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Spastic Paraplegia 3A

Synonyms: ATL1-HSP, SPG3A

, MD, PhD.

Author Information

Initial Posting: ; Last Update: June 18, 2020.

Estimated reading time: 21 minutes

Summary

Clinical characteristics.

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in all affected individuals, these findings occur in a minority of individuals with SPG3A. 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 ATL1-HSP 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 ATL1-HSP is slow, and wheelchair dependency or need for a walking aid (cane, walker, or wheelchair) is relatively rare.

Diagnosis/testing.

The diagnosis of ATL1-HSP is established in a proband with suggestive findings and almost exclusively a heterozygous pathogenic variant in ATL1 identified by molecular genetic testing. Note: The exceptions are two families with biallelic ATL1 pathogenic variants.

Management.

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 that may help delay or minimize muscle tendon contractures, scoliosis, and foot deformities. Distal weakness (typically affecting foot dorsiflexion) can be ameliorated by ankle-foot orthoses. Urinary urgency can be treated with anticholinergic antispasmodic drugs.

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.

ATL1-HSP is almost exclusively inherited in an autosomal dominant manner. More than 95% of individuals diagnosed with SPG3A have an affected parent; the proportion of individuals with ATL1-HSP caused by a de novo pathogenic variant is currently unknown. Each child of an individual with ATL1-HSP has a 50% chance of inheriting the pathogenic variant. Once the ATL1 pathogenic variant has been identified in a family member with autosomal dominant ATL1-HSP, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) should be suspected in individuals with the following clinical findings and family history.

Clinical findings

  • Early age of onset, from infancy to ten years (average age: 4 years)
  • Progressive bilateral and mostly symmetric lower-extremity weakness and spasticity resulting from axonal degeneration of the corticospinal tracts
  • Diminished vibration sense caused by impairment of dorsal columns
  • Urinary bladder hyperactivity

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

Establishing the Diagnosis

The diagnosis of ATL1-HSP is established in a proband with suggestive findings and almost exclusively a heterozygous pathogenic variant in ATL1 identified by molecular genetic testing (see Table 1). Note: The exceptions are two families with biallelic ATL1 pathogenic variants.

Note: Identification of a heterozygous ATL1 variant of uncertain significance does not establish or rule out a diagnosis of ATL1-HSP.

Molecular genetic testing approaches can include a combination of gene-targeted 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. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ATL1-HSP has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

A hereditary spastic paraplegia (HSP)multigene panel that includes ATL1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensivegenomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

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

Table 1.

Molecular Genetic Testing Used in Spastic Paraplegia 3A

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
ATL1 Sequence analysis 3~99% 4
Gene-targeted deletion/duplication analysis 5One reported 4, 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Dürr et al [2004], Ivanova et al [2007], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Clinical Characteristics

Clinical Description

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by slowly progressive bilateral and mostly symmetric spasticity and weakness of the legs, and with a variable degree of 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 affected individuals manifest spastic gait before age ten years. The rate of progression is slow; wheelchair dependency or need for an assistive walking device is relatively rare.

Most persons with early-onset ATL1-HSP have a "pure" or "uncomplicated" hereditary spastic paraplegia (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]. In complicated forms with spastic quadriparesis, involvement of bulbar muscles can result in dysphagia and dysarthria [Yonekawa et al 2014].

Findings also seen in ATL1-HSP can include pes cavus deformities and scoliosis, possibly attributable to the early age of onset.

Other phenotypes observed in the spectrum of ATL1-HSP include the following:

