Clinical Diagnosis

Hereditary spastic paraplegia 8 (SPG8) is diagnosed in individuals with the following [Reid et al 1999, Rocco et al 2000]:

• “Pure” spastic paraplegia of the lower limbs (i.e., hyperreflexia and occasionally clonus without other neurologic findings)

• Onset in the 20s and 30s

• Mutation in KIAA0196

Molecular Genetic Testing

Gene. KIAA0196, encoding the protein strumpellin, is the only gene known to be responsible for hereditary SPG8.

Clinical testing

• Sequence analysis. Sequence analysis of all exons and exon/intron junctions should detect 100% of point mutations and small insertions and deletions [Valdmanis et al 2007]. Of the six families that map to the SPG8 locus [Hedera et al 1999], five families were evaluated and found to have a KIAA0196 mutation [Valdmanis et al 2007].

Table 1. Summary of Molecular Genetic Testing Used in Spastic Paraplegia 8

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
KIAA0196	Sequence analysis of coding regions and exon/intron junctions	Sequence variants	5/5 1	Clinical

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. Valdmanis et al [2007]

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

Testing Strategy

To establish the diagnosis in a proband, molecular genetic testing is necessary to identify a disease-causing mutation in KIAA0196.

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.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with germline mutations in KIAA0196.

KIAA0196 is overexpressed in prostate cancer [Porkka et al 2004].

Natural History

Spastic paraplegia 8 (SPG8) is characterized by progressive lower-limb spasticity (hyperreflexia and extensor plantar reflexes). Affected individuals also demonstrate weakness, a minor component that is probably secondary to reduced mobility.

Some affected individuals have urinary urgency that usually becomes apparent at the same time as the spasticity.

Decreased vibration sense is an additional finding on neurologic examination [Depienne et al 2007].

Intra- and interfamilial phenotypic variability is high. In one family, age of onset was between ages 18 and 26 years [Rocco et al 2000]; in another family the age of onset was between ages 35 and 53 years [Valdmanis et al 2007].

SPG8 is typically more severe than other types of hereditary spastic paraplegia, with affected individuals usually becoming wheelchair bound in their 30s and 40s [Rocco et al 2000]:

• Onset is between ages 18 and 59 years [Hedera et al 1999, Reid et al 1999, Rocco et al 2000]. In one family of 15 affected individuals, insidiously progressive spastic paraparesis began between ages 22 and 60 years (average: 37.2 years). Ten of the 15 were wheelchair bound by age 40 years [Hedera et al 1999].

• In one large family, SPG8 had more wheelchair-dependent family members (6 of 15) than observed in other types of autosomal dominant hereditary spastic paraplegia [Reid et al 1999].

Neuroimaging. In one moderately affected individual MRI showed significant atrophy of the thoracic spinal cord as determined by cross-sectional area measurements [Hedera et al 1999].

Other studies. The following are normal:

• Sensory examination

• Cerebrospinal fluid

• Electrophysiologic studies:

  • Nerve conduction velocity

  • Electromyography

  • Somatosensory evoked potentials

  • Muscle biopsy [Hedera et al 1999, Rocco et al 2000]

Genotype-Phenotype Correlations

The number of mutations reported to date is too small to draw any genotype-phenotype correlations.

Nomenclature

Hereditary spastic paraplegia is classified as "uncomplicated" or "pure" if neurologic impairment is limited to progressive lower-extremity spastic weakness, hypertonic urinary bladder disturbance, mild diminution of lower-extremity vibration sensation, and, occasionally, joint position sensation. Thus, SPG8 is an uncomplicated or pure hereditary spastic paraplegia.

Hereditary spastic paraplegia is classified as "complicated" ("complex") if the impairment present in uncomplicated hereditary spastic paraplegia is accompanied by other system involvement or other neurologic findings such as seizures, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy, in the absence of other disorders such as diabetes mellitus.

Penetrance

The penetrance for SPG8 is estimated between 90% and 100%.

Anticipation

There is no evidence for anticipation in hereditary SPG8.

Prevalence

The prevalence of all hereditary spastic paraplegia is 1-18 in 100,000 [McMonagle et al 2002]. Mutations in KIAA0196 account for approximately 4% of hereditary spastic paraplegia [Valdmanis et al 2007].

