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Spastic Paraplegia 8

Synonym: SPG8

, PhD, , PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: July 25, 2013.

Summary

Clinical characteristics.

Hereditary spastic paraplegia 8 (SPG8) is a pure hereditary spastic paraplegia characterized by slowly progressive spastic paraplegia of the lower limbs (i.e., hyperreflexia and clonus) with onset between ages 18 and 59 years (average: 37.2 years in one study). Other findings can include weakness with muscle wasting of the lower limbs, urinary urgency, and decreased vibration sense. Affected individuals often become wheelchair dependent.

Diagnosis/testing.

Sequence analysis of WASHC5 (formerly KIAA0196), which encodes the protein WASH complex subunit strumpellin, detected a pathogenic variant in five of five families that mapped to the SPG8 locus.

Management.

Treatment of manifestations: Spasticity is managed with physical therapy, assistive walking devices, ankle-foot orthotics, and medications that reduce clonus and muscle tightness.

Prevention of secondary complications: Bladder function should be routinely monitored to avoid urinary tract infections.

Surveillance: Regular neurologic examinations to evaluate disease progression; referral to urology for urodynamic testing and follow up when symptoms appear.

Genetic counseling.

SPG8 is inherited in an autosomal dominant manner. More than 90% of affected individuals have an affected parent. Each child of an individual with SPG8 has a 50% chance of inheriting the pathogenic variant. If the pathogenic variant in the family is known, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

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 of WASHC5 (KIAA0196)

Molecular Genetic Testing

Gene. WASHC5, encoding the protein WASH complex subunit strumpellin, is the only gene in which mutation is known to cause hereditary SPG8.

Table 1.

Summary of Molecular Genetic Testing Used in Spastic Paraplegia 8

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
WASHC5
(KIAA0196)
Sequence analysis 4 of coding regions and exon/intron junctionsSequence variants5/5 5
1.
2.

See Molecular Genetics for information on allelic variants.

3.

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

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Affected individuals from five families that were linked to the SPG8 locus [Hedera et al 1999] had a WASHC5 pathogenic variant [Valdmanis et al 2007].

Testing Strategy

To confirm/establish the diagnosis in a proband, sequence analysis is necessary to identify a pathogenic variant in WASHC5.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

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

Clinical Characteristics

Clinical Description

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]:

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:

Genotype-Phenotype Correlations

The number of pathogenic variants 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 including 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 1-18:100,000 [McMonagle et al 2002]. Pathogenic variants in WASHC5 account for approximately 4% of hereditary spastic paraplegia [Valdmanis et al 2007].

Pathogenic variants in WASHC5 have been identified in the North American, British, and Brazilian populations. It is expected that WASHC5 pathogenic variants would have a similar prevalence in other populations [Valdmanis et al 2007].

Differential Diagnosis

See Hereditary Spastic Paraplegia Overview.

Hereditary spastic paraplegia 8 (SPG8) is indistinguishable clinically from other forms of autosomal dominant hereditary spastic paraplegia. In the absence of a WASHC5 pathogenic variant, the following conditions should be considered: SPG3A, SPG4, SPG6, SPG10, SPG12, SPG13, and SPG19. Of note, SPG3A and SPG4 can account for as much as 50% of autosomal dominant hereditary spastic paraplegia.

Individuals who represent simplex cases (i.e., occurrence only in one individual in a family) may have other non-hereditary spastic paraplegia disorders including the following:

  • Primary lateral sclerosis (PLS)
  • Tropical spastic paraplegia (caused by HTLV1 infection)
  • Multiple sclerosis
  • Tumors in and around the spinal cord
  • Mutation of PSEN1 (the gene encoding presenilin 1) in individuals who later develop Alzheimer disease type 3

Management

Evaluations Following Initial Diagnosis

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

  • Neurologic examination
  • Urodynamic evaluation
  • Clinical genetics consultation

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.
  • Physical 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.

Prevention of Secondary Complications

Bladder function should be routinely monitored to avoid urinary tract infections.

Surveillance

The following are appropriate:

  • Regular neurologic examinations (1-2 per year) to evaluate disease progression and avoid complications of spasticity, including joint contractures
  • Referral to a urologist for urodynamic testing and follow-up when symptoms appear

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • More than 90% of individuals diagnosed with SPG8 have an affected parent.
  • A proband with SPG8 may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
  • If the pathogenic variant 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 pathogenic variant 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 pathogenic variant include 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 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 pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant 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 pathogenic variant 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 pathogenic variant.

