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Spastic Paraplegia 3A

Synonym: SPG3A

, MD, PhD.

Author Information

Initial Posting: ; Last Update: December 11, 2014.

Estimated reading time: 19 minutes


Clinical characteristics.

Spastic paraplegia 3A (SPG3A) is a hereditary spastic paraplegia (HSP) characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs, diminished vibration sense caused by degeneration of the corticospinal tracts and dorsal columns, and urinary bladder hyperactivity. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. Most persons with early-onset SPG3A have a "pure" ("uncomplicated") HSP; however, complicated HSP with axonal motor neuropathy and/or distal amyotrophy with lower motor neuron involvement (Silver syndrome phenotype) have been observed. The rate of progression in SPG3A is slow, and wheelchair dependency or need for a walking aid (cane, walker, or wheelchair) is relatively rare.


The diagnosis of SPG3A can be established only by molecular genetic testing of ATL1, the gene encoding the protein atlastin-1.


Treatment of manifestations: Treatment is symptomatic. Medical treatment of spasticity may begin with oral baclofen or tizanidine, followed by chemodenervation with botulinum A or B toxins if oral antispasticity medications are not tolerated. Intrathecal baclofen pump may be considered for those who improve on oral baclofen but have significant systemic adverse effects. Medical therapy should be combined with intensive physical therapy focused on stretching and strengthening exercises. Distal weakness (typically affecting foot dorsiflexion) can be ameliorated by ankle-foot orthoses. Urinary urgency can be treated with anticholinergic antispasmodic drugs.

Prevention of secondary complications: Muscle tendon contractures, scoliosis, and foot deformities, the most likely secondary complications, may be delayed or minimized with intense and regular physiotherapy for the spasticity.

Surveillance: No consensus exists regarding the frequency of clinical follow up visits, but reevaluation once or twice yearly to identify and treat new complications is recommended.

Agents/circumstances to avoid: Dantrolene, as it can induce irreversible weakness, adversely affecting mobility.

Genetic counseling.

SPG3A is almost exclusively inherited in an autosomal dominant manner. More than 95% of individuals diagnosed with SPG3A have an affected parent; however, the proportion of cases caused by a de novo pathogenic variant is currently unknown. Each child of an individual with SPG3A has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.


Clinical Diagnosis

Spastic paraplegia 3A (SPG3A) is one of the hereditary spastic paraplegias (HSPs), a group of neurodegenerative disorders characterized by progressive bilateral and mostly symmetric lower extremity weakness and spasticity resulting from axonal degeneration of corticospinal tracts, diminished vibration sense caused by impairment of dorsal columns, and urinary bladder hyperactivity.

Because of the significant overlap between the age of onset and severity of disease among the various genetic types of HSP (see Hereditary Spastic Paraplegia), the diagnosis of SPG3A can be established only by molecular testing of ATL1, the gene associated with SPG3A.

Molecular Genetic Testing

Gene. ATL1 (formerly known as SPG3A), encoding the protein atlastin-1, is the only gene known to be associated with spastic paraplegia 3A.

Table 1.

Molecular Genetic Testing Used in Spastic Paraplegia 3A

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
ATL1Sequence analysis 2, 3~100%
Deletion/duplication analysis 4, 5<1%

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


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.


Sequence analysis and scanning of the entire gene for pathogenic variants can have similar variant detection frequencies; however, variant detection rates for scanning may vary considerably between laboratories depending on the specific protocol used.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Single-exon or multiexon deletions in ATL1 are rare; only one single-exon deletion has been reported to date [Sulek et al 2013].

Interpretation of test results. Failure to detect a pathogenic ATL1 sequence variant does not absolutely exclude the diagnosis of SPG3A because the frequency of pathogenic variants involving non-coding regions (introns and promoter region) is unknown.

Testing Strategy

To confirm/establish the diagnosis in a proband

One genetic testing strategy is molecular genetic testing of ATL.

An alternative genetic testing strategy is use of a multigene panel that includes ATL1 and other genes of interest (see Differential Diagnosis). 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; thus, clinicians need to determine which multigene panel 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. (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.

More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of SPG3A.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Characteristics

Clinical Description

Spastic paraplegia 3A (SPG3A) is characterized by clinical findings that tend to be more homogeneous than other forms of AD HSP [Zhao et al 2001, Dürr et al 2004, Hedera et al 2004]. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. The rate of progression is slow; wheelchair dependency or need for an assistive walking device is relatively rare.

Although it has been suggested that SPG3A is a neurodevelopmental rather than a neurodegenerative disorder, recent identification of individuals with adult-onset SPG3A argues strongly against this hypothesis [Sauter et al 2004, Zhu et al 2006]. Persons with adult onset of SPG3A also tend to experience slower progression of their clinical symptoms.

