Spastic Paraplegia 8

Clinical characteristics.

Hereditary spastic paraplegia 8 (SPG8) is a slowly progressive pure spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings). Some affected individuals have urinary urgency that usually becomes apparent at the same time as the spasticity. Onset is between ages ten and 59 years. Affected individuals often become wheelchair dependent. While intra- and interfamilial phenotypic variability is high, SPG8 is typically more severe than other types of hereditary spastic paraplegia.

Diagnosis/testing.

The diagnosis of SPG8 is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WASHC5 identified by molecular genetic testing.

Management.

Treatment of manifestations: A multidisciplinary approach to management of spasticity is recommended including neurology, physical therapy (PT), occupational therapy (OT), urology, speech and language pathology, feeding team, psychiatry/mental health, and social work.

Surveillance: Regular neurologic examinations to evaluate disease progression and response to treatment; urologist for assessment of bladder function and risk for urinary tract infection; PT/OT to assess mobility and activities of daily living; feeding team for nutrition and risk for aspiration; speech and language pathologist re dysarthria; and mental health clinician re depression.

Genetic counseling.

SPG8 is inherited in an autosomal dominant manner. More than 90% of individuals with SPG8 have an affected parent. Each child of an individual with SPG8 has a 50% chance of inheriting the WASHC5 pathogenic variant. Once the WASHC5 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Spastic paraplegia 8 (SPG8) should be suspected/considered in individuals with the following clinical and neuroimaging findings and family history [Reid et al 1999, Rocco et al 2000, Valdmanis et al 2007, de Bot et al 2013].

Clinical findings

• Onset in the 20s and 30s (range: age 20-60 years)
• Slowly progressive "pure" spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings)
• Mild distal decreased vibration sense
• Urinary urgency

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

Other studies. Normal:

• Cerebrospinal fluid
• Electrophysiologic studies:
  • Nerve conduction velocity
  • Electromyography
• Biochemical testing
  • Vitamin B₁₂
  • Very long chain fatty acids
  • Lactate [Gasser et al 2010]

Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of spastic paraplegia 8 is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in WASHC5 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous WASHC5 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches include gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing and genome sequencing) depending on the phenotype [Chrestian et al 2016, Elert-Dobkowska et al 2019].

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Spastic paraplegia 8 (SPG8) is characterized by progressive lower-limb spasticity with hyperreflexia and extensor plantar reflexes. While intra- and interfamilial phenotypic variability is high, SPG8 is typically more severe than other types of hereditary spastic paraplegia.

Onset is between ages ten and 59 years (range: 18-26 years in 1 family [Rocco et al 2000] and 35-53 years in another [Valdmanis et al 2007, Bettencourt et al 2013]).

SPG8 is more often associated with wheelchair dependence than other types of autosomal dominant hereditary spastic paraplegia. 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 another large family, six of 15 affected family members were wheelchair dependent [Reid et al 1999]. In the family reported by Rocco et al [2000], affected individuals usually became wheelchair bound in their 30s and 40s [Rocco et al 2000].

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].

Other studies. Muscle biopsy is normal [Hedera et al 1999, Rocco et al 2000].

Genotype-Phenotype Correlations

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

Nomenclature

"Uncomplicated" (or pure) hereditary spastic paraplegia. Neurologic impairment is limited to progressive lower-extremity spastic weakness, hypertonic urinary bladder disturbance, and mild decrease of lower-extremity vibration sense and, occasionally, joint position sense. While manifestations may be disabling, life span is not shortened.

"Complicated/complex" (syndromic) hereditary spastic paraplegia. The impairment present in uncomplicated hereditary spastic paraplegia is accompanied by other system involvement or other neurologic findings (in the absence of other causes for these additional features, such as diabetes mellitus). Other findings may include ataxia, seizures, intellectual disability, dementia, muscle atrophy, extrapyramidal disturbance, and peripheral neuropathy.

Penetrance

The penetrance for SPG8 is estimated between 90% and 100% [Valdmanis et al 2007].

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%-5% of hereditary spastic paraplegia [Valdmanis et al 2007, Chrestian et al 2016].