  • Adult-onset ATL1-HSP. Although it has been suggested that ATL1-HSP is a neurodevelopmental rather than a neurodegenerative disorder, identification of individuals with adult-onset ATL1-HSP argues strongly against this hypothesis [Sauter et al 2004, Zhu et al 2006]. Persons with adult-onset ATL1-HSP also tend to experience slower disease progression.
  • Hereditary sensory neuropathy type ID (HSN1D), an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. A pathogenic ATL1 missense variant was identified in a single family with HSN1D, in whom other known causative genes had been excluded [Guelly et al 2011, Leonardis et al 2012]. Two additional ATL1 variants were identified in 115 unrelated individuals with the HSN1D phenotype [Guelly et al 2011].
  • Clinical presentation with a pure autonomic failure followed by the development of spastic paraplegia was reported in one individual with a novel pathogenic ATL1 splice site variant in exon 2 [Shin et al 2014]. Whether this represents an allelic condition or an atypical presentation of ATL1-HSP remains to be elucidated.
  • Clinical presentation mimicking a severe neonatal-onset cerebral palsy with quadriparesis was reported in an individual with a de novo ATL1 pathogenic variant [Yonekawa et al 2014]. The individual also experienced abnormal speech and swallowing with pseudobulbar palsy. Electrophysiologic studies showed axonal polyneuropathy.

Findings not universally seen in ATL1-HSP compared to other forms of autosomal dominant HSP include the following [Dürr et al 2004]:

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

Genotype-Phenotype Correlations

No specific genotype-phenotype correlations have been reported; however:

  • Early-onset disease has been associated with missense variants around the GTPase binding domain.
  • Late-onset disease has been associated with frameshift variants in the C terminus that result in premature truncation of the protein, as well as some missense variants in the GTPase binding domain [Tessa et al 2002, Sauter et al 2004].

Penetrance

Overall, penetrance of pathogenic variants is high (~80%-90%) [Dürr et al 2004]. In many familial cases, individuals with a heterozygous 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 heterozygous pathogenic variant detected in three affected individuals but also in nine unaffected family members [D'Amico et al 2004]. Reduced penetrance of this variant was also observed in additional families in which mostly females were unaffected, suggesting (incorrectly) X-linked inheritance [Varga et al 2013].

Prevalence

Prevalence of autosomal dominant (AD) HSP has been estimated at 0.5-5:100,000 [McMonagle et al 2002, Ruano et al 2014].

SPG3A is the third most common cause of AD HSP in all age groups. Metanalysis of epidemiologic studies suggested that SPG3A accounts for about 5% of all AD HSP, with an estimated prevalence of 0.025-0.25:100,000 [Erfanian Omidvar et al 2019]. This estimated frequency of SPG3A is lower than previously reported, at 10%-15% of all AD HSP [Fink et al 1996].

SPG3A, the most common cause of early onset of AD HSP before age ten years, accounts for 40% of AD HSP in this age group [Dürr et al 2004].

Differential Diagnosis

Hereditary spastic paraplegia (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 autosomal dominant (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.

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].

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) accounts for approximately 5% of all AD HSP [Erfanian Omidvar et al 2019], which is lower than previous estimates of 10%-15% [Fink et al 1996]. In an analysis of a large cohort of individuals in whom a SPAST (formerly known as SPG4) pathogenic variant was not identified, 40% had pathogenic variants in ATL1 [Dürr et al 2004].

ATL1-HSP needs to be differentiated from other forms of AD HSP (see Table 2).

Table 2.

Autosomal Dominant Hereditary Spastic Paraplegias of Interest in the Differential Diagnosis of Spastic Paraplegia 3A

GeneDisorderClinical Features of Differential Diagnosis Disorder 1
KIF5A SPG10
  • Axonal motor neuropathy common 2
  • Probably 2nd most common cause of early-onset AD HSP
NIPA1 SPG6
  • Occasionally manifests in infancy 3
  • Probably most aggressive form of AD HSP
  • → wheelchair dependency in a relatively short period of time
REEP2 SPG72
  • Early age of onset (age <4 yrs)
  • Mild postural tremor common 4
SLC33A1 SPG42
  • May have onset in 1st decade
  • Mild, minimally progressive clinical course
  • Pes cavus & distal amyotrophy common 5
  • Reported in a single family
SPAST SPG4
  • Occasionally presents in infancy
  • Tends to have more progressive course 4
  • Most common type of AD HSP
RTN2 SPG12
  • Usual onset age <10 yrs 6
  • Uncomplicated phenotype

