Clinical characteristics.

Spastic paraplegia 4 (SPG4; also known as SPAST-HSP) is characterized by insidiously progressive bilateral lower-limb gait spasticity. More than 50% of affected individuals have some weakness in the legs and impaired vibration sense at the ankles. Sphincter disturbances are very common. Onset is insidious, mostly in young adulthood, although symptoms may start as early as age one year and as late as age 76 years. Intrafamilial variation is considerable.

Diagnosis/testing.

The diagnosis of SPAST-HSP is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in SPAST identified by molecular genetic testing.

Management.

Treatment of manifestations: Antispastic drugs for leg spasticity; anticholinergic antispasmodic drugs for urinary urgency; regular physiotherapy to stretch spastic muscles and prevent contractures. Consideration of botulinum toxin and intrathecal baclofen when oral drugs are ineffective and spasticity is severe and disabling. Urodynamic evaluation in order to initiate treatment when sphincter disturbances become a problem.

Surveillance: Evaluation every 6-12 months to update medications and physical rehabilitation.

Genetic counseling.

SPAST-HSP is inherited in an autosomal dominant manner with age-related, nearly complete penetrance and is characterized by significant intrafamilial clinical variability. Most individuals diagnosed with SPAST-HSP have an affected parent. The proportion of cases caused by a de novo pathogenic variant is low. Each child of an individual with SPAST-HSP has a 50% chance of inheriting the pathogenic variant. Prenatal testing and preimplantation genetic testing are possible if a pathogenic SPAST variant has been identified in an affected family member. Because of variable clinical expression, results of prenatal testing cannot be used to predict whether an individual will develop SPAST-HSP and, if so, what the age of onset, clinical course, and degree of disability will be.

Suggestive Findings

Spastic paraplegia 4 (SPG4; also known as SPAST-HSP) should be suspected in individuals with the following:

• Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait with or without spasticity at rest and mild proximal weakness, often accompanied by urinary urgency
• Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses). Mildly impaired vibration sensation in the ankles is present in the majority of individuals.
• Family history consistent with autosomal dominant inheritance, or exclusion of other causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)

Note: The presence of other signs/symptoms suggestive of complicated hereditary spastic paraplegia does not exclude SPAST-HSP, although it reduces its probability.

Brain and spinal cord MRI

• Often normal in individuals with SPAST-HSP
• Spinal cord atrophy can occur in SPAST-HSP, but is less pronounced than in other genetic causes of HSP.
• Mild vermis atrophy, a thin corpus callosum, subtle white matter changes, and/or cerebellar atrophy have been reported [Duning et al 2010, da Graça et al 2019].

Note: The MRI is useful in identifying anomalies of the brain, cerebro-medullary junction, and medulla that are characteristic of disorders discussed in Differential Diagnosis.

Electromyography (EMG) with nerve conduction velocities (NCV) is used to exclude peripheral nervous system involvement, which could raise the possibility of an alternative diagnosis as severe polyneuropathy is not a frequent symptom of SPAST-HSP. Karle et al performed neurophysiologic examinations of 128 individuals with HSP, including 35 individuals with SPAST-HSP, and showed that massively elongated central motor conduction time argued against SPAST-HSP; however, reduced amplitudes and prolonged latencies were reported, in particular in individuals with a SPAST pathogenic missense variant [Karle et al 2013].

Establishing the Diagnosis

The diagnosis of SPAST-HSP is established in a proband with Suggestive Findings by identification of a heterozygous pathogenic variant in SPAST by molecular genetic testing (see Table 1).

Note: (1) Failure to detect a pathogenic variant/deletion does not absolutely exclude the diagnosis. (2) Once non-genetic causes have been excluded, testing for SPAST-HSP should be considered in simplex cases (i.e., individuals with no family history of spasticity), as SPAST pathogenic variants can be identified in approximately 10%-20% of simplex cases [Erichsen et al 2009a, Shoukier et al 2009, Fei et al 2011].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SPAST-HSP is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with spastic paraplegia are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The cardinal clinical feature of spastic paraplegia 4 (SPAST-HSP) is insidiously progressive bilateral lower-limb spasticity associated with brisk reflexes, ankle clonus, and bilateral extensor plantar responses. Sphincter disturbances are very frequent (77%), in particular urinary urgency and incontinence. Increased reflexes in the upper limbs may also occur (65%), but other symptoms and findings in the upper limbs are rare. A frequent additional feature is decreased, but not abolished, vibration sense at the ankles, occurring in 60% of individuals [Parodi et al 2018]. Around 50% of affected individuals have proximal weakness in the lower limbs [Kanavin & Fjermestad 2018, Parodi et al 2018, Schneider et al 2019].

