Hereditary Spastic Paraplegia Overview

[Familial Spastic Paraplegia, Hereditary Spastic Paraparesis, Strumpell-Lorrain Syndrome]

Clinical Manifestations of HSP

The predominant symptom of hereditary spastic paraplegia (HSP) is insidiously progressive lower-extremity weakness and spasticity.

Classification. HSP is classified clinically as uncomplicated (nonsyndromic) or complicated (syndromic) and genetically by mode of inheritance, chromosomal locus, or causative gene. Genetic loci for HSP are designated SPG for "spastic gait" followed consecutively by the locus number, which is assigned in order of its discovery; e.g., the first locus identified is named SPG1 [Fink 2003]:

• "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 and, occasionally, of joint position sensation [Harding 1983]. Uncomplicated HSP begins at any age, from early childhood through late adulthood, and progresses slowly over many years without exacerbations, remissions, or periods of abrupt worsening. Affected individuals experience progressive difficulty walking 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 typically disabling, uncomplicated HSP does not shorten life span.

• "Complicated" ("complex") HSP is characterized by the impairments present in uncomplicated HSP accompanied by other system involvement or other neurologic findings such as seizures, mental retardation, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy, in the absence of other coexisting disorders (such as diabetes mellitus). Many types of complicated HSP are associated with symmetric muscle atrophy of the distal upper and lower extremities [Refsum & Skillicorn 1954, Gilman & Horenstein 1964, Silver 1966, Neuhauser et al 1976, Sack et al 1978, Abdallat et al 1980, Heijbel & Jagell 1981, Bahemuka & Brown 1982, Joshita et al 1982, Fujii et al 1986, Uyama et al 1988, Costeff et al 1989, Serena et al 1990, Antinolo et al 1992, Farag et al 1994, Thomas et al 1994, Meierkord et al 1997].

Establishing the Diagnosis of HSP

HSP is diagnosed on the basis of the following:

• Characteristic clinical symptoms of insidiously progressive bilateral lower-extremity spastic weakness often accompanied by urinary urgency

• 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 hypertonic urinary bladder

• Family history consistent with autosomal dominant, autosomal recessive, or X-linked recessive inheritance

• Identification of a pathogenic mutation in an HSP-causing gene (Such testing is increasingly available and can confirm the diagnosis of HSP.)

Neurologic examination. Individuals with uncomplicated HSP demonstrate the following:

• Bilateral lower-extremity spasticity and weakness that is 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

• Often, mildly hyperactive deep tendon reflexes in the upper extremities

Neuropathology. The primary pathology in uncomplicated HSP is axonal 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, Harding 1993].

Differential Diagnosis of HSP

Exclusion of other diagnoses including the following:

• Structural abnormalities of the brain or spinal cord

• Leukodystrophy such as adrenomyeloneuropathy, Krabbe disease, and metachromatic leukodystrophy [Bajaj et al 2002]

• B12 deficiency

• Multiple sclerosis

• Tropical spastic paraplegia (caused by HTLV1 infection)

• Dopa-responsive dystonia (also known as hereditary progressive dystonia with marked diurnal variation or "Segawa disease"). This disorder should be considered in individuals, particularly children, with progressive gait disturbance and lower-extremity spasticity of unknown etiology because it is treatable with low-dose levodopa-carbidopa therapy.

• Amyotrophic lateral sclerosis (ALS). In addition to lower motor neuron findings with muscle atrophy and fasciculations, ALS often has corticospinal tract signs, spasticity, hyperreflexia, and extensor plantar responses. ALS is almost invariably more rapidly progressive than HSP. Most ALS is non-familial, but a few familial forms are recognized.

• Primary lateral sclerosis (PLS) is distinguished from HSP by the progression of lower-extremity spastic weakness to involvement of upper extremities and bulbar muscles. Rarely, PLS involvement may begin with the bulbar muscles and then progress to the upper extremities and lower extremities. PLS is further distinguished from ALS by electromyography (EMG), which typically shows chronic denervation pattern in ALS and is usually normal (or shows only minimal chronic denervation) in PLS.
  
  Although the majority of individuals with PLS have no family history of the disorder, a juvenile form of PLS (JPLS), characterized by onset and loss of ability to walk during the second year of life, progressive signs of upper motor neuron disease, wheelchair dependence by adolescence, and later loss of motor speech production, has been described as part of ALS2-related disorders. These disorders involve retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to JPLS to forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis or JALS). IAHSP is characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive upper-limb weakness and spasticity by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome.

• Arginase deficiency is suspected in individuals with the classic symptoms of loss of developmental milestones, progressive spasticity, and short stature. It is a treatable genetic cause of progressive spastic diplegia [Prasad et al 1997].