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 affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the pathogenic variant occurred de novo in the proband. 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 for SPG8 is possible using the 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 WASHC5 pathogenic variant. 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 pathogenic variant 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 position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

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 WASHC5 pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for SPG8 are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Spastic Paraplegia Foundation, Inc.
    7700 Leesburg Pike
    Ste 123
    Falls Church VA 22043
    Phone: 877-773-4483 (toll-free)
    Email: information@sp-foundation.org
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Spastic Paraplegia 8: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Spastic Paraplegia 8 (View All in OMIM)

603563SPASTIC PARAPLEGIA 8, AUTOSOMAL DOMINANT; SPG8
610657WASH COMPLEX, SUBUNIT 5; WASHC5

Gene structure. WASHC5 (KIAA0196) has 29 exons (28 of which are coding) and spans a genomic interval of 60 kb. Its mRNA contains 3925 nucleotides. No alternative transcripts or pseudogenes have been reported for this gene. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 2. All WASHC5 pathogenic variants identified to date are missense variants. They appear in the middle of the gene in exons 11 (p.Asn471Asp), 14 (p.Leu619Phe), and 15 (p.Val626Phe). The p.Val626Phe variant has been found in four families from North America and Britain, suggesting that it is a recurrent variant [Valdmanis et al 2007]. An additional variant, p.Gly696Ala, has been identified in a large Dutch family [de Bot et al 2013].

Table 2.

WASHC5 (KIAA0196) Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.1411A>G
(1491A>G)
p.Asn471AspNM_014846​.3
NP_055661​.3
c.1857G>C
(1937G>C)
p.Leu619Phe
c.1876G>T
(1956G>T)
p.Val626Phe
c.2087G>Cp.Gly696Ala

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. WASHC5 encodes the 1159-amino acid protein WASH complex subunit strumpellin. The protein contains one spectrin repeat and one highly conserved domain of unknown significance [Valdmanis et al 2007]. The spectrin domain is involved in interaction with the cytoskeletal matrix of the cell and can facilitate binding to other spectrin-repeat-containing proteins. WASHC5 is expressed in all tissues; northern blot analysis indicates that the mRNA is present in many regions of the brain [Valdmanis et al 2007]. Strumpellin (KIAA0196) has been identified as a member of the Wiskott-Aldrich syndrome protein and Scar homolog (WASH) complex that also includes KIAA1033 (SWIP), FAM21, CCDC53 and WASH1 [Derivery & Gautreau 2010, Pan et al 2010]. The WASH complex is involved in retromer-dependent endosomal protein sorting. The strumpellin protein also physically binds the valosin-containing protein (VCP) [Clemen et al 2010].

Abnormal gene product. The pathogenic missense variants in WASHC5 are expressed as amino acid substitutions in the abnormal protein and likely result in an abnormal function. As expected for missense variants, the abnormal protein apparently is not truncated as demonstrated by Western blot analysis [Author, personal data].

The p.Asn471Asp pathogenic variant is present in the spectrin-binding domain, indicating that the interaction of this domain with the spectrin protein or some other as-yet unidentified protein may be important; however, this variant did not impair the interaction between strumpellin (KIAA0196) and VCP [Clemen et al 2010]. Further, delivery of WASHC5 mRNA encoding p.Leu619Phe and p.Val626Phe protein variants did not yield an overt phenotype in zebrafish indicating that a toxic gain of function is not a mechanism of action of the mutated protein [Valdmanis et al 2007]. Finally, all three pathogenic variants were still able to co-immunoprecipitate with the WASH complex [Freeman et al 2013].

References

Published Guidelines/Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-1-17. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 2-1-17.

Literature Cited

  • Clemen CS, Tangavelou K, Strucksberg KH, Just S, Gaertner L, Regus-Leidig H, Stumpf M, Reimann J, Coras R, Morgan RO, Fernandez MP, Hofmann A, Müller S, Schoser B, Hanisch FG, Rottbauer W, Blümcke I, von Hörsten S, Eichinger L, Schröder R. Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. Brain. 2010;133:2920–41. [PubMed: 20833645]
  • de Bot ST, Vermeer S, Buijsman W, Heister A, Voorendt M, Verrips A, Scheffer H, Kremer HP, van de Warrenburg BP, Kamsteeg EJ. Pure adult-onset Spastic Paraplegia caused by a novel mutation in the KIAA0196 (SPG8) gene. J Neurol. 2013;260:1765–9. [PubMed: 23455931]
  • Depienne C, Stevanin G, Brice A, Durr A. Hereditary spastic paraplegias: an update. Curr Opin Neurol. 2007;20:674–80. [PubMed: 17992088]
  • Derivery E, Gautreau A. Evolutionary conservation of the WASH complex, an actin polymerization machine involved in endosomal fission. Commun Integr Biol. 2010;3:227–30. [PMC free article: PMC2918762] [PubMed: 20714399]
  • Freeman C, Seaman MN, Reid E. The hereditary spastic paraplegia protein strumpellin: characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function. Biochim Biophys Acta. 2013;1832:160–73. [PMC free article: PMC3714738] [PubMed: 23085491]
  • 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]
  • 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]
  • Pan YF, Viklund IM, Tsai HH, Pettersson S, Maruyama IN. The ulcerative colitis marker protein WAFL interacts with accessory proteins in endocytosis. Int J Biol Sci. 2010;6:163–71. [PMC free article: PMC2850539] [PubMed: 20376207]
  • 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]
  • 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]
  • 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]
  • Young RR. Spasticity: a review. Neurology. 1994;44:S12–20. [PubMed: 7970006]

Chapter Notes

Revision History

  • 25 July 2013 (me) Comprehensive update posted live
  • 13 August 2008 (me) Review posted live
  • 16 June 2008 (pnv) Original submission
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