Clinical Diagnosis

Spastic paraplegia 3A (SPG3A) is one of the hereditary spastic paraplegias (HSPs), a group of neurodegenerative disorders characterized by progressive bilateral and mostly symmetrical lower extremity weakness and spasticity resulting from axonal degeneration of corticospinal tracts, diminished vibration sense caused by impairment of dorsal columns, and urinary bladder hyperactivity.

The diagnosis of SPG3A, one of the specific genetic types of HSP, can only be established by molecular testing of ATL1, the gene associated with SPG3A, because of the significant overlap between the age of onset and severity of the disease among the various types of HSP (see Hereditary Spastic Paraplegia).

Molecular Genetic Testing

Gene. ATL1 (formerly known as SPG3A), encoding the protein atlastin-1, is the only gene known to be associated with spastic paraplegia 3A.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used In Spastic Paraplegia 3A

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
ATL1	Sequence analysis/mutation scanning 2	Sequence variants 3	~100%	Clinical
	Deletion/duplication analysis 4	Exonic and whole-gene deletions 5	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. One ATL1 deletion involving exon 4 has been reported [Sulek et al 2011].

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Failure to detect a pathologic ATL1 sequence variant cannot absolutely exclude the diagnosis of SPG3A because the frequency of mutations involving non-coding regions (introns and promoter region) is unknown.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Genotype/phenotype correlation in persons with hereditary spastic paraplegia (HSP) has a low sensitivity; the diagnosis of SPG3A can be established only by molecular genetic testing. Individuals with HSP with a clear family history of autosomal dominant transmission are typically tested for several genes causing autosomal dominant HSP (AD HSP) (see Differential Diagnosis).

• Individuals with early-onset AD HSP may initially be tested for SPG3A only, followed by testing for other genes commonly associated with AD HSP if a pathologic ATL1 sequence variant is not identified.

• The yield of molecular genetic testing of ATL1 in persons with who are simplex cases (i.e., a single occurrence in a family) is unknown, but molecular genetic testing should be considered if acquired causes of spastic paraparesis have been eliminated [Rainier et al 2006].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

SPG3A is allelic with hereditary sensory neuropathy type ID (HSN ID), which is an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Missense mutation in ATL1 was identified in a single family with HSN I; other known HSN I-associated genes were excluded as the cause of polyneuropathy [Guelly et al 2011].

Natural History

Spastic paraplegia 3A (SPG3A) is characterized by clinical findings that tend to be more homogenous than other forms of AD HSP [Zhao et al 2001, Durr et al 2004, Hedera et al 2004]. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. The rate of progression is slow; wheelchair-dependency or need for an assistive walking device is relatively rare.

Although it has been suggested that SPG3A is a neurodevelopmental rather than a neurodegenerative disorder, recent identification of individuals with adult-onset SPG3A argues strongly against this hypothesis [Sauter et al 2004, Zhu et al 2006]. Persons with adult onset of SPG3A also tend to experience slower progression of their clinical symptoms.

Most persons with early-onset SPG3A have a “pure” or uncomplicated” HSP phenotype. However, complex HSP phenotypes with axonal motor neuropathy and/or distal amyotrophy (like that observed in the Silver syndrome phenotype) have also been reported [Scarano et al 2005, Ivanova et al 2007, Salameh et al 2009].

Signs seen less frequently in SPG3A than in other HSPs include the following [Durr et al 2004]:

• Hyperreflexia of the upper extremities

• Impairment of vibration sensation at the ankles

• Urinary sphincter hyperactivity

Signs seen more frequently in SPG3A than in other HSPs are pes cavus deformities and scoliosis; however, the presence of these findings may be attributable to the earlier age of onset rather than the specific form of HSP.

Genotype-Phenotype Correlations

Most persons with mutations in ATL1 and early-onset disease have point missense mutations clustered around the GTPase binding domain.

Although some ATL1 mutations associated with late-onset HSP are insertional mutations in the C-terminus of the gene that result in a premature truncation of the protein, adult-onset disease has also been observed with missense mutations in the GTPase binding domain [Tessa et al 2002, Sauter et al 2004].

Penetrance

Overall, penetrance of SPG3A-causing mutations is high (~80%-90%) [Durr et al 2004]. In many familial cases, individuals with ATL1- confirmed mutations had a normal neurologic examination even at an advanced age, arguing against significant age-dependent penetrance [Durr et al 2004].

The lowest penetrance, 30%, was reported for the p. Arg415Trp mutation [D’Amico et al 2004].

Anticipation

Anticipation with an earlier age at onset and increased severity in successive generations is not a feature of the majority of SPG3A kindreds. However, a bias of ascertainment towards earlier recognition of HSP in younger generations of a family is commonly observed based on awareness of the disease by other family members and treating physicians.

