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Spastic Paraplegia 4

Synonyms: Hereditary Spastic Paraplegia, Spastin Type; SPAST-Associated HSP; SPG4

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

Author Information

Initial Posting: ; Last Update: August 16, 2012.


Clinical characteristics.

Spastic paraplegia 4 (SPG4; also known as SPAST-associated 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. About one third have sphincter disturbances. 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.


The diagnosis of SPAST-associated HSP in a proband is based on characteristic clinical symptoms and molecular genetic testing of SPAST, the gene in which pathogenic variants are known to cause spastic paraplegia associated with the SPG4 locus. Molecular genetic testing has a pathogenic variant detection rate of 80%-100%, depending on the test method.


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: Every six- to twelve-month evaluation to update medications and physical rehabilitation.

Genetic counseling.

SPAST-associated HSP is inherited in an autosomal dominant manner with reduced penetrance. Most individuals diagnosed with SPAST-associated HSP have an affected parent. The proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with SPAST-associated HSP has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is technically possible though rarely requested. Because of incomplete penetrance and variable expression, results of prenatal testing cannot predict whether or not an individual will develop SPG4 and, if so, what the age of onset, clinical course, and degree of disability will be.


Clinical Diagnosis

The diagnosis of spastic paraplegia 4 (SPG4; also known as SPAST-associated HSP) in a proband is based on the following:

  • Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait without (or with only mild) spasticity at rest and very mild proximal weakness, often accompanied by urinary urgency
  • Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses), often accompanied by mildly impaired vibration sensation in the ankles
  • Family history consistent with autosomal dominant inheritance, or exclusion of known causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)
  • Molecular genetic testing of SPAST. Detection of pathogenic variants or deletions in SPAST confirms the diagnosis.
    Note: Failure to detect a pathogenic variant/deletion does not absolutely exclude the diagnosis.

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

Brain and spinal cord MRI is useful in identifying anomalies of the cerebro-medullary junction and the cervical and dorsolumbar medulla that are characteristic of disorders discussed in Differential Diagnosis.

Most MRI investigations are uninformative for SPAST-associated HSP, but mild vermis atrophy and/or a thin corpus callosum have been occasionally reported [Nielsen et al 2004, Orlacchio et al 2004b]. Spinal atrophy was confirmed in HSP, but less pronounced in SPG4 compared with other genetic forms of HSP [Hedera et al 2005]. Cerebellar atrophy was also reported in two individuals without ataxia [Orlacchio et al 2004b] and congenital arachnoid cysts were seen in one family [Orlacchio et al 2004a]. Subtle white matter changes have been reported [Duning et al 2010] and may prove useful biomarkers of disease, but the results must be confirmed in further studies.

Electromyography (EMG) with nerve conduction velocities (NCV) is used to exclude peripheral nervous system involvement, which could raise the possibility of an alternative diagnosis.


  • Spinal evoked potentials may eventually reveal delayed prolongation of the central conduction time [Nielsen et al 2001].
  • Whether paired transcranial magnetic stimulation may help confirm the diagnosis of SPG4 remains to be determined [Nielsen et al 2001].
  • Motor and somatosensory evoked potentials were significantly affected in SPG4 [Sartucci et al 2007]. Whether these findings may be used as a marker for spasticity as suggested by these investigators remains to be determined.
  • Reduced regional cerebral blood flow may be specific for SPAST-associated HSP [Scheuer et al 2005].
  • Proton magnetic resonance spectroscopy showed significant associations with cognitive impairment in a study of eight individuals with SPG4 [Erichsen et al 2009b].

Molecular Genetic Testing

Gene. SPAST, encoding the protein spastin, is the gene in which pathogenic variants are known to cause the SPG4 type of hereditary spastic paraplegia.

Clinical testing

Table 1.

Molecular Genetic Testing Used in SPG4

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
SPASTSequence analysis 4Sequence variants75%-80% 5
Deletion/duplication analysis 6(Multi)exon deletion or duplication20%-25% 7

See Molecular Genetics for information on allelic variants.


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.


Benign variants can affect the phenotype (see Genotype-Phenotype Correlations and Molecular Genetics).


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Exon and multiexon deletions and duplications account for approximately 20%-25% of SPAST pathogenic variants [Beetz et al 2006, Depienne et al 2007b].

Testing Strategy

To confirm/establish the diagnosis in a proband, molecular genetic testing of SPAST should be considered.