Pathogenic variants in WASHC5 have been identified in 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 8 (SPG8), the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

No cures or specific drug treatments exist for hereditary spastic paraplegia; management is supportive (see Table 3). A multidisciplinary approach to management of spasticity is reviewed by Young [1994].

Surveillance

Evaluation of Relatives at Risk

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

Pregnancy Management

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Bettencourt et al [2013] reported two individuals with partial response to L-dopa, a finding that requires further study as the mechanism of action is unknown.

Of the two studies currently recruiting patients with hereditary spastic paraplegia, one involves a therapy. The NCT04180098 study will assess the effectiveness of the physical therapy intervention C-Mill in improving gait adaptability.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 individuals with a de novo WASHC5 pathogenic variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo WASHC5 pathogenic variant include neurologic evaluation and molecular genetic testing of both parents.
• If the WASHC5 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. * Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo WASHC5 pathogenic variant.
• The family history of some individuals diagnosed with SPG8 may appear to be negative because of failure to recognize the disorder in family members with a milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the WASHC5 pathogenic variant first occurred, the parent 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 and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: Age of onset, severity, type of symptoms, and rate of disease progression may vary between family members heterozygous for the same WASHC5 pathogenic variant.
• If the proband has a known WASHC5 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the WASHC5 pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for SPG8 because of the possibility of age-related penetrance in a parent heterozygous for the WASHC5 variant or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with SPG8 has a 50% chance of inheriting the WASHC5 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the WASHC5 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

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.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the SPG8-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, 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.
• For more information, see 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.

In a family with an established diagnosis of SPG8, it is appropriate to consider testing of symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once the WASHC5 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SPG8 are possible. Note: Age of onset, severity of disease, type of symptoms, and rate of disease progression are variable and cannot be accurately predicted by molecular genetic testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

WASHC5 encodes strumpellin, a Wiskott-Aldrich syndrome (see WAS-Related Disorders) protein and Scar homolog (WASH) complex that also includes KIAA1033 (SWIP), FAM21, CCDC53, WASH1 [Derivery & Gautreau 2010, Pan et al 2010]. 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. The WASH complex is involved in retromer-dependent endosomal protein sorting. Strumpellin physically binds the valosin-containing protein (VCP) [Clemen et al 2010].

WASHC5 is expressed in all tissues; the mRNA is present in many regions of the brain [Valdmanis et al 2007].

Mechanism of disease causation. Unknown; however, a haploinsufficiency mechanism has been proposed based on the following:

• Cells lacking strumpellin have abnormally enlarged lysosomes. Furthermore, defective endosomal tubule fission was found to cause these lysosomal abnormalities, a mechanism shared with spastin disease models (see Spastic Paraplegia 4) [Allison et al 2017, Song et al 2018].
• The p.Asn471Asp pathogenic variant, within the spectrin-binding domain, does not impair the interaction of strumpellin and VCP, but could impair interactions with other proteins [Clemen et al 2010].
• Delivery of WASHC5 mRNA, encoding the p.Leu619Phe and p.Val626Phe protein variants, did not yield an overt phenotype in zebrafish, failing to show a toxic gain-of-function mechanism [Valdmanis et al 2007].
• A pathogenic heterozygous deletion of exon 11-15 includes the spectrin repeat domain and the conserved domain [Ishiura et al 2014].
• Ma et al [2018] also reported a frameshift variant affecting the same domains (c.1128delG; p.Met377CysfsTer24), further supporting their important role in SPG8.
• Finally, the pathogenic variants p.Val626Phe, p.Leu619Phe, and p.Asn471Asp were still able to co-immunoprecipitate with the WASH complex without changing its localization [Freeman et al 2013].

A murine WASHC5 knockout was embryonic lethal when homozygous and did not show a clinical or biochemical phenotype when heterozygous [Jahic et al 2015].

Revision History

• 21 May 2020 (bp) Comprehensive update posted live
• 25 July 2013 (me) Comprehensive update posted live
• 13 August 2008 (me) Review posted live
• 16 June 2008 (pnv) Original submission

Published Guidelines / Consensus Statements

• American Academy of Pediatrics Committee on Bioethics, Committee on Genetics; American College of Medical Genetics and Genomics Social, Ethical, and Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 6-27-22. [PubMed: 23428972]
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 6-27-22.

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