• Friedreich ataxia [Badhwar et al 2004]

• Machado-Joseph disease (SCA3)

• Early-onset Alzheimer disease with a PS1 mutation [Rogaeva et al 2003]

Prevalence of HSP

The prevalence of autosomal dominant hereditary spastic paraplegia in Ireland is 1.27:100,000 population [McMonagle et al 2002].

Founder effects have been reported [Orlacchio et al 2004].

Autosomal Dominant HSP

Table 1. Summary of Autosomal Dominant Hereditary Spastic Paraplegia

Locus Name 1 (Chromosomal Locus) 2	Gene Symbol/ Protein Name 3	HSP Syndrome 4	Age of Onset/ Age Range	Clinical Testing/ References
SPG3A	SPG3A / atlastin 5	Uncomplicated/ complicated	~6 years/ 2-50 years	/ Hazan et al [1993], Zhao et al [2001], Muglia et al [2002]
SPG4	SPAST / spastin 6	Uncomplicated/ complicated	~29 years/ 0-74 years	/ Hazan et al [1994], Claudiani et al [2005], Errico et al [2002], Errico et al [2004], Evans et al [2005], Hazan et al [1999]
SPG6	NIPA1 7	Uncomplicated	~22 years/ 12-35 years	Fink et al [1995], Rainier et al [2003], Chen et al [2005], Reed et al [2005], Munhoz et al [2006]
SPG8	KIAA0196	Uncomplicated	~37 years/ 22-60 years	Reid et al [1999], Rocco et al [2000], Valdmanis et al [2007]
SPG9 (10q23.3-q24.1)		Complicated	Childhood through adulthood	Lo Nigro et al [2000], Seri et al [1999]
SPG10	KIF5A / kinesin heavy chain isoform 5A 8	Uncomplicated/ complicated	Usually infancy or childhood; sometimes adulthood (35 years)	/ Reid et al [2002]
SPG12 (19q13)		Uncomplicated	~7 years/ Childhood to adolescence	Reid et al [2000], Ashley-Koch et al [2001], Orlacchio et al [2002]
SPG13	HSPD1 / 60 kd heat shock protein	Uncomplicated	~39 years/ 17-68 years	/ Fontaine et al [2000], Hansen et al [2002]
SPG17	BSCL2 / seipin 9	Complicated	Adolescence to early adulthood	/ Patel et al [2001], Irobi et al [2004], Warner et al [2004], Windpassinger et al [2004]
SPG19 (9q)		Uncomplicated	36-55 years	Valente et al [2002]
SPG29 (1p31.1-21.1)		Complicated	~15 years	Orlacchio et al [2005]
SPG31	REEP1	Uncomplicated	Childhood to young adulthood	/ Zuchner et al [2006]
SPG33	ZFYVE27	Uncomplicated	Adulthood	/ Mannan et al [2006]

From reviews by Fink [2003]

1. Locus name SPG = spastic gait

2. Chromosomal locus included if gene is unidentified

3. Protein names in common usage included

4. Uncomplicated spastic paraplegia: no other disease manifestations are present

Complicated spastic paraplegia: other disease manifestations are present

Protein functions:

5. Predicted to be GTPase similar to dynamins

6. Cytosolic and nuclear protein (depending on transcript), with AAA domain that binds to microtubules and appears to have microtubule-severing properties

7. Protein function unknown

8. Molecular motor involved in axonal transport

9. Integral membrane protein in endoplasmic reticulum

SPG3A HSP typically begins in early childhood and may resemble spastic diplegic cerebral palsy. Children with very early onset may have relatively non-progressive spastic gait (in contrast to the insidious worsening that is typically associated with later-onset HSP). SPG3A HSP is usually uncomplicated; some individuals can have lower motor neuron involvement (axonal neuropathy) that results in distal wasting.

Penetrance for pathogenic SPGA3 mutations is high although it may be incomplete. De novo SPGA3 mutations have been observed.

SPG4 HSP is the single most common type of uncomplicated autosomal dominant HSP, accounting for 40%-45% of such cases. SPG4 HSP typically progresses inexorably. Although the vast majority of individuals with SPG4 HSP exhibit uncomplicated HSP, some have memory impairment, dementia, seizures, ataxia, and even lower motor neuron involvement.

Penetrance for pathogenic SPAST mutations is age dependent and high (~85%), although both incomplete penetrance and apparent de novo mutations have been observed.

Apparent genetic anticipation (earlier onset and more severe symptoms in subsequent generations) has been reported in SPG4 HSP (although not associated with tandem repeat expansion).

SPG6 HSP progresses insidiously and may become severe.

Penetrance for pathogenic NIPA1 gene mutations is age dependent and high. Incomplete penetrance has not been reported.