  • Sequence analysis of SPAST should be pursed first. If a pathogenic variant is not identified, then deletion/duplication analysis of SPAST can be done. Alternatively, sequence analysis and deletion/duplication testing can be performed in parallel. Detection of a pathogenic variant or deletion/duplication in SPAST confirms the diagnosis.
  • Failure to detect a pathogenic variant or deletion does not completely exclude the diagnosis although it makes it unlikely.

Note: Once non-genetic causes have been excluded, testing for SPAST-associated 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% of simplex cases [Depienne et al 2007a].

Clinical Characteristics

Clinical Description

The cardinal clinical feature of SPG4 (SPAST-associated HSP) is insidiously progressive bilateral lower-limb spasticity associated with frequent brisk reflexes, ankle clonus, and Babinski signs. Individuals with SPAST-associated HSP may also have increased reflexes in the upper limbs, but they are very rarely tetraspastic. More than 50% of affected individuals have proximal weakness in the lower limbs and one third have sphincter disturbances.

Onset is mostly in early adulthood, although symptoms may appear as early as age one year (when the child starts to walk) and as late as age 76 years [Author, personal observation]. A subset of individuals with a SPAST pathogenic variant may remain asymptomatic their entire life [Durr et al 1996].

SPG4 is the most frequent type of dominant hereditary spastic paraplegia in many countries; the main symptoms and findings described in the reports listed appear to be the same as those originally reported [Basri et al 2006, Crippa et al 2006, Ivanova et al 2006, Magariello et al 2006, McDermott et al 2006, Depienne et al 2007b, Erichsen et al 2007, Meijer et al 2007, Orlacchio et al 2008].

Disease severity generally worsens with the duration of the disease, although some individuals remain mildly affected all their lives. Families in which some individuals are mildly affected while others are severely affected are reported [Matsuura et al 1997, Nance et al 1998, Nielsen et al 1998, Hentati et al 2000, Lindsey et al 2000, McMonagle et al 2000, Santorelli et al 2000, Higgins et al 2001, Mead et al 2001, Svenson et al 2001, Meijer et al 2002, Depienne et al 2007b].

Wheelchair use and walking only with assistance occur in 17% and 20% of individuals, respectively. Disease progression is more rapid in individuals with late onset (age >35 years) than in those with early onset. However, Orlacchio et al [2005] studied a large family with the 906delT variant and found a significant correlation between disability and disease duration.

Other findings. The most frequent additional feature is decreased, but not abolished, vibration sense at the ankles, occurring in 33%-59% of individuals [Fonknechten et al 2000, Lindsey et al 2000, Mead et al 2001, Tallaksen et al 2003, Orlacchio et al 2004b].

Pes cavus and mild spastic dysarthria may be observed.

Subtle cognitive impairment has been documented [Byrne et al 1998, Heinzlef et al 1998, Webb & Hutchinson 1998, Reid et al 1999, Byrne et al 2000, McMonagle et al 2000, White et al 2000, Tallaksen et al 2003, Erichsen et al 2007, Ribaï et al 2008, 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 could be established [Erichsen et al 2007].

Seizures, intellectual disability, and cerebellar ataxia are rare:

  • Nielsen et al [2004] reported a family with SPAST-associated HSP with a variable complex phenotype including ataxia, dysarthria, unipolar depression, epilepsy, migraine, and/or cognitive impairment.
  • Ribaï et al [2008] reported three families with SPAST-associated HSP with intellectual disability, extensive social dependence, and/or isolated psychomotor delay.

Neuropathy, reported in a few affected individuals, was most probably not related to the presence of the SPAST pathogenic variant [Schulte et al 2003, Fukunaga et al 2007]. Posterior fossa abnormalities have also been reported in two unrelated families [Scuderi et al 2009], and again the relation to the presence of a SPAST pathogenic variant is unclear.

A few individuals with severe dementia – one with neuronal loss, tau-immunoreactive neurofibrillary tangles in the hippocampus, and Lewy bodies in the substantia nigra on neuropathologic examination – have been reported [White et al 2000]. However, too few neuropathologic studies have been performed in persons with SPAST-associated HSP for a general picture of the distribution of cortical and medullar lesions in the disease to emerge [Tallaksen et al 2003].

In the Irish population a higher than expected rate of psychosis was found in individuals with HSP including SPG4 [McMonagle et al 2006]; however, the association with SPG4 is uncertain. Depression is reported to be frequent (41%) and unrelated to disease severity [du Montcel et al 2008].

