Clinical characteristics.

The hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous disorders characterized by lower extremity spasticity and weakness (occurring in variable proportion). When symptoms begin after childhood, they usually progress slowly and steadily. When symptoms begin in very early childhood, they may be non-progressive and resemble spastic diplegic cerebral palsy.

HSP is classified as "uncomplicated" if neurologic impairment is limited to lower extremity spastic weakness, hypertonic urinary bladder disturbance, and mild diminution of lower extremity vibration sensation. HSP is classified as "complicated" if the impairment present in uncomplicated HSP is accompanied by other systemic or neurologic abnormalities such as ataxia, seizures, cognitive impairment, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy (in the absence of other causes for these additional features).

Neurologic examination of individuals with uncomplicated HSP demonstrates variable degrees of increased muscle tone (spasticity) particularly in the hamstrings, quadriceps, gastrocnemius-soleus, and adductor muscles; weakness in the iliopsoas, hamstring, and tibialis anterior muscles; hyperreflexia at the patella and ankles; often (though not always) mildly reduced vibration sensation in the toes; extensor plantar responses; and spastic gait.

Diagnosis/testing.

HSP is diagnosed by:

• Typical clinical symptoms of spastic gait impairment and neurologic findings of lower extremity spasticity and weakness;
• Often (though not always) a family history of similarly affected first-degree relative(s); and
• Exclusion of other disorders.

Magnetic resonance imaging (MRI) of the brain and spinal cord are usually normal; cerebrospinal fluid studies, electromyography, and nerve conduction studies are usually normal in uncomplicated HSP.

Genetic testing is increasingly available and particularly useful to confirm a clinical diagnosis of HSP. Since molecular genetic testing at present does not include all genes known to cause HSP, the absence of an identified pathogenic variant in a gene known to cause HSP does not exclude the diagnosis of HSP.

Genetic counseling.

Genetic types of HSP can be inherited in an autosomal dominant, autosomal recessive, X-linked, or maternally inherited (mitochondrial) manner. When studied, genetic penetrance is high (estimated at 90%). Genetic counseling depends on an accurate diagnosis and determining the mode of inheritance in each family. Genetic testing may be useful in determining the genetic type of HSP. Prenatal testing for some types of spastic paraplegia is possible for pregnancies at increased risk if the pathogenic variant(s) have been identified in the family.

Management.

At present, no treatment prevents or reverses nerve degeneration in HSP. Treatment is directed towards reducing symptoms and improving strength and balance through physical therapy and rehabilitation; assistive devices to improve functional gait (e.g., ankle-foot orthotic devices); medications and stretching to reduce spasticity (e.g., oral and intrathecal Lioresal^®, intramuscular botulinum toxin [Botox^®] injection); and medications to reduce urinary urgency.

Clinical Manifestations of HSP

The predominant symptoms of hereditary spastic paraplegia (HSP) are lower extremity weakness and spasticity. When symptoms begin in very early childhood, they may be non-progressive and resemble spastic diplegic cerebral palsy. When symptoms begin later in childhood or later they usually progress slowly and steadily. After a number of years, it is not usual for individuals with progressively worsening gait to experience a "functional plateau" (i.e., the rate of further worsening of gait impairment is similar to that attributable to age).

Classification. HSP is classified clinically as uncomplicated (nonsyndromic) or complicated (syndromic) and genetically by mode of inheritance, chromosome locus, and/or causative allelic variant. Genetic loci for HSP are designated SPG (for "spastic paraplegia") 1 through 56 in order of their discovery [Fink 2013].

• "Uncomplicated" ("pure") HSP is characterized by neurologic impairment limited to progressive lower extremity spastic weakness, hypertonic urinary bladder disturbance, and mild diminution of lower extremity vibration sensation [Harding 1983].
  Uncomplicated HSP begins at any age, from early childhood through late adulthood. Symptoms may be non-progressive (when they begin in very early childhood); or worsen slowly over many years (when symptoms begin after childhood). HSP with early-onset symptoms that are non-progressive may resemble spastic diplegic cerebral palsy.
  Affected individuals experience difficulty walking (that may either be non-progressive or worsen insidiously) and often require canes, walkers, or wheelchairs. Urinary urgency and lower extremity paresthesiae may occur.
  Individuals with uncomplicated HSP typically retain normal strength and dexterity of the upper extremities and have no involvement of speech, chewing, or swallowing. Though symptoms may be disabling, uncomplicated HSP does not shorten life span.
• "Complicated" HSP is characterized by the impairments present in uncomplicated HSP accompanied by other system involvement or other neurologic findings including ataxia, seizures, intellectual disability, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy, in the absence of other causes for these additional features.