Most persons with early-onset SPG3A have a "pure" or "uncomplicated" HSP phenotype. However, complex HSP phenotypes with axonal motor neuropathy and/or distal amyotrophy (like that observed in the Silver syndrome phenotype) have also been reported [Scarano et al 2005, Ivanova et al 2007, Salameh et al 2009].

Signs seen less frequently in SPG3A than in other HSPs include the following [Dürr et al 2004]:

  • Hyperreflexia of the upper extremities
  • Impairment of vibration sensation at the ankles
  • Urinary sphincter hyperactivity

Signs seen more frequently in SPG3A than in other HSPs are pes cavus deformities and scoliosis; however, the presence of these findings may be attributable to the earlier age of onset rather than the specific form of HSP.

Genotype-Phenotype Correlations

Most persons with pathogenic variants in ATL1 and early-onset disease have pathogenic missense variants clustered around the GTPase binding domain.

While some ATL1 pathogenic variants associated with late-onset HSP are insertional variants in the C-terminus of the gene that result in a premature truncation of the protein, adult-onset disease has also been observed with missense variants in the GTPase binding domain [Tessa et al 2002, Sauter et al 2004].


Overall, penetrance of pathogenic variants is high (~80%-90%) [Dürr et al 2004]. In many familial cases, individuals with an ATL1 pathogenic variant had a normal neurologic examination even at an advanced age, arguing against significant age-dependent penetrance [Dürr et al 2004].

The lowest penetrance, 30%, was reported for the p.Arg415Trp pathogenic variant [D'Amico et al 2004].


Anticipation with an earlier age at onset and increased severity in successive generations is not a feature of the majority of SPG3A kindreds. However, a bias of ascertainment towards earlier recognition of HSP in younger generations of a family is commonly observed based on awareness of the disease by other family members and treating physicians.


"Silver syndrome phenotype" refers to the inherited findings of spasticity and axonal motor neuropathy and/or distal amyotrophy [Silver 1966]. It is now known that these findings can be seen in a number of hereditary neurologic disorders caused by pathogenic variants in different genes (e.g., SPG3A caused by pathogenic variants in ATL1 and BSCL2-related neurologic disorders caused by pathogenic variants in BSCL2) [Windpassinger et al 2004].


Estimated prevalence of AD HSP varies from 1.27:100,000 in the survey in Ireland to 12.4:100,000 based on a Norwegian epidemiologic study [Skre 1974, McMonagle et al 2002].

ATL1 pathogenic variants have been confirmed as the most common cause of early-onset HSP, accounting for approximately 30%-50% of all AD HSP with onset before age ten years [Abel et al 2004, Dürr et al 2004].

SPG3A accounts for approximately 10%-15% of all AD HSP cases [Fink et al 1996]. In an analysis of a large cohort of patients in whom a SPAST (formerly known as SPG4) pathogenic variant was not identified, 40% had pathogenic variants in ATL1 [Dürr et al 2004].

Differential Diagnosis

HSP is a progressive condition with a gradual worsening of spasticity and weakness of the lower extremities. Overall, the age of onset, disease severity, and rate of progression differ among different types of AD HSP; there is also considerable variability within the same genetic forms of HSP.

For a general discussion of the differential diagnosis of spastic paraplegia/paraparesis syndrome, see Hereditary Spastic Paraplegia Overview.

While the association of infantile or early (age <10 years) onset and pathogenic variants in ATL1 has been confirmed by many studies, this genotype-phenotype correlation is not sufficient for the specific diagnosis of SPG3A on clinical grounds alone as an early age of onset can be seen in other types of AD HSP. Overall, a low specificity of genotype/phenotype correlations in AD HSP requires the molecular diagnosis of a specific type of HSP.

SPG3A needs to be differentiated from other forms of AD HSP, such as BSCL2-related neurologic disorders, in which the Silver syndrome phenotype can be observed. [Salameh et al 2009].

SPG3A needs to be differentiated from other forms of AD HSP with possible early age of onset.

Additional considerations for SPG3A include a diplegic form of cerebral palsy (CP), as the majority of such patients tend to have very early onset of symptoms and a slow progression, which may suggest a static clinical course [Rainier et al 2006]. The presence of a positive family history with an affected parent typically does not present any diagnostic dilemmas. However, incomplete penetrance or a de novo pathogenic variant may lead to the diagnosis of diplegia caused by periventricular leukomalacia or perinatal hypoxic-ischemic injury. Normal pre- and perinatal history and unremarkable neuroimaging should prompt consideration of HSP, including SPG3A.