Only three individuals have been reported with lower motor neuron symptoms and/or bulbar dysfunction and respiratory insufficiency [Brugman et al 2005, Meyer et al 2005, McDermott et al 2006].These presentations remain therefore extremely rare.

Restless leg syndrome may be a frequent undiagnosed associated condition with HSP, but whether this is particular to SPG4 is not known [Sperfeld et al 2007].

Bladder dysfunction remains one of the most frequent problems for affected individuals and remains largely unexplored. No significant differences between SPAST-HSP and other HSP were detected in one study of bladder disturbances in 49 affected individuals [Braschinsky et al 2010].

Hand tremor has been reported in 10% of a large cohort of Dutch individuals with SPG4 [de Bot et al 2010].

Genotype-Phenotype Correlations

The largest study comparing missense and truncating variants found no clear genotype-phenotype correlations [Fonknechten et al 2000].

No significant difference in either age at onset or clinical severity exists among groups of individuals with missense or truncating variants, although a meta-analysis demonstrated a tendency to earlier onset in individuals with missense variants compared to those with other SPAST variants [Yip et al 2003].

The age at onset and clinical severity are highly variable for a given variant, even in the same family. 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 [2004b] reported wide phenotypic variability with the p.Asn386Ser variant. The intra- and interfamilial range of age at onset and disease duration was large. Some individuals had intellectual disability and others showed brain MRI abnormalities including thin corpus callosum or cerebellar atrophy [Orlacchio et al 2004b].

Svenson et al [2004] reported two rare nonsynonymous allelic variants (a nucleotide variant that results in a change of the amino acid) (c.131C>T [p.Ser44Leu] and c.134C>A [p.Pro45Gln]). Individuals who have both a SPAST pathogenic variant on one allele and either a c.131C>T or c.134C>A variant on the other allele seem to have very early onset, suggesting that these alleles could modify the HSP phenotype. The allelic variant c.131C>T has a frequency of 0.6%-2% in a control population [Svenson et al 2004, McDermott et al 2006, personal communication]; c.134C>A is even rarer. Nevertheless, early onset is not restricted to individuals who have both a pathogenic variant and one of these variants. The extensive phenotypic variability in SPAST-associated HSP cannot therefore be explained exclusively by the c.131C>T and c.134C>A variants.

A positive correlation between genotype and electrophysiologic phenotype has been reported [Bönsch et al 2003]. In a study using transcranial magnetic stimulation, individuals from two pedigrees with different SPAST pathogenic variants showed different degrees of disturbance in the motor system with respect to motor evoked potential amplitude, central motor conduction time, and central motor threshold [Bönsch et al 2003]. These results must be confirmed, however, with more families.


Penetrance is age dependent and incomplete even in older individuals who have a SPAST pathogenic variant. It is estimated to be 85% by age 45 years [Fonknechten et al 2000]. Using data from a series of individuals with SPAST variants diagnosed in Paris, the calculated penetrance is approximately 50% at age 27 years and 80% at 50 years [Author, personal observation]. Age dependence is explained partly by variability in age at onset and partly by difficulty in determining with precision the age of onset when it is insidious.

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.


Anticipation (earlier age at onset or increased severity in successive generations) had been proposed by several groups based on data from several families [Raskind et al 1997]. The exclusion of the involvement of a CAG repeat expansion in SPAST led to the hypothesis that the clinically observed anticipation in some families was in fact the result of ascertainment bias. The bias includes the variability in age at onset and the tendency to investigate pyramidal signs earlier in children compared to the investigation of spastic gait in the parents.


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


Skre [1974] estimated the prevalence of all dominant hereditary spastic paraplegia in Norway to be 12.4:100,000. McMonagle et al [2002] estimated the prevalence of pure dominant hereditary spastic paraplegia in Ireland to be 1.27:100,000. The estimate for most countries is approximately 2:100,000-6:100,000.

SPAST-associated HSP is estimated to account for 15%-40% of the pure dominant forms of hereditary spastic paraplegia [Meijer et al 2002]. Reports from many European countries as well as the US, Canada, Japan, and China appear to indicate that SPAST-associated HSP is the most frequently occurring form of autosomal dominant HSP [Erichsen et al 2009a, Takiyama et al 2010, Fei et al 2011].

Geographic prevalence may vary: Meijer et al [2002] found fewer families with SPAST-associated HSP among North American families than expected from reports in European families [Fonknechten et al 2000].