Mutations in KIAA0196 have been identified in the North American, British, and Brazilian populations. It is expected that KIAA00196 mutations would have a similar prevalence in other populations [Valdmanis et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spastic paraplegia 8 (SPG8), the following evaluations are recommended:

• Neurologic examination

• Urodynamic evaluation

Treatment of Manifestations

No cures or specific drug treatments exist for hereditary spastic paraplegia. 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.

• Antispasmodic drugs (e.g., baclofen, BOTOX^®, dantrolene, tizanidine), used one at a time, are usually helpful, especially early in the disease course. Baclofen can be tried first, and can be used with an intrathecal pump in some cases. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic, otherwise three to four times per day. These drugs alleviate symptoms by decreasing cramps and making leg muscles less tight, which can facilitate walking. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.

Surveillance

The following are appropriate:

• Regular neurologic examinations to evaluate disease progression.

• Referral to a urologist for urodynamic testing and follow-up when symptoms appear.

Testing 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. Note: There may not be clinical trials for this disorder.

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 8 (SPG8) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• More then 90% of individuals diagnosed with SPG8 have an affected parent.

• A proband with SPG8 may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. 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 neurologic evaluation and molecular genetic testing of both parents. 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 more than 90% of individuals diagnosed with SPG8 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.

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

• If the disease-causing mutation found in the proband cannot be detected in the 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 SPG8 has a 50% chance of inheriting the mutation.

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

Related Genetic Counseling Issues

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 or clinical evidence of the disorder, 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 is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for SPG8 is available using the same techniques described in Molecular Genetic Testing. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. In addition, there are no interventions that prevent or delay the onset of symptoms in an at-risk individual who is identified as having a KIAA0196 mutation. When testing at-risk individuals for SPG8, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of SPG8, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage; employment and educational discrimination; and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up evaluations.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

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 involves 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 of an affected family member must be identified before prenatal testing can be performed.

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

For availability of prenatal testing see .

Note: If no laboratories offering prenatal testing are listed in the GeneTests Laboratory Directory, such testing may still be available (1) through a laboratory not listed in GeneTests or (2) through laboratories offering custom mutation analysis.

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

Literature Cited

1. Depienne C, Stevanin G, Brice A, Durr A. Hereditary Spastic Paraplegia: an update. Curr Opin Neurol. 2007;20:674–80. [PubMed: 17992088]
2. Hedera P, Rainier S, Alvarado D, Zhao X, Williamson J, Otterud B, Leppert M, Fink JK. Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. Am J Hum Genet. 1999;64:563–9. [PMC free article: PMC1377766] [PubMed: 9973294]
3. McMonagle P, Webb S, Hutchinson M. The prevalence of "pure" autosomal dominant hereditary spastic paraparesis in the island of Ireland. J Neurol Neurosurg Psychiatry. 2002;72:43–6. [PMC free article: PMC1737699] [PubMed: 11784824]
4. Porkka KP, Tammela TL, Vessella RL, Visakorpi T. RAD21 and KIAA0196 at 8q24 are amplified and overexpressed in prostate cancer. Genes Chromosomes Cancer. 2004;39:1–10. [PubMed: 14603436]
5. Reid E, Dearlove AM, Whiteford ML, Rhodes M, Rubinsztein DC. Autosomal dominant spastic paraplegia: refined SPG8 locus and additional genetic heterogeneity. Neurology. 1999;53:1844–9. [PubMed: 10563637]
6. Rocco P, Vainzof M, Froehner SC, Peters MF, Marie SK, Passos-Bueno MR, Zatz M. Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: analysis of muscle beta 1 syntrophin. Am J Med Genet. 2000;92:122–7. [PubMed: 10797436]
7. Valdmanis PN, Meijer IA, Reynolds A, Lei A, MacLeod P, Schlesinger D, Zatz M, Reid E, Dion PA, Drapeau P, Rouleau GA. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet. 2007;80:152–61. [PMC free article: PMC1785307] [PubMed: 17160902]
8. Young RR. Spasticity: a review. Neurology. 1994;44:S12–20. [PubMed: 7970006]

Revision History

• 13 August 2008 (me) Review posted live

• 16 June 2008 (pnv) Original submission