SPG8 HSP is characterized by severe spasticity, hyperreflexia, lower-limb weakness, and decreased vibration sensation [Valdmanis et al 2007].

SPG9 HSP is characterized by cataracts, gastroesophageal reflux, and motor neuronopathy.

SPG10 HSP is complicated when associated with distal atrophy. Early (infant) onset and late (age 35 years) onset have been reported [Fichera et al 2004, Lo Giudice et al 2006].

SPG13 is often associated with vibratory sensory loss and severe handicap [Fontaine et al 2000].

SPG17 HSP is part of the spectrum of BSCL2-related neurologic disorders that includes Silver syndrome and variants of Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy type V, and spastic paraplegia 17. Features of these disorders include slow disease progression, upper motor neuron involvement (i.e., gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (i.e., amyotrophy of the peroneal muscles and small muscles of the hand), abnormal vibration sense, and pes cavus and other foot deformities. Penetrance is reduced.

SPG29 HSP includes hearing impairment and persistent vomiting from hiatal hernia.

SPG33 HSP has been described in a single German family with pes cavus and adult onset of a progressive spastic gait with normal sensation [Mannan et al 2006].

Autosomal Recessive HSP

Table 2. Autosomal Recessive Hereditary Spastic Paraplegia

Locus Name 1 (Chromosomal Locus) 2	Gene Symbol/ Protein Name 3	HSP Syndrome 4	Age of Onset/ Age Range	Clinical Testing/ References
SPG5A (8q12-q13)		Uncomplicated	1-20 years	/ Hentati et al [1994]
SPG7	SPG7 / paraplegin 5	Uncomplicated/ complicated	25-42 years	/ De Michele et al [1998], Elleuch et al [2006]
SPG11	SPG11 (KIAA1840)	Uncomplicated/ complicated	Childhood through adulthood	/ Martinez Murillo et al [1999], Sperfeld et al [2004], Winner et al [2004], Stevanin et al [2007]
SPG14 (3q27-q28)		Complicated	30 years	Vazza et al [2000]
SPG15 (14q23.3-q24.2)	ZFYVE26 / spastizin	Complicated	13-23 years	Hughes et al [2001], Hanein et al [2008]
SPG20	SPG20 / spartin 6	Complicated	Childhood	/ Cross & McKusick [1967], Crosby & Proukakis [2002], Patel et al [2002], Proukakis et al [2004]
SPG21	SPG21 / maspardin 7	Complicated	Childhood	Simpson et al [2003]
SPG23 (1q24-q32)		Complicated	Childhood	Blumen et al [2003]
SPG24 (13q14)		Complicated	Childhood	Hodgkinson et al [2002]
SPG25 (6q23-q24)		Complicated	Adulthood	Zortea et al [2002]
SPG26 (12p11.1-q14)		Complicated	Childhood	Wilkinson et al [2005]
SPG27 (10q22.1-q24.1)		Uncomplicated/ complicated	Adulthood	Meijer et al [2004]
SPG28 (14q21.3-q22.3)		Uncomplicated	Childhood	Bouslam et al [2005]
SPG30 (2q37)		Complicated	Adolescence	Klebe et al [2006]
SPOAN 8 syndrome (11q13)		Complicated	Infancy	Macedo-Souza et al [2005]

From reviews by Fink [2003]

1. Locus name SPG = spastic gait

2. Chromosomal locus included only when gene is unknown

3. Protein name only included per common usage

4. Uncomplicated spastic paraplegia: no other disease manifestations are present

Complicated spastic paraplegia: other disease manifestations are present

Protein functions:

5. Mitochondrial protein

6. N-terminal region similar to spastin; homologous to proteins involved in the morphology and endosome trafficking

7. Localizes to endosome/trans-golgi vesicles, may function as protein transport and sorting

8. SPOAN = spastic paraplegia, optic atrophy, neuropathy

SPG7 HSP is characterized by insidiously progressive bilateral lower-limb weakness and spasticity. Most affected individuals have proximal or generalized weakness in the legs and impaired vibration sense. Additional features may include hyperreflexia in the arms, sphincter disturbances, spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, and amyotrophy.

SPG11 HSP is variably associated with cognitive decline, thin corpus callosum variably, upper extremity weakness, dysarthria, and nystagmus [Lossos et al 2006].

SPG14 HSP is associated with mental retardation and distal motor neuropathy.

SPG15 HSP is associated with pigmented maculopathy, distal amyotrophy, dysarthria, mental retardation, and further intellectual deterioration (Kjellin syndrome).

SPG20 (Troyer syndrome) is characterized by spastic tetraparesis, dysarthria, distal amyotrophy, short stature, and learning difficulties. Most affected children have delay in reaching early developmental milestones (walking and talking), followed by slow deterioration in both gait and speech. Emotional lability and affective disorders such as inappropriate euphoria and/or crying are common. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis.

