.
  • Hoffman and Tromner signs may be observed.
  • High-arched feet (pes cavus) are generally present and are usually prominent in older patients.

Causes

Familial spastic paraplegia is a hereditary condition.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab 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.

TREATMENT

Section 6 of 11  

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• Follow-up
• Miscellaneous
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• References

Rehabilitation Program

Physical Therapy

Regular physical therapy (PT) is important for maintaining and improving range of motion (ROM) and muscle strength. Furthermore, PT is necessary to maintain aerobic conditioning of the cardiovascular system. Although PT does not reduce the degenerative process within the spinal cord, individuals with HSP must maintain an exercise regimen performed at least several times each week, as guided by their physical therapist. Exercise can help the patient to retain or improve muscle strength, minimize atrophy of the muscles caused by disuse, increase endurance, reduce fatigue, prevent spasms and cramps, and maintain or improve ROM. Exercise also has a positive psychological effect, helping to reduce stress and produce feelings of well-being.

Patients with HSP may experience spasticity and weakness (ie, increased muscle tone and reduced muscle strength). Because of the increased resistance to passive stretching, spasticity may make it difficult for patients to exercise certain muscles. Antispasmodic drugs may help the patient to reduce the spasticity and may allow weakened muscles to be targeted in order to improve the effectiveness of PT.

Different types of exercised incorporated into PT programs for patients with HSP may include strengthening, stretching, and aerobic exercises, as follows:

• Strengthening exercises - These help to strengthen muscles that have not yet weakened. Strengthened muscles help to compensate for muscles that have weakened, decreasing the rate of functional impairment. Exercise may also help to slow the development of disuse atrophy, which occurs in muscles that are not being used (eg, in calf muscles of people who use wheelchairs). Back-strengthening exercises may help to reduce or eliminate back pain associated with HSP. Such pain is probably not due to HSP itself but to strain on the back resulting from HSP (eg, poor gait, poor posture, use of a mobility device).
• Stretching exercises - These help to maintain or increase ROM and to reduce such problems as tendinitis, bursitis, and muscle cramps.
• Aerobic exercises - These improve cardiovascular fitness, reduce fatigue, and increase endurance and general fitness. Walking, bicycle riding, water aerobics, and swimming are among many excellent forms of aerobic exercise.

Medical Issues/Complications

Currently, no specific treatment exists to prevent, retard, or reverse progressive disability in patients with HSP. Nonetheless, treatment approaches used for chronic paraplegia from other causes are useful.

Possible complications associated with HSP include the following:

• Gastrocnemius-soleus contracture
• • This condition is more common when symptoms begin in childhood rather than in adulthood.
  • It also occurs when PT has not been sufficient.
• Cold feet
• • Many people with HSP complain of cold feet. This is a common complaint in many disorders of the upper or lower motor neurons.
  • Cold feet may be related to abnormal thermoregulation of cutaneous vessels; however, circulation is usually preserved.
• Fatigue
• • Fatigue is a common symptom of HSP. One obvious cause is the extra effort required for walking, because of muscle weakness in the legs.
  • Various medications prescribed for HSP cause drowsiness or fatigue. Many patients with HSP may not get their required amount sleep, because of leg cramps or spasms or as a result of the frequent need to urinate during the night.
  • A less obvious cause of fatigue may be the fact that because of a more sedentary lifestyle, people with HSP often are not aerobically fit and therefore have reduced endurance. Stress or depression also can contribute to fatigue.
• Back or knee pain
• • Back and/or knee pain is common in people with HSP. The pain is not directly due to HSP itself but is instead often caused by muscle weakness and gait abnormalities resulting from HSP.
  • As certain muscles become weaker, other muscles need to compensate for that weakness. Compensatory measures create an awkward gait that causes strain on many muscles and joints.
  • Patients may thrust their shoulders back or swing their legs outward as they walk. Use of certain mobility devices also may put a strain on the arms or back.
• Stress and depression
• • Stress, depression, and denial are not unusual in patients with HSP or any other chronic illness.
  • Denial is not necessarily a problem, as long as the person in denial is not depriving himself or herself of proper treatment and care. Denial allows some people to cope and set their worries aside.
  • Some people with HSP face denial by family members who refuse to admit that a problem exists. This can create a frustrating and stressful situation.

Consultations

• Physical medicine and rehabilitation specialist
• Neurologist

MEDICATION

Section 7 of 11  

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• Medication
• Follow-up
• Miscellaneous
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• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.⁶

Drug Category: Antispasmodics

Bladder spasticity has been improved with oxybutynin (Ditropan).