Nomenclature

“Silver syndrome phenotype” refers to the inherited findings of spasticity and axonal motor neuropathy and/or distal amyotrophy [Silver 1966]. It is now known that these findings can be seen in a number of hereditary neurologic disorders caused by mutations in different genes (e.g., SPG3A caused by mutations in ATL1 and BSCL2-related neurologic disorders caused by mutations in BSCL2) [Windpassinger et al 2004].

Prevalence

Estimated prevalence of AD HSP varies from 1.27:100,000 in the survey in Ireland to 12.4:100,000 based on a Norwegian epidemiologic study [Skre 1974, McMonagle et al 2002].

ATL1 mutations have been confirmed as the most common cause of early-onset HSP, accounting for approximately 30%-50% of all AD HSP with onset before age ten years [Abel et al 2004, Durr et al 2004].

SPG3A accounts for approximately 10%-15% of all AD HSP cases [Fink et al 1996]. Analysis of a large cohort of patients with excluded mutations in SPAST (formerly known as SPG4) showed that 40% of these patients have mutations in ATL1 [Durr et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spastic paraplegia 3A (SPG3A), the following evaluations may be indicated:

• Orthopedic evaluation in persons with early onset of SPG3A who have developed musculoskeletal complications including scoliosis or foot deformities

• Physical and occupational therapy evaluation in children with early onset of disease

• Urologic evaluation in persons with prominent urinary bladder hyperactivity

• Electromyography and nerve conduction studies in persons with associated axonal neuropathy or neurogenic pain in the lower extremities caused by possible lumbo-sacral radiculopathy secondary to lumbar hyperlordosis and degenerative vertebral changes

Treatment of Manifestations

Therapy for spasticity, distal weakness, and urinary bladder dysfunction, the primary manifestations of SPG3A, is symptomatic.

Spasticity can be treated with:

• Oral baclofen or tizanidine

• Chemodenervation with botulinum A or B toxins; may be tried in those who do not tolerate oral antispasticity medications

• Intrathecal baclofen pump; a good alternative for patients who improve on oral baclofen but cannot tolerate a therapeutic dose because of systemic adverse effects

Each of the above therapies should be combined with intensive physical therapy focused on stretching and strengthening exercises.

The role of surgical therapy for spasticity (including hamstring and heel cord lengthening and release of the adductor longus) remains unknown, but such treatment should be considered if contractures appear. See also Prevention of Secondary Complications.

Distal weakness, typically affecting foot dorsiflexion, can be ameliorated by ankle-foot orthoses; referral to orthotic services may be helpful.

Urinary urgency can be treated with anticholinergic antispasmodic drugs.

Prevention of Secondary Complications

Musculoskeletal abnormalities including muscle tendon contractures, scoliosis, and foot deformities are the secondary complications most likely to occur, resulting from long-standing spasticity and weakness. Intense and regular therapy for spasticity, including physiotherapy, can delay and minimize the appearance of these complications. The higher incidence of orthopedic problems in patients with SPG3A may be related to early age of onset and these patients should be followed by an orthopedist if problems are present.

Urinary bladder incontinence can be a secondary complication of a neurogenic bladder and urologic care may be needed.

Patients with advanced disease may experience falls with a risk of traumatic injury. A walking aid (cane, walker, or wheelchair) may need to be considered in patients experiencing falls.

Surveillance

There is no consensus regarding the frequency of clinical follow-up visits, but every person with HSP should be reevaluated once or twice a year to identify new complications early and to initiate aggressive therapy as indicated.

Agents/Circumstances to Avoid

Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Spastic paraplegia 3A (SPG3A) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals (>95%) diagnosed with spastic paraplegia 3A have an affected parent.

• A proband with SPG 3A may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is currently unknown.

• Although no instances of germline mosaicism have been reported, it remains a possibility.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a comprehensive neurologic examination. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most (>95%) individuals diagnosed with SPG3A have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (< 5%).

• The sibs of a proband with clinically unaffected parents are still at increased risk for spastic paraplegia 3A because of the possibility of reduced penetrance in a parent.

• If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with spastic paraplegia 3A has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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 of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed. In rare instances when the disease-causing mutation was not identified, linkage analysis method can be used if the family is informative enough and a tight linkage to the SPG3A has been established [Hedera et al 2001].

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

Requests for prenatal testing for conditions that (like SPGA) do not affect intellect or shorten life expectancy are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

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

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Author Notes

Author’s Web page

Acknowledgments

P. Hedera is supported by NIH (NINDS) grant K02NS057666

Revision History

• 9 February 2012 (cd) Revision: single-exon deletion in ATL1 found to cause SPG3A [Sulek et al 2011]; HSN ID identified as allelic disorder

• 21 September 2010 (me) Review posted live

• 26 April 2010 (ph) Original submission