Cerebral palsy. Additional considerations for ATL1-HSP include a diplegic or quadriplegic form of cerebral palsy, as the majority of such individuals tend to have very early onset of clinical manifestations and a slow progression, which may suggest a static clinical course [Rainier et al 2006, Yonekawa et al 2014, Andersen et al 2016]. 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 ATL1 pathogenic variant (i.e., an apparently negative family history) 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 ATL1-HSP.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 3A (SPG3A; also known as ATL1-HSP), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 3A

System/ConcernEvaluationComment
Spasticity Neurologic examAssess degree of spasticity. 1
Motor & sensory
neuropathy
NCV, EMG
Musculoskeletal Physical medicine & rehabilitation / PT evalTo include assessment of:
  • Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
  • Need for adaptive devices
  • Footwear needs
  • Physical therapy needs
OrthopedicsTo assess for scoliosis, foot deformities
OT
  • To assess small motor function, e.g., hands, feet, face, fingers, & toes
  • To assess ADLs
Bladder function Referral to urologist; consider urodynamic eval.To address spastic bladder symptoms: urgency, frequency, difficulty voiding
Bowel function Referral to gastroenterologistTo assess constipation & fecal incontinence 1
Bulbar muscle
weakness
Assessment by speech/language pathologist
  • Speech disorder (dysarthria)
  • Swallowing disorder (dysphagia)
Genetic counseling By genetics professionals 2To inform affected persons & their families re nature, MOI, & implications of ATL1-HSP to facilitate medical & personal decision making
Family support/
resources
Assess:

Based on information provided by Spastic Paraplegia Foundation

ADLs = activities of daily living; EMG = electromyography; NCV = nerve conduction velocity; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Spastic Paraplegia Rating Scale (SPRS) [Schüle et al 2006]

2.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

Treatment for spasticity, distal weakness, and urinary bladder dysfunction (the primary manifestations of ATL1-HSP) is symptomatic. See Table 4.

Management by multidisciplinary specialists including a physiatrist, physical therapist, and speech therapist is recommended.

Table 4.

Treatment of Manifestations in Individuals with Spastic Paraplegia 3A

Manifestation/ConcernTreatmentConsiderations/Other
Spasticity /
Distal weakness
Individualized PT program
  • Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures 1
  • Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance
  • Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADLs
Reduction of spasticity
  • Massage, ultrasound, electrical stimulation, whirlpool
  • Anodal spinal direct current stimulation 2
Antispasmodic drugsBaclofen, botulinum toxin, dantrolene, tizanidine (used 1 at a time), 3 especially early in disease course to ↓ cramps, make leg muscles less tight, & facilitate walking
Musculoskeletal Correction & stabilization of scoliosisOrthopedic consult for management of scoliosis: bracing, possible spinal surgery
Correction of pes cavusPhysical therapy for pes cavus, orthotics, botulinum toxin therapy, possible corrective surgery by orthopedic surgery
Bladder dysfunction Spastic bladder symptoms: urgency, frequency, difficulty voiding, incontinenceTreatment can incl anticholinergics such as oxybutynin (Ditropan XL®), solifenacin (Vesicare®), and mirabegron (Myrbetriq®).
Dysphagia Gastroenterologist / nutrition / feeding team eval
  • Determine exact cause of swallowing malfunction.
  • Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
Dysarthria Speech/language pathologistTo help maintain vocal control, improve speech, breathing techniques, & communication in general
Bowel function Symptoms: constipation & fecal incontinenceStool softeners
Mobility & ADLs PT
  • Feet: appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
  • Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
  • Transfers (e.g., from bed to wheelchair, wheelchair to car)
  • Training how to fall to minimize risk of injury
OT
  • To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
  • To assist w/household modifications to meet special needs
Social support Social services & support groupsTo help cope w/diagnosis

ADLs = activities of daily living; PT = physical therapy/therapist; OT = occupational therapy/therapist

1.

The role of surgical hamstring and heel cord lengthening and release of the adductor longus remains unknown, but should be considered if contractures appear.

2.

Demonstrated by Ardolino et al [2018] in a randomized controlled trial

3.

Baclofen can be tried first, and can be used with an intrathecal pump in some cases. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic, otherwise three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.