Age at onset of symptoms ranges from infancy to the eighth decade. Age at onset is variable even among family members with the same pathogenic variant. A recent study including more than 500 individuals with SPAST-HSP confirmed that the age at onset is characterized by a bimodal distribution, with a major first peak before the first decade, and a second, lower one between the third and fifth decades. Penetrance is not complete; an estimated 6% of individuals remain asymptomatic throughout life. Penetrance is reported to be lower in females than in males [Parodi et al 2018].

Disease severity generally worsens with the duration of the disease, although some individuals remain mildly affected all their lives. Disease severity is variable even among family members with the same pathogenic variant. After long disease duration (20 years), approximately 50% of individuals need assistance for walking, and approximately 10% require a wheelchair. Disease progression is more rapid in individuals with late onset (age >35 years) than in those with early onset [Loureiro et al 2013, Chrestian et al 2016, Polymeris et al 2016, Parodi et al 2018].

Comparing men and women, Parodi et al [2018] observed that symptomatic females more often had increased upper-limb reflexes than males, representing a more severe and diffused disorder in women.

Leg spasms are frequent and may also develop before the onset of spasticity. Spasms are more frequent after physical activity, and tend to disappear when spasticity becomes more severe.

Bladder dysfunction remains one of the most frequent problems for affected individuals and may be more frequent in individuals with SPAST-HSP than in all individuals with HSP; Schneider et al [2019] reported urologic involvement in 91.2% of individuals with SPAST-HSP compared to 74.5% of individuals with HSP. The most frequent symptoms are urinary incontinence, hesitancy, increased frequency of micturition, and urgency. Incomplete bladder emptying may also occur [Braschinsky et al 2010]. The anal sphincter may also be affected, resulting in uncontrollable flatulence or fecal incontinence, affecting respectively 31.4% and 8.7% of individuals with HSP in one study [Kanavin & Fjermestad 2018]. In a study of urodynamic findings in 29 individuals with HSP, Fourtassi et al [2012] described signs of central neurogenic bladder in 82.7%, with detrusor overactivity in 52% and detrusor sphincter dyssynergia in 65.5%.

Pes cavus and mild spastic dysarthria may be observed.

Subtle cognitive impairment has been documented [Erichsen et al 2009b]; but its relation to the disease remains undetermined. Cognitive deficits appear late in the disease course and are not present in all affected members of a given family. When detected by neuropsychological testing, the impairment is often subtle, limited to executive dysfunction, and without noticeable effect on daily living. No definite correlation with the type of pathogenic variant in SPAST has been established.

Extensive neuropsychological assessment of nine adults with SPAST-HSP (including one asymptomatic individual) identified cognitive impairment fulfilling multidomain non-amnesic mild cognitive impairment criteria, with executive impairment and impaired social cognition [Chamard et al 2016] as suggested by Tallaksen et al [2003], where a familial aggregation of cognitive impairment suggested the implication of modifiers. In the large SPAST-HSP study by Parodi et al [2018], intellectual disability was described in 4.2%.

Other findings compatible with a complex form of HSP are uncommon in SPAST-HSP but do not exclude the diagnosis. Also, whether these additional findings are related to SPAST-HSP or coincidental remains to be clarified.

Neuropathy has been reported in individuals with SPAST-HSP, but without compelling evidence of a shared underlying pathologic mechanism. Kumar et al [2012] found peripheral abnormalities in nerve conduction studies in two of 11 individuals with SPAST-HSP.

Non-motor symptoms are more frequent than previously acknowledged. Servelhere et al [2016] studied 30 individuals and found that fatigue, pain, and depression were frequent and often severe manifestations in individuals with SPAST-HSP.

Restless legs syndrome has been associated with SPAST-HSP [Sperfeld et al 2007], but this remains to be confirmed.

Hand tremor was reported in 10% of a large cohort of Dutch individuals with SPAST-HSP [de Bot et al 2010].

Seizures, intellectual disability, and cerebellar ataxia are rare. A few individuals with severe dementia have been reported [Murphy et al 2009]. However, too few neuropathologic studies have been performed in persons with SPAST-HSP for a general picture of the distribution of cortical and medullar lesions in the disease to emerge.

Neuroimaging. Newer MRI studies using advanced neuroimaging techniques have shown widespread involvement of gray and white matter in individuals with SPAST-HSP [Lindig et al 2015, Rezende et al 2015, Liao et al 2018, Rucco et al 2019]. In a study of 11 individuals, fractional anisotropy was reduced in the corticospinal tracts, cingulate gyri, and splenium of the corpus callosum [Rezende et al 2015]. Resting-state fMRI studies in 12 individuals with SPAST-HSP showed abnormal functional activity in several brain areas [Liao et al 2018]. Rucco et al [2019] performed magnetoencephalography of ten individuals with SPAST-HSP and described global network rearrangements. Using diffusion tensor imaging and tract-based special statistics, Lindig et al [2015] found that imaging findings in the 15 included individuals correlated with disease duration and severity.