SPG4, caused by pathogenic variants in SPAST (encoding spastin) is the most common type of AD HSP; it may occasionally present in infancy, although it tends to have a more progressive course [Blair et al 2007].

SPG6 (OMIM 600363), caused by pathogenic variants in NIPA1 (encoding magnesium transporter NIPA1), may occasionally also manifest in infancy [Bien-Willner et al 2006]. This is probably the most aggressive form of AD HSP, leading to wheelchair dependency in a relatively short period of time.

SPG10 (OMIM 604187), caused by pathogenic variants in KIF5A (encoding kinesin 5A), is probably the second most common cause of early-onset AD HSP. Axonal motor neuropathy is common [Reid et al 2002].

SPG42 (OMIM 612539), caused by pathogenic variants in SLC33A1 (encoding acetyl-coenzyme A transporter 1), may also start in the first decade of life and has a mild, minimally progressive clinical course. Pes cavus and distal amyotrophy are common [Lin et al 2008]. This form of HSP has been reported in a single family.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 3A (SPG3A), the following evaluations may be indicated:

  • Orthopedic evaluation in persons with early onset of SPG3A who have developed musculoskeletal complications including scoliosis or foot deformities
  • Physical and occupational therapy evaluation in children with early onset of disease
  • Urologic evaluation in persons with prominent urinary bladder hyperactivity
  • Electromyography and nerve conduction studies in persons with associated axonal neuropathy or neurogenic pain in the lower extremities caused by possible lumbo-sacral radiculopathy secondary to lumbar hyperlordosis and degenerative vertebral changes
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Therapy for spasticity, distal weakness, and urinary bladder dysfunction, the primary manifestations of SPG3A, is symptomatic.

Spasticity can be treated with:

  • Oral baclofen or tizanidine
  • Chemodenervation with botulinum A or B toxins; may be tried in those who do not tolerate oral antispasticity medications
  • Intrathecal baclofen pump; a good alternative for patients who improve on oral baclofen but cannot tolerate a therapeutic dose because of systemic adverse effects

Each of the above therapies should be combined with intensive physical therapy focused on stretching and strengthening exercises.

The role of surgical therapy for spasticity (including hamstring and heel cord lengthening and release of the adductor longus) remains unknown, but such treatment should be considered if contractures appear. See also Prevention of Secondary Complications.

Distal weakness, typically affecting foot dorsiflexion, can be ameliorated by ankle-foot orthoses; referral to orthotic services may be helpful.

Urinary urgency can be treated with anticholinergic antispasmodic drugs.

Prevention of Secondary Complications

Musculoskeletal abnormalities including muscle tendon contractures, scoliosis, and foot deformities are the secondary complications most likely to occur, resulting from long-standing spasticity and weakness. Intense and regular therapy for spasticity, including physiotherapy, can delay and minimize the appearance of these complications. The higher incidence of orthopedic problems in patients with SPG3A may be related to early age of onset and these patients should be followed by an orthopedist if problems are present.

Urinary bladder incontinence can be a secondary complication of a neurogenic bladder and urologic care may be needed.

Patients with advanced disease may experience falls with a risk of traumatic injury. A walking aid (cane, walker, or wheelchair) may need to be considered in patients experiencing falls.


There is no consensus regarding the frequency of clinical follow-up visits, but every person with HSP should be reevaluated once or twice a year to identify new complications early and to initiate aggressive therapy as indicated.

Agents/Circumstances to Avoid

Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.

Evaluation of Relatives at Risk

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

Pregnancy Management

The use of regional anesthesia, such as spinal or epidural anesthesia, during delivery in affected women with spinal cord involvement has traditionally been avoided due to the theoretic risk of exacerbating the degree of weakness and spasticity. However, several cases of successful regional anesthesia in affected individuals with hereditary spastic paraplegia have been reported [Thomas et al 2006].

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.

Genetic Counseling

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

Mode of Inheritance

Spastic paraplegia 3A (SPG3A) is typically inherited in an autosomal dominant manner.

Recently, a family with SPG3A with presumed autosomal recessive inheritance was reported by Khan et al [2014]. Such inheritance is extremely rare and as yet unconfirmed.

Risk to Family Members

Parents of a proband

  • Most individuals (>95%) diagnosed with spastic paraplegia 3A have an affected parent.
  • A proband with SPG 3A may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is currently unknown.
  • If the ATL1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include a comprehensive neurologic examination.
  • The family history of some individuals diagnosed with SPG3A may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected and/or has an ATL1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (< 5%).
  • The sibs of a proband with clinically unaffected parents are still at increased risk for spastic paraplegia 3A because of the possibility of reduced penetrance in a parent.
  • If the ATL1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with spastic paraplegia 3A has a 50% chance of inheriting the ATL1 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 an ATL1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with SPG3A is possible after molecular genetic testing has identified the specific pathogenic variant in the family. Such testing should be performed in the context of formal genetic counseling and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of SPG3A regardless of age.