Differential Diagnosis

See Hereditary Spastic Paraplegia overview for a review of the differential diagnosis. In the case of a definite autosomal dominant hereditary spastic paraplegia, other types of autosomal dominant pure spastic paraplegia that need to be considered are SPG3, SPG6, SPG8, SPG10, SPG12, SPG13, SPG19, SPG31, SPG33, and SPG37.

SPG4 (SPAST-associated HSP) is the most frequently occurring form of autosomal dominant hereditary spastic paraplegia, accounting for an estimated 15%-40% of the pure dominant forms of hereditary spastic paraplegia [Meijer et al 2002, McDermott et al 2006, personal communication]. Because SPAST is the gene most commonly involved in autosomal dominant HSP (AD-HSP), it is the first and most relevant gene to be tested.

With the exceptions of SPG31, SPG10, and SPG3A, no significant differences have been established between SPG4 and other types of pure dominant spastic paraplegia. Peripheral neuropathy is more frequently associated with subtypes SPG31 and SPG10 [Goizet et al 2009, Goizet et al 2011]. SPG3A, encoding atlastin, is the second most frequently involved gene in AD-HSP. Durr et al [2004] have shown that SPG3A-related disease is a pure form of HSP associated with earlier onset than SPG4 HSP. In SPG3A, impairment of vibration sense at the ankles and increased reflexes in the upper limbs are less frequently seen than in SPG4. There are also fewer sphincter disturbances, more muscle wasting in the lower limbs, and more scoliosis in SPG3 than SPG4 [Durr et al 2004]. As a consequence, an individual with pure and very early-onset HSP should be tested for SPG3A before being considered for testing for SPG4.

In simplex cases (spasticity in one individual in a family), all possible causes of spasticity in the legs have to be considered because some non-genetic causes of spasticity are more common than SPG4.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spastic paraplegia 4 (SPG4), the following evaluations 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 SPG4 remains unclear. So far, no consensus exists on the type of tests that should be performed, the timing of the tests, and the purpose. 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 SPG4, 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 (not a feature of SPG4 per se) may occur in individuals with SPG4 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.
  • A thorough examination for associated restless legs syndrome (RLS) also appears to be warranted [Sperfeld et al 2007].
  • Clinical genetics consultation is appropriate.

Treatment of Manifestations

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.

Botulinum toxin and intrathecal baclofen can be proposed when oral drugs are ineffective and spasticity is severe and disabling. One open-label study with botulinum toxin injections showed an increase in gait velocity in persons with HSP after six months [Rousseaux et al 2007].

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. At the present time there is no consensus on treatment of sphincter disturbances (both urinary and anal) and management remains therefore symptomatic [Braschinsky et al 2010].

Prevention of Secondary Complications

Follow up of the sphincter disturbances is important to prevent bladder dysfunction.

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]. In children orthopedic treatment and botulinum toxin injections may also contribute to better ambulatory function. More systematic studies are, however, needed to confirm these observations.


Specialized outpatient evaluations are suggested every six 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 in the US and in Europe 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.


A double-blind crossover trial with gabapentin did not show improvement of spasticity in persons with SPG4 [Scheuer et al 2007].

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

SPG4 (SPAST-associated HSP) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Note: Although most individuals diagnosed with SPG4 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, late onset of the disease in the affected parent, or incomplete penetrance.

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 or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • When the parents are clinically unaffected and do not have the pathogenic variant identified in the proband, the risk to the sibs of a proband appears to be low. If a SPAST pathogenic variant cannot be detected in the DNA of either parent of the proband, the possibility of germline mosaicism in a parent should be considered. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with SPG4 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 or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for SPG4 is possible using the techniques described in Molecular Genetic Testing. Such 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 identified as having a SPAST pathogenic variant. When testing at-risk individuals for SPG4, an affected family member should be tested first to confirm diagnosis in the family and to identify the specific variant.

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 SPG4, 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.

Testing of at-risk individuals during childhood. Consensus holds that individuals younger than age 18 years who are at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. In addition, no preventive treatment is available.

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.

Family planning

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

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 pathogenic variant has been identified in the family, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible. Because of incomplete penetrance and variable expression, results of prenatal testing cannot predict whether or not an individual will develop SPG4 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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


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.

  • Spastic Paraplegia Foundation, Inc.
    7700 Leesburg Pike
    Ste 123
    Falls Church VA 22043
    Phone: 877-773-4483 (toll-free)
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
  • Norsk forening for Arvelig-Spastisk Paraparese / Ataksi (NASPA)
    The Norwegian association for individuals with hereditary spastic paraplegia and ataxia
    PO Box 9217
    Oslo 0134
    Phone: 24 10 24 00
    Fax: 24 10 24 99

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 4: Genes and Databases

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

Table B.