Genotype-Phenotype Correlations

Recently, after analyzing a cohort of more than 500 individuals with SPAST-HSP, Parodi et al [2018] showed that missense variants were associated with an earlier age of onset (by 10 years), when compared to truncating variants. This finding provides an explanation for the bimodal age of onset distribution typical of SPAST-HSP.

It is important to note that age at onset and clinical severity are highly variable for a given variant, even in the same family. The observed difference in age of onset between related individuals ranged from 27 years to 69 years [Parodi et al 2018]. Furthermore, two family members with the same variant can have in one case a pure spastic paraparesis and in the other a complex disease. For example, Orlacchio et al [2004] reported wide phenotypic variability with the p.Asn386Ser variant, with some individuals presenting with intellectual disability and others showing brain MRI abnormalities including thin corpus callosum or cerebellar atrophy.

The most plausible explanation for intra and interfamilial variability is the presence of genetic modifiers. Svenson et al [2004] reported two rare nonsynonymous SPAST variants, c.131C>T (p.Ser44Leu) and c.134C>A (p.Pro45Gln) acting as age-of-onset modifiers. In several analyzed families, the individuals who had a SPAST pathogenic variant on one allele and either a c.131C>T or c.134C>A variant on the other allele (in trans) had a very early onset, suggesting that these alleles could modify the HSP phenotype [Svenson et al 2004, McDermott et al 2006, personal communication]. The SPAST variant c.131C>T has a frequency of 0.4% in a control population, c.134C>A is even more rare in the gnomAD Database (see bioRxiv). In addition to the two SPAST variants, an HSPD1 variant was proposed as a SPAST-HSP age-at-onset modifier [Svenstrup et al 2009], but its role remains under discussion.

Penetrance

Penetrance is age dependent and mostly complete in individuals with SPAST-HSP. It is estimated to be 85% by age 45 years [Fonknechten et al 2000] and complete at 70 years [Parodi et al 2018]. It should be emphasized that age dependence is explained partly by variability in age at onset and partly by the difficulty in determining the precise age of onset; thus, neurologic examination is important. Penetrance is greater if pyramidal signs as well as spastic gait are considered: approximately 6% of individuals who have a SPAST variant are completely asymptomatic on examination; approximately 20% have abnormal signs when examined, but no awareness of being affected.

Penetrance may be sex dependent. Parodi et al [2018] reported a higher penetrance in males (94%) than females (88%), and greater sex discordance in individuals with onset before the third decade (91% vs 70%).

Nomenclature

The gene in which mutation is responsible for spastic paraplegia at the SPG4 locus, SPAST, was previously known as SPG4.

SPAST-HSP may also be referred to as SPG4. Previously it was also known as hereditary spastic paraplegia, spastin type [Marras et al 2016].

Prevalence

The most recent epidemiologic study estimates a global prevalence of autosomal dominant-HSP (AD-HSP) of 1-5:100,000 [Ruano et al 2014].

Among AD-HSPs, SPAST is the most frequently associated gene in both familial and simplex cases [Lo Giudice et al 2014, Ruano et al 2014]. Reports from many European countries as well as the US, Canada, Japan, and China appear to indicate that SPAST-HSP accounts for 40% of inherited AD-HSPs and 20% of simplex HSPs [Erichsen et al 2009a, Takiyama et al 2010, Fei et al 2011, Lo Giudice et al 2014, Ruano et al 2014].

Geographic prevalence may vary; Meijer et al [2002] found fewer families with SPAST-HSP among North American families than expected from reports in European families.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 4 (SPAST-HSP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neuro-urologic examination is advised for individuals who have sphincter disturbances.
• Whether neuropsychological testing should be performed to assess the cognitive impairment frequently reported in individuals with SPAST-HSP remains unclear. So far, no consensus exists on the type of tests that should be performed, or on the timing or purpose of the tests. Considering that cognitive impairment is often absent or is detectable only by neuropsychological testing, one should be wary of increasing the burden of individuals with SPAST-HSP, and probably only recommend further testing when required by the affected individual.
• Electrophysiologic investigations may be advisable in case of pain and/or edema in the lower limbs to evaluate for associated neuropathy. Neuropathy, while not a feature of SPAST-HSP per se, may occur in individuals with SPAST-HSP for other reasons and should be investigated and adequately treated. Because of the underlying HSP, the neuropathy may remain undiagnosed if routine investigations are not conducted.
• Spinal MRI examination to exclude any additional degenerative disorder can be considered if unusual symptoms or pain are present.
• Consultation with a clinical geneticist and/or genetic counselor is appropriate.

Treatment of Manifestations

Treatment is symptomatic as there is still no curative or disease-modifying treatment for SPAST-HSP. Care by a multidisciplinary team that includes a general practitioner, neurologist, clinical geneticist, physiotherapist, physical therapist, social worker, and psychologist should be considered.