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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with SPG3A has the ATL1 pathogenic variant, the ATL1 variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk 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 ATL1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for SPGA are possible.

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 rather than early diagnosis. While decisions regarding prenatal testing are 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.

  • HSP Research Foundation
    P.O. Box 4064
    Warrimoo New South Wales NSW 2774
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Spastic Paraplegia Foundation, Inc.
    7700 Leesburg Pike
    Ste 123
    Falls Church VA 22043
    Phone: 877-773-4483 (toll-free)

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 3A: Genes and Databases

Locus NameGeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SPG3AATL114q22​.1Atlastin-1HSP mutation database (ATL1)
ATL1 homepage - Leiden Muscular Dystrophy pages

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 3A (View All in OMIM)

606439ATLASTIN GTPase 1; ATL1

Gene structure. ATL1 is 73 kb in length and spans from nucleotide position 51,026,743 to 51,099,782. Transcript variants encoding two different isoforms with 13 or 14 transcribed exons have been found for this gene. Complementary DNA length varies from 2,74 bp to 2,812 bp for different variants. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Both synonymous and nonsynonymous single polymorphisms (benign variants) have been identified (see Table 2).

Table 2.

Selected ATL1 Benign Variants

DNA Nucleotide ChangeReference SNP NumberPredicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the author. 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.

NA = not applicable

Pathogenic variants. Most pathogenic variants in ATL1 are unique and no obvious hot spots for recurrent variants have been identified [Dürr et al 2004]. One genomic deletion of exon 4 has been reported [Sulek et al 2013].

Table 3.

Selected ATL1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
Reference Sequences
c.1243C>Tp.Arg415Trp 2NM_015915​.3

Note on variant classification: Variants listed in the table have been provided by the author. 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


Normal gene product. ATL1 encodes a 558-amino acid protein named atlastin-1 belonging to the subclass of GTPases called dynamins. Dynamins play a role in vesicle transport, especially in the process of recycling of the vesicles. The protein has two transmembrane domains and also contains the GTP binding domain with a catalytic activity [Zhu et al 2003]. Atlastin-1 is predominantly expressed in the pyramidal neurons giving the origin to the pyramidal tracts, which undergo axonal degeneration in patients with HSP. It localizes predominantly to the endoplasmatic reticulum (ER) and Golgi complex but is also found in other subcellular compartments, including the axonal growth cones [Zhu et al 2003, Zhu et al 2006]. Atlastin-1 plays an important role in the formation of the tubular ER network, where it may coordinate the interaction between microtubules and the tubular ER network [Hu et al 2009, Park et al 2010]. Atlastin-1 also interacts with spastin, which causes the most common form of AD HSP and is known to function as a microtubule-severing protein [Sanderson et al 2006].

Abnormal gene product. Most disease-causing missense variants in ATL1 are clustered around the GTPase domain, resulting in reduction of catalytic activity. However, it is still not clear whether SPG3A results from a loss of atlastin-1 function: a dominant-negative effect of mutated protein forms on a wild type of atlastin-1 has also been suggested. Atlastin-1 forms tetrameric complexes and heterocomplexes of wild type and mutated atlastin-1 molecules may inactivate the normal function of wild type atlastin-1, consistent with a dominant-negative effect [Zhu et al 2003]. Expression of pathogenic variants of atlastin-1 results in abnormal connectivity of ER complex and these ER-shaping defects may represent a novel neuropathogenic mechanism [Hu et al 2009]. Additionally, atlastin-1 appears to be enriched in neuronal growth cones, and knockdown of atlastin-1 expression was found to impair axonal elongation [Zhu et al 2006].


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 11-5-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 11-5-18.

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  • Bien-Willner R, Sambuughin N, Holley H, Bodensteiner J, Sivakumar K. Childhood-onset spastic paraplegia with NIPA1 gene mutation. J Child Neurol. 2006;21:974–7. [PubMed: 17092466]
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Chapter Notes

Author Notes

Author's web page


P Hedera is supported by NIH (NINDS) grant K02NS057666

Revision History

  • 11 December 2014 (me) Comprehensive update posted live
  • 9 February 2012 (cd) Revision: single-exon deletion in ATL1 found to cause SPG3A [Sulek et al 2013]; HSN ID identified as allelic disorder
  • 21 September 2010 (me) Review posted live
  • 26 April 2010 (ph) Original submission
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