Hereditary Spastic Paraplegia

Author(s): Christina Jenner, MD , Sunil Sabharwal MD, Chloe Slocum, MD

Originally published:07/11/2013

Last updated:08/25/2016

1. DISEASE/DISORDER:

Definition

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse inherited neurodegenerative disorders that cause lower limb spasticity and weakness. HSP syndromes have traditionally been classified as either uncomplicated (pure) or complicated. Uncomplicated HSP is the most common and is characterized purely by spastic paraplegia, whereas complicated HSP is associated with a wide array of neurologic conditions, such as deafness, amyotrophy in the upper limbs, ichthyosis, optic neuropathy, dementia, and mental retardation.

Etiology

The genetics of HSP are complex and heterogeneous. Over fifty spastic paraplegia gene (SPG) genetic loci have been identified to date. The mode of inheritance for HSP can be autosomal dominant, recessive, or X-linked. Autosomal dominant HSP is the most prevalent form and accounts for approximately 70% of all cases. Most cases of uncomplicated (pure) HSP are inherited in the autosomal dominant fashion. The most common HSP-related genes that account for over 50% of the cases are SPAST (also known as SPG4) and SPG3A. In contrast, the complicated forms tend to demonstrate autosomal recessive inheritance.

Epidemiology including risk factors and primary prevention

The prevalence of HSP is estimated to be at 3 to 10 cases per 100,000. The onset of the disease process begins anywhere from early childhood to 70 years of age.

Patho-anatomy/physiology

The common pathologic feature in HSP is retrograde degeneration of the distal portion of the longest nerve fibers in the corticospinal tracts and posterior columns. It is believed that HSP is associated with a disruption of axonal transport and membrane trafficking, which is critical to axonal health and function. Membrane trafficking is a highly organized and regulated system that allows interaction between the plasma membrane and other membrane-bound components of the cell. Axonal transport depends on microtubule tracts and is necessary for a variety of cellular functions. The long axons of the corticospinal tracts and posterior columns are particularly reliant on such processes. In some cases, mitochondrial dysfunction may also be also associated with HSP.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

This is a slowly progressive neurodegenerative disease process, which gradually results in spasticity and weakness in the bilateral lower extremities. Although there is clinical variability in HSP onset and progression, abrupt onset or rapid symptom progression are not characteristic and should suggest a different diagnosis. When HSP manifests in the first couple years of life, it is often nonprogressive for a couple decades followed by slow worsening thereafter. Later onset of symptoms in early childhood or in adults is characterized by slow, gradual progression. Lifespan is often normal in many cases of uncomplicated HSP. It is important to recognize that there is often variation in severity and progression within and between HSP families.

Specific secondary or associated conditions and complications

Uncomplicated HSP is often associated with pes cavus, neurogenic bladder, and reduced vibratory sensation in the lower extremities. For the complicated subtype of HSP, multiple neurologic conditions may be seen in addition to spastic paraplegia, including but not limited to the following: mental retardation, ataxia, extrapyramidal signs, hypoplasia of corpus callosum, adducted thumbs, hydrocephalus, seizures, cataracts, amyotrophy, hyperbilirubinemia, and deafness.

2. ESSENTIALS OF ASSESSMENT

History

Typically, patients have a history of normal gestation, delivery, and early childhood with the subsequent development of increased tone in the legs and gait disturbance. Onset of HSP is subtle, with development of leg stiffness. The insidious development of these symptoms can arise anywhere from early childhood to approximately 70 years of age. Lower extremity spasticity is often reported to be worse in cold weather, following exertion, and at the end of the day. The development of neurogenic bladder is a common late manifestation of the disease process, and typically presents as urinary urgency. Cognitive impairment may occur, especially with some forms of complication in HSP.

A thorough family history is essential for patients with HSP. The presence of typical clinical features in other family members strongly supports the diagnosis, but the absence of family history does not exclude the diagnosis. Family history may be absent because of gene mutation, late age of symptom onset, mild symptoms that are attributed to other causes, or autosomal recessive or X-linked inheritance, in which carriers are often asymptomatic.

Physical examination

Examination of the lower extremities in patients with HSP typically reveals spasticity and weakness that is mostly symmetric. The extent of weakness is variable and may be mild, especially with early-onset disease, even in the presence of severe spasticity. Spasticity is especially prominent in the hamstrings, adductor, and gastroc-soleus muscles, and weakness is often most obvious in the hamstrings, iliopsoas, and tibialis anterior muscles. This is often accompanied by brisk reflexes, extensor plantar responses, decreased vibratory sensation in the toes, and pes cavus. Decreased vibratory sensation may be present in the toes, but severe dorsal column impairment is not typical of uncomplicated HSP. Although hyperreflexia in the upper extremities may be present, significant spasticity or weakness in the arms should lead to questioning of the diagnosis, as should the presence of bulbar muscle weakness, the presence of a sensory level, or markedly asymmetric involvement.

In complex HSP, examination of the cranial nerves may reveal optic neuropathy, retinal pigmentary degeneration, and/or ophthalmoplegia. Other signs that may be seen in patients with complex HSP include ichthyosis, amyotrophy, dementia, cataracts, and mental retardation.