OMIM Entries for Spastic Paraplegia 4 (View All in OMIM)


Gene structure. SPAST spans approximately 90 kb and is composed of 17 exons (NM_014946.3). For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. The coding region contains very few benign variants.

  • One synonymous polymorphism (c.879G>A) located in exon 6 is found in about 1.5%-2% of persons of northern European origin [Author, personal data].
  • A nonsynonymous polymorphism (c.1292G>A;p.Arg431Gln) was reported only once, in the spouse of an affected individual [Meijer et al 2002]. The status of this variant remains unknown.
  • Svenson et al [2004] reported two rare nonsynonymous allelic variants (c.131C>T and c.134C>A) in a control population with frequencies of 0.6% and 0.2%, respectively. The SPAST: c.131T and SPAST: c.134A heterozygous alleles were shown to segregate independently of the disease in two families and independently of a heterozygous pathogenic variant in another family. The variant c.131C, which encodes a serine at residue 44, could theoretically be phosphorylated by a proline-directed serine/threonine cyclin-dependent kinase (Cdk). Individuals who have a documented SPAST pathogenic variant on one allele and either a c.131T or c.134A variant on the other allele appear to have very early-onset disease, suggesting that these alleles could modify the HSP phenotype [Svenson et al 2004]. (see Genotype-Phenotype Correlations)

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).

Table 2.

Selected SPAST Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
p.Ser44Leu 2NM_014946​.3
p.Pro45Gln 2

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 (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


Rare alleles that may modify the HSP phenotype

Pathogenic variants

  • All types of DNA alterations are observed: missense, nonsense, and splice site variants, small deletions and insertions, and rare large-scale deletions. Recurrent variants in SPAST are exceptional.
  • Single-nucleotide variants include nonsense (~10%) and splice site variants (~26%), small deletions (~22%) or insertions (~11%) creating a frameshift, and missense variants (31%). With the exception of missense variants, most pathogenic single-nucleotide variants result in premature termination codons (PTC). The corresponding mRNA is likely recognized and degraded via the nonsense-mediated mRNA decay (NMD), with the exception of truncating variants located in exon 17.
  • With only rare exceptions, missense variants are located in the AAA cassette (see Normal gene product).

Normal gene product. SPAST encodes a 616-amino acid protein that is a putative nuclear member of the AAA (ATPases associated with diverse cellular activities) protein family named spastin. SPAST is ubiquitously expressed in adult and fetal human tissues, showing slightly higher expression in the fetal brain. SPAST undergoes alternate splicing with variable inclusion of exon 4 (NM_199436.1). No pathogenic variants have been reported in exon 4, however, suggesting that the protein isoform NP_955468.1 of this transcript is the predominant functional form of spastin in the adult nervous system.

Paraplegin, encoded by SPG7 (mutation of which cause SPG7, an autosomal recessive form of HSP), is also a member of the AAA family (see Hereditary Spastic Paraplegia Overview). These proteins share very little homology outside the AAA motif and spastin belongs to another AAA subclass as do paraplegin and other related metalloproteinases. This subclass includes katanin, a microtubule-severing protein. The AAA domain of spastin is located in the C terminus of the protein between amino acids 342 and 599.

Immunohistochemical studies on post mortem human brain revealed that spastin is widely expressed in the neurons of the central nervous system, including the cortex and striatum [Wharton et al 2003]. Distal degeneration of long tracts in the spinal cord is associated with a microglial reaction. Observations are consistent with an alteration of the cytoskeleton in the motor system as well as a tau-pathology outside the motor system.