Establishing the Diagnosis of HSP

HSP is diagnosed on the basis of the following:

• Characteristic clinical symptoms of bilateral lower extremity spastic weakness often accompanied by urinary urgency that may be non-progressive (with early childhood onset symptoms); or slowly progressive (with symptom onset after childhood)
• Neurologic examination demonstrating corticospinal tract deficits affecting both lower extremities (spastic weakness, hyperreflexia, typically associated with bilateral extensor plantar responses), often accompanied by mildly impaired vibration sensation in the distal lower extremities and symptoms of hypertonic urinary bladder
• Family history consistent with autosomal dominant, autosomal recessive, or X-linked inheritance or maternal (mitochondrial) inheritance
• Exclusion of alternate disorders (see Differential Diagnosis)
• Molecular genetic testing; increasingly available and potentially useful confirming the clinical diagnosis HSP

Neurologic examination. Individuals with uncomplicated HSP demonstrate the following:

• Bilateral lower extremity spasticity (maximal in hamstrings, quadriceps, adductors, and gastrocnemius-soleus muscles) and weakness (maximal in the iliopsoas, hamstring, and tibialis anterior muscles). Spasticity and weakness are variable. Some individuals have spasticity and no demonstrable weakness, whereas others have spasticity and weakness in approximately the same proportions.
• Lower extremity hyperreflexia and extensor plantar responses
• Often, mildly impaired vibration sensation in the distal lower extremities

Neuropathology. The most commonly reported pathology in uncomplicated HSP is axon degeneration that is maximal at the distal ends of the corticospinal tracts and, to a lesser extent, at the distal ends of dorsal column fibers. Mild loss of anterior horn cells may occur. Demyelination, if present, is consistent with the degree of axonal degeneration [Schwarz & Liu 1956, Behan & Maia 1974].

Differential Diagnosis of HSP

The differential diagnosis includes:

• Structural abnormalities involving the brain or spinal cord (e.g., tethered cord syndrome and spinal cord compression)
• Other motor neuron disorders such as slowly progressive amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS)
• Leukodystrophies such as steadily progressive multiple sclerosis, B₁₂ deficiency, Krabbe disease, metachromatic leukodystrophy, and adrenomyeloneuropathy
• Spinocerebellar ataxias (SCAs) (e.g., Machado-Joseph disease [SCA 3], Friedreich ataxia, spastic ataxia of Charlevoix-Saguenay or other spastic ataxias). See Hereditary Ataxias.
• Infection (e.g., human immunodeficiency virus [HIV AIDs], tropical spastic paraplegia (also known as human T-cell leukemia virus 1 [HTLV1] -associated myelopathy), and neurosyphilis
• Metabolic disorders (reviewed in Sedel et al [2007]) including homocysteine re-methylation defects (due to methylene tetrahydrofolate reductase (MTHFR) deficiency) and cobalamin C disease, urea cycle defects, biotinidase deficiency, phenylketonuria, glycine encephalopathy, cerebral folate deficiency, homocarnosinosis, cerebrotendinous xanthomatosis, Sjögren-Larsson syndrome, adult polyglucosan body disease, and nucleoside phosphorylase deficiency
• Early-onset dementias including frontotemporal dementia-ALS (see Amyotrophic Lateral Sclerosis Overview) and familial Alzheimer disease caused by mutation of PSEN1 (encoding presenilin-1), PSEN2 (encoding presenilin-2), or APP (encoding amyloid precursor protein) (see Early-Onset Familial Alzheimer Disease)
• Dopa-responsive dystonia. It is important to consider dopa-responsive dystonia in all individuals-- particularly children-- with progressive gait disturbance. See GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia, Tyrosine Hydroxylase Deficiency.

Prevalence of HSP

The prevalence of HSP has been estimated to range from 1.3:100,000 (in Ireland) [McMonagle et al 2002], to 9.6: 100,000 (in Spain) [Sedel et al 2007].

Genetic types of hereditary spastic paraplegia (HSP). To date, more than 56 HSP loci and 41HSP-related genes have been identified.

Evaluation Strategy

Evaluation strategy to establish the cause of spastic paraplegia in an affected person includes the following:

• Clinical evaluation. A thorough medical history, neurologic history, and physical examination
• Family history. A three-generation family history with attention to other relatives with possible HSP. Documentation of relevant findings in family members can be accomplished either through direct examination of those individuals or through review of their medical records including neuroimaging, neuropathology, neurologic examination, and results of molecular genetic testing.
• Molecular genetic testing, available clinically for many of the HSPs
  • One genetic testing strategy is serial single gene molecular genetic testing based on some combination of factors that may include (but are not limited to) the following:
    • Mode of inheritance
    • Clinical findings (e.g., age at onset, additional clinical features, MRI findings)
    • Prevalence of the disorder (e.g., mutation of SPG4 (encoding spastin), the single most common cause of dominantly inherited HSP, accounts for approximately 30 to 40% of affected individuals)
    • Patient’s ethnicity
  • An alternative genetic testing strategy is use of a multigene panel that includes a combination of genes mentioned in Table 1, Table 2, Table 3, and Table 4. Note: The genes included and the methods used in multigene panels vary by laboratory and over time.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Mode of Inheritance

Hereditary spastic paraplegia (HSP) may be transmitted in an autosomal dominant manner, an autosomal recessive manner, or an X-linked manner, depending on the genetic subtype in a family.