Drug Category: Skeletal muscle relaxants

Antispasticity medications can be useful. However, one of the drawbacks of using these agents is that some patients find that the stiffness of spasticity helps them to overcome the muscle weakness that also occurs in HSP. When patients are medicated to reduce stiffness, walking may become more difficult. Adverse effects can also be a problem. If the patient does well with the medications, however, discomfort associated with spasticity can generally be reduced, mobility can be improved, and the effectiveness of PT can be enhanced. Patients in relatively early stages of the illness have achieved symptomatic improvement with oral dantrolene, as well as with oral and intrathecal baclofen.

Drug Category: Benzodiazepines

These agents may act in the spinal cord to induce muscle relaxation.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention:

• Because familial spastic paraplegia is a hereditary condition, no deterrence or prevention measures exist.

Complications:

• Patients with HSP may have several possible complications, including the following:
• • Gastrocnemius-soleus contracture
  • Cold feet
  • Fatigue
  • Back and knee pain
  • Stress and depression
• See the Medical Issues/Complications section for more information.

Prognosis:

• See the History section.

Patient Education:

• For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article BOTOX® Injections.

MISCELLANEOUS

Section 9 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to rule out reversible forms of spinal cord lesions (mechanical cord compression or spinal cord tumor) when considering a diagnosis of HSP invites problems.

MULTIMEDIA

Section 10 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Photograph of a 16-year-old girl with complicated hereditary spastic paraplegia. She has a spastic gait disturbance, mental retardation, and extrapyramidal symptoms. Note the dysmorphic features.
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Media type:  Photo

Media file 2:  Dysmorphic appearance of a 16-year-old girl with complicated hereditary spastic paraplegia. This patient displays a short stature (145 cm) and hair loss. Anterior (left), lateral (middle), and posterior (right) views are shown.
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Media type:  Photo

Media file 3:  General appearance of sisters with complicated hereditary spastic paraplegia. They are aged 16 and 17 years. Physical examination revealed increased deep tendon reflexes in all 4 extremities, with an extensor plantar reflex. Sensory losses in the patients have affected mainly their joint positions and vibration sensations.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Sawhney IM, Bansal SK, Upadhyay PK, et al. Evoked potentials in hereditary spastic paraplegia. Ital J Neurol Sci. Sep 1993;14(6):425-8. [Medline].
2. Reid E. Pure hereditary spastic paraplegia. J Med Genet. Jun 1997;34(6):499-503. [Medline]. [Full Text].
3. Appleton RE, Farrell K, Dunn HG. 'Pure' and 'complicated' forms of hereditary spastic paraplegia presenting in childhood. Dev Med Child Neurol. Apr 1991;33(4):304-12. [Medline].
4. Fink JK. Advances in the hereditary spastic paraplegias. Exp Neurol. Nov 2003;184 Suppl 1:S106-10. [Medline].
5. Tallaksen CM, Durr A, Brice A. Recent advances in hereditary spastic paraplegia. Curr Opin Neurol. Aug 2001;14(4):457-63. [Medline].
6. Züchner S. The genetics of hereditary spastic paraplegia and implications for drug therapy. Expert Opin Pharmacother. Jul 2007;8(10):1433-9. [Medline].
7. Paisan-Ruiz C, Dogu O, Yilmaz A, et al. SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia. Neurology. Apr 15 2008;70(16 Pt 2):1384-9. [Medline].
8. Hazan J, Fonknechten N, Mavel D, et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet. Nov 1999;23(3):296-303. [Medline].
9. Depienne C, Stevanin G, Brice A, et al. Hereditary spastic paraplegias: an update. Curr Opin Neurol. Dec 2007;20(6):674-80. [Medline].
10. Fink JK, Rainier S. Hereditary spastic paraplegia: spastin phenotype and function. Arch Neurol. Jun 2004;61(6):830-3. [Medline].
11. Orlacchio A, Patrono C, Gaudiello F, et al. Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4. Neurology. May 20 2008;70(21):1959-66. [Medline].
12. Tzoulis C, Denora PS, Santorelli FM, et al. Hereditary spastic paraplegia caused by the novel mutation 1047insC in the SPG7 gene. J Neurol. Jun 23 2008;[Medline].
13. Fink JK, Heiman-Patterson T, Bird T, et al. Hereditary spastic paraplegia: advances in genetic research. Hereditary Spastic Paraplegia Working Group. Neurology. Jun 1996;46(6):1507-14. [Medline].
14. Hazan J, Lamy C, Melki J, et al. Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q. Nat Genet. Oct 1993;5(2):163-7. [Medline].
15. Schady W, Smith CM. Sensory neuropathy in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry. Jun 1994;57(6):693-8. [Medline]. [Full Text].
16. Schady W, Dick JP, Sheard A, et al. Central motor conduction studies in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry. Sep 1991;54(9):775-9. [Medline]. [Full Text].
17. Claus D, Waddy HM, Harding AE, et al. Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study. Ann Neurol. Jul 1990;28(1):43-9. [Medline].

Article Last Updated: Jul 29, 2008