Subcellular localization of spastin is dual. Overexpressed full-length spastin proteins are found in the cytoplasm or the perinuclear area of cell lines [Errico et al 2002, McDermott et al 2003], while the endogenous protein is at least partly located in the nucleus of HeLa cells and mouse motor neurons [Charvin et al 2003]. Wharton et al [2003] confirmed on post mortem human brain that spastin showed both cytoplasmic and nuclear expression in neurons. In pyramidal neurons of the motor cortex and in immortalized motor neurons, spastin is localized to the synaptic terminals and growth cones [Wharton et al 2003]. A synaptic localization of spastin has also been shown for its Drosophila ortholog [Sherwood et al 2004, Trotta et al 2004]. Claudiani et al [2005] have shown that two spastin isoforms of 68 and 60 kd, respectively, were synthesized from the SPAST mRNA through usage of two different translational start sites. The 60-kd isoform is predominantly nuclear whereas the 68-kd, full-length isoform contains two nuclear export signals that efficiently drive export to the cytoplasm and is therefore mostly cytoplasmic. [Claudiani et al 2005]. The situation is further complicated by alternative splicing of exon 4, resulting in the presence of minor exon 4-deleted versions of the long and short isoforms [Svenson et al 2001, Sanderson et al 2006]. To date no pathogenic variants have been reported in exon 4, suggesting that the isoform lacking exon 4 is the predominant functional form of spastin in the brain. However, controversial experimental data exist regarding the isoform that is more abundant in the brain and spinal cord [Claudiani et al 2005, Solowska et al 2008]; further study is therefore necessary to determine which isoform is really relevant to the disorder.

It is now well established that spastin plays a role in microtubule dynamics. Overexpression of spastin promotes microtubule disassembly in cellular models [Errico et al 2002], indicating that spastin acts as a microtubule-severing protein such as katanin, an AAA protein of the same subfamily that contributes to the regulation of microtubule length and dynamics during mitosis and meiosis. Furthermore, Ciccarelli et al [2003] identified a region of approximately 80 amino acids in the N terminus of spastin that they named MIT (for microtubule-interacting and trafficking molecules domain); the region is also shared by spartin, the protein mutated in the Amish type of hereditary spastic paraplegia (Troyer syndrome). This region corresponds to a domain present in several proteins, all of which are implicated in endosomal trafficking models [Ciccarelli et al 2003]. These observations led to the proposition that spastin plays a role in intracellular organelle trafficking via its interaction with the microtubule cytoskeleton.

Abnormal gene product. Haploinsufficiency has been postulated on the basis of the observation of reduced spastin mRNA in individuals with premature protein termination [Bürger et al 2000]. The level of spastin mRNA has been tested and found to be reduced, probably as a consequence of RNA instability. Reduced levels of functional spastin are not well tolerated, since two leaky splice site variants that create both wild type and aberrant splice variants are pathogenic.

Approaches have thus been developed to reproduce haploinsufficiency: loss of function of Drosophila spastin, either by RNAi or knock out, affected the morphology and function of the neuromuscular synapse by modulating microtubule dynamics in synaptic terminals [Sherwood et al 2004, Trotta et al 2004]. More recently, mice in whom Spast was deleted were reported to develop progressive axonal degeneration restricted to the central nervous system, associated with a late and mild motor deficit [Tarrade et al 2006]. The degenerative process, slightly observable in heterozygous mice but increased in homozygous mice, is characterized by focal axonal swellings and abnormal accumulation of organelles and cytoskeletal components. Mutated cortical neurons develop neurite swellings associated with focal impairment of retrograde transport in culture. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules and dynamic microtubules, confirming that spastin deficiency has a major impact on neurite maintenance and transport [Tarrade et al 2006].

The finding that SPAST pathogenic variants in the AAA domain lead to constitutive binding to microtubules suggests a dominant-negative effect [Errico et al 2002]. McDermott et al [2003] have shown that the abnormal interaction of mutated spastin with microtubules results in a change in the distribution of intracellular organelles such as mitochondria or peroxisomes. The impairment of microtubule-dependent organelle transport could thus be responsible for the degeneration of long corticospinal axons underlying the pathogenesis of hereditary spastic paraplegia [McDermott et al 2003]. However, the aforementioned results were obtained by overexpression of mutated and wild type spastin fusion proteins, mostly in cell lines, which may not be the appropriate model to mimic the defects in pyramidal tract neurons in affected individuals. In contrast to a peptide from the short spastin isoform, the expression of a peptide from the full-length isoform in cultured neurons altered normal axonal growth and inhibited fast axonal transport. These results could be consistent with a “gain-of-function” mechanism underlying HSP [Solowska et al 2008]. However, the mutation spectrum in SPAST, which includes mostly pathogenic variants introducing premature termination codons and 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]. This hypothesis is further supported by the observation that spastin down-regulation has a negative impact on the assembly rate of microtubules and that spastin depletion alters the development of primary hippocampal neurons leading to abnormal neuron morphology, dystrophic neurites, and axonal growth defects [Riano et al 2009].


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 3-26-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 3-26-18.

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Chapter Notes

Revision History

  • 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 to live Web site
  • 17 April 2003 (me) Review posted to live Web site
  • 25 September 2002 (ct) Original submission
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