Risk to Family Members – Autosomal Dominant HSP

Parents of a proband

• Most individuals diagnosed as having an autosomal dominant HSP have an affected parent, although occasionally a proband with HSP may have the disorder as the result of a de novo pathogenic variant.
• The frequency of de novo variants causing autosomal dominant HSP is unknown.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%.
• The age of onset and degree of disability are highly variable among members of the same family, in different families with the same pathogenic variant, or between genetic types of HSP.

Offspring of a proband. Each child of an individual with autosomal dominant HSP is at a 50% risk of inheriting the pathogenic variant.

Risk to Family Members – Autosomal Recessive HSP

Parents of a proband

• The parents of an affected individual are obligate heterozygotes, and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• The unaffected sibs of an affected individual have a 2/3 chance of being heterozygous.
• Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive HSP are obligate heterozygotes (carriers) for a mutated allele causing HSP.

Risk to Family Members – X-Linked HSP

Parents of a proband

• Women who have an affected son and another affected male relative are obligate heterozygotes.
• If pedigree analysis reveals that an affected male represents a simplex case (an affected male with no known family history of spastic paraplegia), several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo pathogenic variant and his mother is not a carrier.
  • His mother has a de novo pathogenic variant, either as "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body), or as "germline mosaicism" (i.e., in her germ cells only).
  • His maternal grandmother has a de novo pathogenic variant.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's mother.
• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Sons who inherit the variant will be affected; daughters who inherit the variant are carriers and will be unaffected.
• The age of onset, penetrance, and degree of disability are not predictable in members of the same family, in different families with the same pathogenic variant, or between genetic types of HSP.

Offspring of a proband. All daughters of an affected male are carriers; none of his sons will be affected.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).

Related Genetic Counseling Issues

Caution must be exercised when counseling an individual who has all the signs and symptoms of HSP but who has no other similarly affected relatives. Such individuals may be diagnosed as having primary lateral sclerosis (PLS). While such individuals with no known family history of HSP may have autosomal recessive HSP (and thus low risk of transmitting the disorder to offspring), it is also possible that they have X-linked HSP, autosomal dominant HSP with reduced penetrance, a de novo pathogenic variant, mistaken paternity, or an environmentally acquired disorder.

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for hereditary spastic paraplegia are possible.

Treatment of Manifestations

At present, there is no specific treatment to prevent or reverse nerve degeneration in HSP. Treatments are directed at reducing symptoms and improving balance, strength, and agility. Current recommendations:

• Daily regimen of physical therapy directed toward improving cardiovascular fitness, maintaining and improving muscle strength and gait, and reducing spasticity is recommended.
• Occupational therapy, assistive walking devices, and ankle-foot orthotics are often used.
• Drugs to reduce muscle spasticity (e.g., Lioresal^® [oral or intrathecal], tizanidine, dantrolene, Botox^® injections) and reduce urinary urgency (e.g., oxybutynin)

Prevention of Secondary Complications

Daily regimen of physical therapy is recommended to improve cardiovascular fitness, maintain and improve muscle strength and gait, and reduce spasticity.

Surveillance

Patients should be evaluated periodically (annually or as needed) by a neurologist and physiatrist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms.

Agents/Circumstances to Avoid

Exposure to medications or chemicals that cause neuropathy should be avoided if possible.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

HSP symptoms generally do not change significantly during pregnancy (although, if medications such as baclofen are reduced or discontinued during pregnancy, spasticity may be increased). In general, uncomplicated HSP does not pose increased risk for pregnancy, labor, or delivery. In general, having uncomplicated HSP does not increase risk associated with obstetric anesthesia.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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Revision History

• 6 February 2014 (me) Comprehensive update posted live
• 3 February 2009 (cd) Revision: sequence analysis for SPG5A available clinically
• 21 May 2008 (cd) Revision: mutations in ZFYVE26 identified as causative of SPG15
• 4 March 2008 (cd) Revision: sequence analysis of entire coding region available for SPG8 and SPG33
• 4 October 2007 (cd) Revision: sequence analysis for SPG10 available on a clinical basis
• 11 July 2007 (me) Comprehensive update posted to live Web site
• 21 October 2004 (cd) Revision: arginase deficiency added
• 26 February 2004 (cd) Revision: testing for SPG6 clinically available
• 15 October 2003 (cd) Revision: test availability
• 22 September 2003 (me) Comprehensive update posted to live Web site
• 15 August 2000 (me) Overview posted to live Web site
• 21 March 2000 (jf) Original submission