Symptomatic treatment includes use of the following:

• Antispastic drugs for leg spasticity
• Anticholinergic antispasmodic drugs for urinary urgency
• Regular physiotherapy for stretching of spastic muscles. Stretching should be done manually at all levels (hips, knees, ankles) and preceded by heat conditioning. Early regular physiotherapy can prevent contractures to a certain extent. Intensive and early physiotherapy delays the development of symptoms related to spasticity and prolongs the ability to walk [Author, personal observation]. To date, the effectiveness of physical therapy in individuals with HSP is only documented in a small number of case reports and uncontrolled studies.

Botulinum toxin and intrathecal baclofen can be proposed when oral drugs are ineffective and spasticity is severe and disabling. In children, orthopedic treatment and botulinum toxin injections may also contribute to better ambulatory function. A recent study of a mixed cohort of 33 individuals with HSP suggested that botulinum toxin-A injections provide some benefits, not only for spasticity, but also for fatigue [Servelhere et al 2018]. However, studies are scarce and more systematic studies are needed to confirm these observations.

Urodynamic evaluation should be performed early in all affected individuals complaining of urgency or other problems, such as voiding difficulties, urine retention, and/or frequent urinary infections. Such symptoms should be monitored and treated according to individual needs and disease evolution. Follow up of the sphincter disturbances is important to prevent bladder dysfunction. Treatment options include anticholinergic drugs and intravesical botulinum-toxin injections [Joussain et al 2019].

Surveillance

Specialized outpatient evaluations are suggested every six to 12 months to update medications and physical rehabilitation.

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 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.

Other

A double-blind crossover trial with gabapentin did not show improvement of spasticity in persons with SPAST-HSP [Scheuer et al 2007].

Mode of Inheritance

Spastic paraplegia 4 (SPAST-HSP) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Individuals diagnosed with SPAST-HSP usually have a symptomatic parent who has the SPAST pathogenic variant; however, a parent with the SPAST pathogenic variant may have no symptoms.
• An individual with SPAST-HSP may, more rarely, have the disorder as the result of a de novo pathogenic variant [Parodi et al 2018].
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include neurologic examination for evidence of spasticity and molecular genetic testing if a SPAST pathogenic variant has been identified in a family member.
• If the 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.
• The family history of some individuals diagnosed with SPAST-HSP may appear to be negative because of failure to recognize the disorder in family members, reduced (age-related) penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Note: Significant intrafamilial variability in age of onset and clinical severity is observed in SPAST-HSP.
• If the proband has a known SPAST 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 of a proband are clinically unaffected but have not undergone molecular genetic testing, sibs of the proband are still presumed to be at increased risk for SPAST-HSP because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with SPAST-HSP has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has the SPAST variant present in the affected family member, his or her family members are 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 identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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

• Predictive testing for at-risk relatives is possible once a SPAST 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 at-risk individuals age <18 years)

• For asymptomatic minors at risk for typically 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 SPAST-HSP, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once a SPAST pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Because of variable clinical expression, the results of prenatal testing cannot be used to predict whether an individual will develop SPAST-HSP and, if so, what the age of onset, clinical course, or degree of disability will be.

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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Introduction. SPAST encodes a 616-amino acid protein named spastin, a putative nuclear member of the AAA (ATPases associated with diverse cellular activities). Claudiani et al [2005] have shown that two spastin isoforms – M1 and M87, of 68 kd and 60 kd, respectively – were synthesized from the SPAST mRNA through usage of two different translational start sites. Spastin-M87 was detected in both spinal cord and cerebral cortex, whereas appreciable levels of spastin-M1 were observed only in spinal cord [Solowska et al 2010].

Spastin is widely expressed in the neurons of the central nervous system, including the cortex and striatum. Distal degeneration of long tracts in the spinal cord is associated with a microglial reaction [Wharton et al 2003]. In addition, the presence of a large number of thin axons in the pyramidal tracts may suggest the existence of a regeneration process [Parodi et al 2018]. Tau-pathology outside the motor system may also be observed [Wharton et al 2003] but is not common to all the analyzed cases [Parodi et al 2018].

Within the cells, spastin acts as a microtubule-severing protein and is responsible for different aspects of microtubule dynamics, such as their length, number, and mobility [Errico et al 2002]. Four proteic domains allow spastin to accomplish its enzymatic function, as well as to interact with other proteins.

• Spastin N-terminal domain is involved in both lipid metabolism [Papadopoulos et al 2015] and endoplasmic reticulum morphogenesis, after interacting with ATL1/SPG3A and REEP1/SPG31 [Park et al 2010].
• The microtubule-interacting and trafficking domain (MIT) allows spastin to interact with CHIMP1 and IST1, two proteins belonging to the endosomal-sorting complex required for transport (ESCRT-III), being therefore involved in both cytokinesis and endosomal-tubule recycling [Reid et al 2005, Connell et al 2009, Allison et al 2013].
• The microtubule-binding domain (MTBD) and the AAA ATPase cassette are responsible for the microtubule binding and ATP hydrolysis [White et al 2007].

