Hereditary Spastic Paraplegia Overview

John K Fink, MD
Department of Neurology
University of Michigan
Ann Arbor, Michigan
ude.hcimu@knifkj
Initial Posting: August 15, 2000; Last Update: February 6, 2014.

Summary

Disease 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 mutation 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 disease-causing mutation(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.

Definition

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, chromosomal locus, and/or causative mutation. 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) andfamilial 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.

Full article courtesty of: http://www.ncbi.nlm.nih.gov/books/NBK1509/