SPG21 HSP is associated with dementia, cerebellar and extrapyramidal signs, thin corpus callosum, and white matter abnormalities (Mast syndrome). Gait disturbance begins in adolescence through adulthood; cognitive impairment may be noted in childhood.

SPG23 HSP is associated with skin pigment abnormality.

SPG24 HSP is variably associated with spastic dysarthria and pseudobulbar signs.

SPG25 HSP is associated with spinal disc herniations.

SPG26 HSP is a progressive spastic paraparesis with dysarthria and distal amyotrophy in both upper and lower limbs and intellectual impairment.

SPG27 HSP is associated with dysarthria.

SPG30 HSP is associated with mild ataxia and sensory neuropathy.

SPOAN (spastic paraplegia, optic atrophy, neuropathy) is associated with progressive joint contractures and spine deformities. The onset of spastic paraplegia occurs in infancy, progressive neuropathy in childhood through adolescence, and dysarthria in the third decade.

X-Linked Recessive HSP

Table 3. X-Linked Recessive Hereditary Spastic Paraplegia

Locus Name 1 (Chromosomal Locus) 2	Gene Symbol/ Protein Name	HSP Syndrome 3	Age of Onset	Clinical Testing/ References
SPG1	L1CAM / neural cell adhesion molecule L1	Complicated	Congenital	/ Jouet et al [1994]
SPG2	PLP1 / myelin proteolipid protein 4	Complicated	Childhood or adolescence	/ Kobayashi et al [1994]
SPG16 (Xq11.2)		Uncomplicated/ complicated	Childhood	Steinmuller et al [1997], Tamagaki et al [2000]
Allan-Herndon- Dudley	SLC16A2 / monocarboxylate transporter 8	Complicated	Congenital	Bialer et al [1992], Schwartz et al [2005]

From reviews by Fink [2003]

1. Locus name SPG = spastic gait

2. Chromosomal locus included only when gene is unknown

3. Uncomplicated spastic paraplegia: no other disease manifestations are present

Complicated spastic paraplegia: other disease manifestations are present

4. Protein function: intrinsic myelin protein

SPG1 (see L1 Syndrome) is characterized by hydrocephalus, mental retardation, spasticity of the legs, and adducted thumbs. The phenotypic spectrum of L1 syndrome includes X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome (mental retardation, aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs), SPG1 (X-linked complicated hereditary spastic paraplegia type 1), and X-linked complicated corpus callosum agenesis.

SPG2 HSP. Males may exhibit either severe infantile dysmyelination (Pelizeaus-Merzbacher syndrome) or slowly progressive spastic paraplegia (SPG2) (see PLP1-Related Disorders). Some, but not all, males with SPG2 HSP have peripheral neuropathy and subtle white matter abnormalities on spinal and brain MRI.

SPG16 HSP is associated with motor aphasia, reduced vision, mild mental retardation, and bowel and bladder dysfunction.

Allan-Herndon-Dudley syndrome is associated with neck muscle hypotonia in infancy, mental retardation, dysarthria, ataxia, spastic paraplegia, and abnormal facies.

Mode of Inheritance

Hereditary spastic paraplegia (HSP) may be transmitted in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive 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 gene mutation.

• The frequency of de novo mutations 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 mutant allele, the risk to the sibs of inheriting the mutant 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 gene mutation, 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 mutation.

Risk to Family Members — Autosomal Recessive HSP

Parents of a proband

• The parents of an affected child are obligate heterozygotes, and therefore carry one mutant 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 mutant allele causing HSP.

Risk to Family Members — X-Linked Recessive 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 disease-causing mutation and his mother is not a carrier.

  • His mother has a de novo disease-causing mutation, either as a "germline mutation" (i.e., 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 disease-causing mutation.

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 disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Sons who inherit the mutation will be affected; daughters who inherit the mutation 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 gene mutation, 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 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 recessive HSP, autosomal dominant HSP with reduced penetrance, a de novo mutation, 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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA. DNA banking is particularly important in situations in which molecular genetic testing is available on a research basis only and/or the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for some forms of HSP is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) must be identified before prenatal testing can be performed. For laboratories offering custom prenatal testing, see .

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) has/have been identified. For laboratories offering PGD, see .

Treatment of Manifestations

No cures or specific drug treatments exist for hereditary spastic paraplegia (HSP). An approach to management of spasticity is reviewed by Young [1994]:

• 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 clonus and muscle tightness include the following:

  • Benzodiazepines

  • Baclofen (in advanced cases, sometimes intrathecal baclofen)

  • Tizanidine

  • Dantrolene

  • Botox injections to relieve muscle tightness [Rousseaux et al 2007]

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 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