Mechanism of disease causation. Spastin loss of function, and consequent haploinsufficiency, has been proposed as the mechanism of disease causation: the majority of SPAST pathogenic variants affect the AAA cassette domain and almost 20% of affected individuals were found to have large deletions [Depienne et al 2007a, Parodi et al 2018]. In addition, reduced spastin mRNA was observed in individuals with premature protein termination [Bürger et al 2000].

An alternative to the loss-of-function model, the finding that SPAST pathogenic variants in the AAA domain led to constitutive binding to microtubules, could suggest a dominant-negative effect [Errico et al 2002]. The abnormal spastin-microtubule interaction was observed leading to organelle transport impairments, possibly underlying degeneration of the corticospinal axons [McDermott et al 2003].

An additional alternative hypothesis was recently proposed by Solowska et al [2010] and Solowska et al [2014]. After observing that some of the SPAST pathogenic variants located outside the AAA cassette may act through another pathogenic mechanism, they generated a mouse model overexpressing human spastin and carrying a SPAST pathogenic variant. Adult homozygous mice presented with spastic-like tremors and gait impairments as well as decreased microtubule stability, leading the researchers to conclude in favor of a gain (rather than loss) -of-function mechanism [Qiang et al 2019].

In conclusion, the debate concerning SPAST-HSP pathogenic mechanism remains open. It must be emphasized that the SPAST mutation spectrum, which mostly includes pathogenic variants introducing premature termination codons and therefore leading to degradation of the mRNA by nonsense-mediated decay, argues in favor of haploinsufficiency (i.e., disease occurs once the level of functional spastin falls below a critical level), rather than a dominant-negative effect [Patrono et al 2002, Schickel et al 2007]. The recent observation that missense pathogenic variants are associated with earlier onset [Parodi et al 2018] may suggest, in specific cases, the existence of pathogenic mechanisms other than haploinsufficiency.

SPAST-specific laboratory considerations. SPAST undergoes alternate splicing with variable inclusion of exon 4. No pathogenic variants have been reported in exon 4, however, suggesting that the isoform lacking exon 4 is the predominant functional form of spastin in the adult nervous system. This transcript variant is NM_199436.1 (see Table A, Gene).

Both exon/multiexon deletions and duplications may be pathogenic SPAST variants.

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 10-15-21.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 10-15-21.

