Spastic Paraplegia 8
Summary
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.
Diagnosis
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 variant in WASHC5 identified by molecular genetic testing (see Table 1).
Note: 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).
Option 1
A hereditary spastic paraplegia multigene panel that includes WASHC5 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Spastic Paraplegia 8
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| WASHC5 | Sequence analysis 3 | >99% 4 |
| Gene-targeted deletion/duplication analysis 5 | One reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
- 4.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis detects deletions ranging from a single exon to the whole gene.
- 6.
Ishiura et al [2014]
Clinical Characteristics
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].
Differential Diagnosis
Hereditary spastic paraplegia 8 (SPG8) is indistinguishable clinically from other forms of autosomal dominant hereditary spastic paraplegia (see Hereditary Spastic Paraplegia Overview, Causes).
Other conditions that may be associated with spasticity include hereditary disorders (e.g., amyotrophic lateral sclerosis, adrenomyeloneuropathy, mitochondrial disorders) and acquired disorders (e.g., tropical spastic paraplegia caused by HTLV1 infection, vitamin B12 deficiency, multiple sclerosis, and cervical myelopathy) (see Hereditary Spastic Paraplegia Overview, Differential Diagnosis) [Gasser et al 2010].
Management
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.
Table 2.
Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 8
| System/Concern | Evaluation | Comment |
|---|---|---|
| Spasticity | Neurologic exam | Assess degree of spasticity & assoc signs. |
| Musculoskeletal | Orthopedics / physical medicine & rehabilitation / PT eval | To incl assessment of:
|
| OT | To assess:
| |
| Bladder function | Referral to urologist; consider urodynamic eval. | To address spastic bladder symptoms: urgency, frequency, difficulty voiding |
| Bowel function | Referral to gastroenterologist | To assess constipation & fecal incontinence 1 |
| Bulbar muscle weakness | Assessment by speech & language pathologist |
|
| Mental health | Eval for symptoms of depression | |
| Genetic counseling | By genetics professionals 2 | To inform affected individuals & their families re nature, MOI, & implications of SPG8 to facilitate medical & personal decision making |
| Family support / resources | Assess:
|
Based on information provided by Spastic Paraplegia Foundation
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
- 1.
Kanavin & Fjermestad [2018]
- 2.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
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].
Table 3.
Treatment of Manifestations in Individuals with Spastic Paraplegia 8
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Spasticity | Individualized PT program |
|
| Reduction of spasticity | Massage, ultrasound, whirlpool, anodal spinal direct current stimulation 1 | |
| Antispasmodic drugs | Baclofen, botulinum toxin, dantrolene, tizanidine (used 1 at a time) 2 esp early in disease course to decrease cramps, make leg muscles less tight, & facilitate walking | |
| Bladder function | Spastic bladder symptoms: urgency, frequency, difficulty voiding | Treatment can incl anticholinergics such as oxybutynin (Ditropan XL®), solifenacin (Vesicare®), and mirabegron (Myrbetriq®). |
| Dysphagia | Gastroenterology / nutrition / feeding team eval | Determine exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. |
| Dysarthria | Speech & language pathologist | To help maintain vocal control; improve speech, breathing techniques, & communication in general |
| Bowel function | Symptoms: constipation & fecal incontinence | Stool softeners |
| Mobility |
| |
| Activities of daily living | PT |
|
| OT |
| |
| Clinical depression | Psychiatry | Psychotherapy & SSRI |
| Social support | Social services & support groups | To help cope w/diagnosis |
OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor
- 1.
Demonstrated by Ardolino et al [2018] in a randomized controlled trial.
- 2.
Oral baclofen can be tried first, and can also 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. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.
Surveillance
Table 4.
Recommended Surveillance for Individuals with Spastic Paraplegia 8
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Spasticity | Neurologic exam re disease progression & response to current treatment | 1-2 per yr |
| Bladder function | Per treating urologist, incl monitoring for urinary tract infection | 1-2 per yr |
| Dysphagia | Gastroenterology / nutrition / feeding team re nutrition & risk for aspiration | 1-2 per yr |
| Dysarthria | Per neurologic & speech/language assessment | 1-2 per yr |
| Bowel function | Per symptoms | 1-2 per yr |
| Mobility | Neurologic exam, rehabilitation medicine, & PT assessment | 1-2 per yr |
| Activities of daily living | OT & PT | As needed |
| Clinical depression | Per mental health clinician | 1-2 per yr |
OT = occupational therapy; PT = physical therapy
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.