Functional assessment

Gait analysis is an important aspect of assessment in HSP, because gait disturbance is a primary symptom. The relative contribution, extent, and distribution of weakness and spasticity influence the manner in which gait is affected; therefore, careful analysis is important to individualize a therapeutic plan. Gait abnormalities may include reduced stride length, toe walking, circumduction, dragging of toes, scissoring, hyperlordosis, or hyperextension at the knees.

Laboratory studies

Genetic testing: the mapping and cloning of HSP genes has led to increasing availability of specific molecular genetic tests, although gene testing is commercially available for only a subset of genes. A genetic diagnosis can now be made in over 75% of cases of autosomal dominant HSP. Additional genetic testing may be available on a research basis.

The primary role of additional laboratory testing is to exclude alternative diagnoses. Investigations may include tests for vitamin B12, copper, ceruloplasmin, very long chain fatty acids, white cell enzymes, plasma amino acids, serum lipoprotein analysis, serology for syphilis, and human immunodeficiency virus.

Imaging

Magnetic resonance imaging (MRI) of the brain and spinal cord can exclude other disorders, such as multiple sclerosis, leukodystrophies, and structural abnormalities. MRI of the brain may reveal possible hypoplasia of the corpus callosum in some patients with complicated HSP. MRI of the spine may reveal thinning of the spinal cord, especially in the thoracic region.

Supplemental assessment tools

Electromyography and nerve conduction studies are usually normal in uncomplicated HSP, but some forms of complicated HSP may be associated with peripheral neuropathy and evidence of lower motor involvement.

Early predictions of outcomes

Caution is warranted in estimating the degree of eventual disability as a result of variation in severity and disease progression. In general, subjects from families with well-documented uncomplicated HSP are not likely to develop complicated HSP. This is helpful in predicting outcomes, because uncomplicated HSP makes upper extremity functional impairment, speech or swallowing problems, or a significantly reduced lifespan much less likely.

Environmental

Environmental modifications may be indicated to accommodate progressive impairment of ambulation.

Social role and social support system

Given the rarity of the disorder, patients and families may feel alone and anxious. Support groups and other forums that facilitate interaction with others who have the same disorder are helpful in sharing information and experiences.

Professional Issues

The limitations in the ability to predict prognosis and variability in disease onset and progression should be kept in mind when providing counseling to patients and families with HSP.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

There is no available treatment to slow or reverse the disease process.

At different disease stages

Management of HSP is done with the goal of maintaining the greatest degree of functional independence for each patient. Contracture prevention and spasticity management are important for many of these individuals and can include any or all of the following: stretching, splinting, anti-spasticity medications (e.g., baclofen, tizanidine, or dantrolene sodium), and intrathecal baclofen pump placement. Physical therapy and occupational therapy should be initiated to assess functional mobility and activities of daily living. A regularly followed exercise regimen should incorporate daily or twice daily stretching and daily exercises to promote improved endurance and activity tolerance and to prevent deconditioning. Ankle-foot orthoses can be helpful to reduce toe dragging. Canes, walkers, or wheelchairs may eventually be required, though some individuals with HSP never require assistive devices for ambulation. Education on prevention of pressure ulcer formation and appropriate neurogenic bowel and bladder management should also be initiated. Medications, such as oxybutynin, are helpful in managing urinary urgency.

Patient & family education

Genetic counseling in HSP is improved by the availability of gene testing. Even with genetic testing, providers should be cautious given the variability of presentation of HSP phenotypes.

Emerging/unique Interventions

Measures of lower limb spasticity, gait quality, and mobility can be helpful in determining effectiveness of treatment.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

A significant proportion of undiagnosed spastic paraplegia is genetic in origin. Consider the possibility of HSP in adults with gradual onset of spastic paraplegia, where a cause cannot be determined, even in the absence of an obvious family history. A detailed family investigation is important in such cases, keeping in mind that some affected individuals may have very mild or subtle symptoms.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

Novel insights into the processes that maintain axons and advances in the cellular mechanisms involving axonal transport, membrane trafficking, mitochondrial activity and the potential for pharmacologic manipulation of these pathways, should help identify potential therapeutic solutions for HSP and other neurodegenerative disorders with axonal pathology in the future.

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

The increasing number of genes being identified in association with HSP has led to the growing recognition about the heterogeneous nature of this disorder. With advances in gene sequencing technology, more genes for HSP and related disorders are very likely to be uncovered in the near future.

REFERENCES

Bibliography

Blackstone, C. Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci. 2012;35:25-47.

Fink, JK. Hereditary spastic paraplegia. Curr Neurol Neurosci Rep. 2006;6:65-76.

Fink, JK. Hereditary spastic paraplegia: clinic-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126:307-328.

Salinas, S; Proukakis, C; Crosby, A; Warner, TT. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 2008;7:1127-1138.

Original Version of the Topic:

Matthew S. Brown, DO, Sunil Sabharwal, MD. Hereditary Spastic Paraplegia. Publication Date:2013/07/11.

Author Disclosure

Christina Jenner, MD
Nothing to Disclose

Sunil Sabharwal MD
Demos Publication, Receipt of Royalties, Author/Editor. American Board of PM&R, non-remunarative position of influence, Board of Directors

Chloe Slocum, MD
Nothing to Disclose

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