Literature Cited

• Allison R, Lumb JH, Fassier C, Connell JW, Ten Martin D, Seaman MN, Hazan J, Reid E. An ESCRT-spastin interaction promotes fission of recycling tubules from the endosome. J Cell Biol. 2013;202:527–43. [PMC free article: PMC3734076] [PubMed: 23897888]
• Beetz C, Nygren AO, Schickel J, Auer-Grumbach M, Bürk K, Heide G, Kassubek J, Klimpe S, Klopstock T, Kreuz F, Otto S, Schüle R, Schöls L, Sperfeld AD, Witte OW, Deufel T. High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology. 2006;67:1926–30. [PubMed: 17035675]
• Braschinsky M, Zopp I, Kals M, Haldre S, Gross-Paju K. Bladder dysfunction in hereditary spastic paraplegia: what to expect? J Neurol Neurosurg Psychiatry. 2010;81:263–6. [PubMed: 19726407]
• Bürger J, Fonknechten N, Hoeltzenbein M, Neumann L, Bratanoff E, Hazan J, Reis A. Hereditary spastic paraplegia caused by mutations in the SPG4 gene. Eur J Hum Genet. 2000;8:771–6. [PubMed: 11039577]
• Chamard L, Ferreira S, Pijoff A, Silvestre M, Berger E, Magnin E. Cognitive impairment involving social cognition in SPG4 hereditary spastic paraplegia. Behav Neurol. 2016;2016:6423461. [PMC free article: PMC5027053] [PubMed: 27688599]
• Chrestian N, Dupré N, Gan-Or Z, Szuto A, Chen S, Venkitachalam A, Brisson JD, Warman-Chardon J, Ahmed S, Ashtiani S, MacDonald H, Mohsin N, Mourabit-Amari K, Provencher P, Boycott KM, Stavropoulos DJ, Dion PA, Ray PN, Suchowersky O, Rouleau GA, Yoon G. Clinical and genetic study of hereditary spastic paraplegia in Canada. Neurol Genet. 2016;3:e122. [PMC free article: PMC5141523] [PubMed: 27957547]
• Claudiani P, Riano E, Errico A, Andolfi G, Rugarli EI. Spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus. Exp Cell Res. 2005;309:358–69. [PubMed: 16026783]
• Connell JW, Lindon C, Luzio JP, Reid E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic. 2009;10:42–56. [PMC free article: PMC2709849] [PubMed: 19000169]
• da Graça FF, de Rezende TJR, Vasconcellos LFR, Pedroso JL, Barsottini OGP, França MC Jr. Neuroimaging in hereditary spastic paraplegias: current use and future perspectives. Front Neurol. 2019;9:1117. [PMC free article: PMC6346681] [PubMed: 30713518]
• de Bot ST, van den Elzen RT, Mensenkamp AR, Schelhaas HJ, Willemsen MA, Knoers NV, Kremer HP, van de Warrenburg BP, Scheffer H. Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations. J Neurol Neurosurg Psychiatry. 2010;81:1073–8. [PubMed: 20562464]
• Depienne C, Fedirko E, Forlani S, Cazeneuve C, Ribaï P, Feki I, Tallaksen C, Nguyen K, Stankoff B, Ruberg M, Stevanin G, Durr A, Brice A. Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. J Med Genet. 2007a;44:281–4. [PMC free article: PMC2598038] [PubMed: 17098887]
• Depienne C, Stevanin G, Brice A, Durr A. Hereditary spastic paraplegias: an update. Curr Opin Neurol. 2007b;20:674–80. [PubMed: 17992088]
• Duning T, Warnecke T, Schirmacher A, Schiffbauer H, Lohmann H, Mohammadi S, Young P, Deppe M. Specific pattern of early white-matter changes in pure hereditary spastic paraplegia. Mov Disord. 2010;25:1986–92. [PubMed: 20669295]
• Erichsen AK, Koht J, Stray-Pedersen A, Abdelnoor M, Tallaksen CM. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain. 2009a;132:1577–88. [PubMed: 19339254]
• Erichsen AK, Server A, Landrø AI, Sandvik L, Tallaksen CME. Proton magnetic resonance spectroscopy and cognition in patients with spastin mutations. J Neurol Sci. 2009b;277:124–9. [PubMed: 19084842]
• Errico A, Ballabio A, Rugarli EI. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 2002;11:153–63. [PubMed: 11809724]
• Fei QZ, Tang WG, Rong TY, Tang HD, Liu JR, Guo ZL, Fu Y, Xiao Q, Wang XJ, He SB, Cao L, Chen SD. Two novel mutations in the Spastin gene of Chinese patients with hereditary spastic paraplegia. Eur J Neurol. 2011;18:1194–6. [PubMed: 21834905]
• Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bönsch D, Samson D, Coutinho P, Hutchinson M, McMonagle P, Burgunder JM, Tartaglione A, Heinzlef O, Feki I, Deufel T, Parfrey N, Brice A, Fontaine B, Prud'homme JF, Weissenbach J, Dürr A, Hazan J. Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet. 2000;9:637–44. [PubMed: 10699187]
• Fourtassi M, Jacquin-Courtois S, Scheiber-Nogueira MC, Hajjioui A, Luaute J, Charvier K, Maucort-Boulch D, Rode G. Bladder dysfunction in hereditary spastic paraplegia: a clinical and urodynamic evaluation. Spinal Cord. 2012;50:558–62. [PubMed: 22289900]
• Joussain C, Levy J, Charlanes A, Even A, Falcou L, Chartier Kastler E, Denys P. Urological dysfunction in patients with hereditary spastic paraplegia. Neurourol Urodyn. 2019;38:1081–5. [PubMed: 30848841]
• Kanavin ØJ, Fjermestad KW. Gastrointestinal and urinary complaints in adults with hereditary spastic paraparesis. Orphanet J Rare Dis. 2018;13:58. [PMC free article: PMC5902872] [PubMed: 29661209]
• Karle KN, Schüle R, Klebe S, Otto S, Frischholz C, Liepelt-Scarfone I, Schöls L. Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP). Orphanet J Rare Dis. 2013;8:158. [PMC free article: PMC3852552] [PubMed: 24107482]
• Kumar KR, Sue CM, Burke D, Ng K. Peripheral neuropathy in hereditary spastic paraplegia due to spastin (SPG4) mutation--a neurophysiological study using excitability techniques. Clin Neurophysiol. 2012;123:1454–9. [PubMed: 22192498]
• Liao X, Huang M, Xing W, Wu X, Liao W, Wang X, Tang B, Shen L. Resting state fMRI studies in SPG4-linked hereditary spastic paraplegia. J Neurol Sci. 2018;384:1–6. [PubMed: 29249364]
• Lindig T, Bender B, Hauser TK, Mang S, Schweikardt D, Klose U, Karle KN, Schüle R, Schöls L, Rattay TW. Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations. J Neurol. 2015;262:1961–71. [PubMed: 26050637]
• Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A. Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol. 2014;261:518–39. [PubMed: 24954637]
• Loureiro JL, Brandão E, Ruano L, Brandão AF, Lopes AM, Thieleke-Matos C, Miller-Fleming L, Cruz VT, Barbosa M, Silveira I, Stevanin G, Pinto-Basto J, Sequeiros J, Alonso I, Coutinho P. Autosomal dominant spastic paraplegias: a review of 89 families resulting from a Portuguese survey. JAMA Neurol. 2013;70:481–7. [PubMed: 23400676]
• Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, Mercimek-Mahmutoglu S, Ebrahimi-Fakhari D, Warner TT, Durr A, Assmann B, Lohmann K, Kostic V, Klein C. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord. 2016;31:436–57. [PubMed: 27079681]
• McDermott CJ, Burness CE, Kirby J, Cox LE, Rao DG, Hewamadduma C, Sharrack B, Hadjivassiliou M, Chinnery PF, Dalton A, Shaw PJ, et al. Clinical features of hereditary spastic paraplegia due to spastin mutation. Neurology. 2006;67:45–51. [PubMed: 16832076]
• McDermott CJ, Grierson AJ, Wood JD, Bingley M, Wharton SB, Bushby KM, Shaw PJ. Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation. Ann Neurol. 2003;54:748–59. [PubMed: 14681884]
• Meijer IA, Hand CK, Grewal KK, Stefanelli MG, Ives EJ, Rouleau GA. A locus for autosomal dominant hereditary spastic ataxia, SAX1, maps to chromosome 12p13. Am J Hum Genet. 2002;70:763–9. [PMC free article: PMC384953] [PubMed: 11774073]
• Meyer T, Schwan A, Dullinger JS, Brocke J, Hoffmann KT, Nolte CH, Hopt A, Kopp U, Andersen P, Epplen JT, Linke P. Early-onset ALS with long-term survival associated with spastin gene mutation. Neurology. 2005;65:141–3. [PubMed: 16009903]
• Murphy S, Gorman G, Beetz C, Byrne P, Dytko M, McMonagle P, Kinsella K, Farrell M, Hutchinson M. Dementia in SPG4 hereditary spastic paraplegia: clinical, genetic, and neuropathologic evidence. Neurology. 2009;73:378–84. [PubMed: 19652142]
• Orlacchio A, Kawarai T, Totaro A, Errico A, St George-Hyslop PH, Rugarli EI, Bernardi G. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol. 2004;61:849–55. [PubMed: 15210521]
• Papadopoulos C, Orso G, Mancuso G, Herholz M, Gumeni S, Tadepalle N, Jüngst C, Tzschichholz A, Schauss A, Höning S, Trifunovic A, Daga A, Rugarli EI. Spastin binds to lipid droplets and affects lipid metabolism. PLoS Genet. 2015;11:e1005149. [PMC free article: PMC4395272] [PubMed: 25875445]
• Park SH, Zhu PP, Parker RL, Blackstone C. Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest. 2010;120:1097–110. [PMC free article: PMC2846052] [PubMed: 20200447]
• Parodi L, Fenu S, Barbier M, Banneau G, Duyckaerts C, Tezenas du Montcel S, Monin ML, Ait Said S, Guegan J, Tallaksen CME, Sablonniere B, Brice A, Stevanin G, Depienne C, Durr A, et al. Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain. 2018;141:3331–42. [PubMed: 30476002]
• Parodi L, Fenu S, Stevanin G, Durr A. Hereditary spastic paraplegia: more than an upper motor neuron disease. Rev Neurol (Paris). 2017;173:352–60. [PubMed: 28449883]
• Patrono C, Casali C, Tessa A, Cricchi F, Fortini D, Carrozzo R, Siciliano G, Bertini E, Santorelli FM. Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia. J Neurol. 2002;249:200–5. [PubMed: 11985387]
• Polymeris AA, Tessa A, Anagnostopoulou K, Rubegni A, Galatolo D, Dinopoulos A, Gika AD, Youroukos S, Skouteli E, Santorelli FM, Pons R. A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings. J Neurol. 2016;263:1604–11. [PubMed: 27260292]
• Qiang L, Piermarini E, Muralidharan H, Yu W, Leo L, Hennessy LE, Fernandes S, Connors T, Yates PL, Swift M, Zholudeva LV, Lane MA, Morfini G, Alexander GM, Heiman-Patterson TD, Baas PW. Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse. Hum Mol Genet. 2019;28:1136–52. [PMC free article: PMC6423423] [PubMed: 30520996]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Reid E, Connell J, Edwards TL, Duley S, Brown SE, Sanderson CM. The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B. Hum Mol Genet. 2005;14:19–38. [PubMed: 15537668]
• Rezende TJ, de Albuquerque M, Lamas GM, Martinez AR, Campos BM, Casseb RF, Silva CB, Branco LM, D'Abreu A, Lopes-Cendes I, Cendes F, França MC Jr. Multimodal MRI-based study in patients with SPG4 mutations. PLoS One. 2015;10:e0117666. [PMC free article: PMC4320056] [PubMed: 25658484]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42:174–83. [PubMed: 24603320]
• Rucco R, Liparoti M, Jacini F, Baselice F, Antenora A, De Michele G, Criscuolo C, Vettoliere A, Mandolesi L, Sorrentino G, Sorrentino P. Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks. Neurol Sci. 2019;40:979–84. [PMC free article: PMC6478644] [PubMed: 30737580]
• Scheuer KH, Svenstrup K, Jennum P, Rogvi-Hansen B, Werdelin L, Fenger K, Nielsen JE. Double blind crossover trial of gabapentin in SPG4-linked hereditary spastic paraplegia. Eur J Neurol. 2007;14:663–6. [PubMed: 17539946]
• Schickel J, Pamminger T, Ehrsam A, Münch S, Huang X, Klopstock T, Kurlemann G, Hemmerich P, Dubiel W, Deufel T, Beetz C. Isoform-specific increase of spastin stability by N-terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. Eur J Neurol. 2007;14:1322–8. [PubMed: 17916079]
• Schneider SA, Beckinger VE, Möller B, Knüpfer S, Hamann M, Deuschl G. Urinary symptoms, quality of life, and patient satisfaction in genetic and sporadic hereditary spastic paraplegia. J Neurol. 2019;266:207–11. [PubMed: 30467602]
• Servelhere KR, Faber I, Martinez A, Nickel R, Moro A, Germiniani FMB, Moscovich M, Blume TR, Munhoz RP, Teive HAG, França MC Jr. Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations. Arq Neuropsiquiatr. 2018;76:183–8. [PubMed: 29809239]
• Servelhere KR, Faber I, Saute JA, Moscovich M, D'Abreu A, Jardim LB, Teive HA, Lopes-Cendes I, Franca MC Jr. Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations. Eur J Neurol. 2016;23:408–11. [PubMed: 26806216]
• Shoukier M, Neesen J, Sauter SM, Argyriou L, Doerwald N, Pantakani DV, Mannan AU. Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia. Eur J Hum Genet. 2009;17:187–94. [PMC free article: PMC2986068] [PubMed: 18701882]
• Solowska JM, D'Rozario M, Jean DC, Davidson MW, Marenda DR, Baas PW. Pathogenic mutation of spastin has gain-of-function effects on microtubule dynamics. J Neurosci. 2014;34:1856–67. [PMC free article: PMC3905148] [PubMed: 24478365]
• Solowska JM, Garbern JY, Baas PW. Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia. Hum Mol Genet. 2010;19:2767–79. [PMC free article: PMC2893808] [PubMed: 20430936]
• Sperfeld AD, Unrath A, Kassubek J. Restless legs syndrome in hereditary spastic paraparesis. Eur Neurol. 2007;57:31–5. [PubMed: 17108692]
• Svenson IK, Kloos MT, Gaskell PC, Nance MA, Garbern JY, Hisanaga S, Pericak-Vance MA, Ashley-Koch AE, Marchuk DA. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics. 2004;5:157–64. [PubMed: 15248095]
• Svenstrup K, Bross P, Koefoed P, Hjermind LE, Eiberg H, Born AP, Vissing J, Gyllenborg J, Nørremølle A, Hasholt L, Nielsen JE. Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia. J Neurol Sci. 2009;284:90–5. [PubMed: 19423133]
• Takiyama Y, Ishiura H, Shimazaki H, Namekawa M, Takahashi Y, Goto J, Tsuji S, Nishizawa M. Japan spastic paraplegia research consortium (JASPAC). Rinsho Shinkeigaku. 2010;50:931–4. [PubMed: 21921516]
• Tallaksen CM, Guichart-Gomez E, Verpillat P, Hahn-Barma V, Ruberg M, Fontaine B, Brice A, Dubois B, Durr A. Subtle cognitive impairment but no dementia in patients with spastin mutations. Arch Neurol. 2003;60:1113–8. [PubMed: 12925368]
• Wharton SB, McDermott CJ, Grierson AJ, Wood JD, Gelsthorpe C, Ince PG, Shaw PJ. The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. J Neuropathol Exp Neurol. 2003;62:1166–77. [PubMed: 14656074]
• White SR, Evans KJ, Lary J, Cole JL, Lauring B. Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing. J Cell Biol. 2007;176:995–1005. [PMC free article: PMC2064084] [PubMed: 17389232]

Author History

Christel Depienne, PhD; Hôpital Pitié Salpêtrière (2003-2019)
Alexandra Durr, MD, PhD (2003-present)
Livia Parodi, PhD (2019-present)
Siri Lynne Rydning, MD (2019-present)
Chantal Tallaksen, MD, PhD (2003-present)

Revision History

• 13 June 2019 (sw) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 18 June 2009 (me) Comprehensive update posted live
• 23 April 2007 (cd) Revision: deletion/duplication analysis clinically available
• 10 August 2005 (me) Comprehensive update posted live
• 17 April 2003 (me) Review posted live
• 25 September 2002 (ct) Original submission