Surveillance

There is no consensus regarding the frequency of clinical follow-up visits, but routine reevaluations are warranted (see Table 5).

Table 5.

Recommended Surveillance for Individuals with Spastic Paraplegia 3A

System/ConcernEvaluationFrequency
Spasticity Neurologic exam re disease progression & response to current treatment1-2x/yr
Bladder function Per treating urologist, including monitoring for urinary tract infection
Dysphagia Gastroenterologist / nutrition / feeding team re nutrition & risk for aspiration
Dysarthria Per neurologic assessment & speech/language assessment
Scoliosis General medical exam of musculoskeletal system
Bowel function Per symptoms
Mobility & ADLs Rehabilitation medicine, PT, & OT

ADLs = activities of daily living; PT = physical therapist; OT = occupational therapist

Agents/Circumstances to Avoid

Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely affect 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 women with ATL1-HSP and spinal cord involvement has traditionally been avoided due to the theoretic risk of exacerbating the degree of weakness and spasticity. However, several instances of successful regional anesthesia in individuals with hereditary spastic paraplegia have been reported [Thomas et al 2006, Ponsonnard et al 2017].

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. 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is almost exclusively inherited in an autosomal dominant manner.

Autosomal recessive inheritance of ATL1-HSP has been reported in two families [Khan et al 2014, Willkomm et al 2016]. For information about genetic counseling issues related to autosomal recessive inheritance, see Hereditary Spastic Paraplegia Overview.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals (>95%) diagnosed with ATL1-HSP have an affected parent.
  • A proband with ATL1-HSP may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals diagnosed with ATL1-HSP as the result of a de novo pathogenic variant is unknown.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant (i.e., a proband who appears to represent a simplex case).
  • 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.
    * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
  • The family history of some individuals diagnosed with ATL1-HSP 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.

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

  • If a parent of the proband is affected and/or is known to have the ATL1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%. A sib who inherits a familial ATL1 pathogenic variant is likely to develop clinical manifestations of the disorder. (Overall penetrance of ATL1 pathogenic variants is high; only three families with incomplete penetrance have been reported in the literature [D'Amico et al 2004, Varga et al 2013].) Intrafamilial variability in SPG3A is less common than in other types of hereditary spastic paraplegia.
  • If the ATL1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the ATL1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low (<5%). However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ATL1-HSP because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant ATL1-HSP 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

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 Testing

Once the ATL1 pathogenic variant has been identified in a family member with autosomal dominant ATL1-HSP, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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

Resources

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
    Australia
  • 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)
    Email: information@sp-foundation.org

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

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)

182600 SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; SPG3A
606439 ATLASTIN GTPase 1; ATL1
613708 NEUROPATHY, HEREDITARY SENSORY, TYPE ID; HSN1D

Molecular Pathogenesis

ATL1 encodes atlastin-1, which belongs to the subclass of GTPases called dynamins. Dynamins play a role in vesicle transport, especially in the process of recycling of the vesicles. Atlastin-1 has two transmembrane domains and a GTP binding domain with 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 individuals with ATL1-HSP. It localizes predominantly to the endoplasmic 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, Hu et al 2009, Park et al 2010].

Atlastin-1 interacts with spastin, encoded by SPAST, in which heterozygous pathogenic variants cause spastic paraplegia 4 (also known as SPAST-HSP), the most common cause of autosomal dominant hereditary spastic paraplegia [Sanderson et al 2006].

Mechanism of disease causation. A gain-of-function or dominant negative mechanism has been proposed based on the following observations:

  • Most disease-causing missense variants cluster around the GTPase domain, resulting in reduction of catalytic activity.
  • Atlastin-1 forms tetrameric complexes; therefore, heterocomplexes of normal and abnormal atlastin-1 may interfere with tetramer activity [Zhu et al 2003].
  • Expression of pathogenic variants of atlastin-1 results in abnormal connectivity of ER complex. These ER-shaping defects may represent a novel neuropathogenic mechanism [Hu et al 2009].
  • Atlastin-1 is expressed in neuronal growth cones. Knockdown of atlastin-1 expression was found to impair axonal elongation [Zhu et al 2006].

Table 6.

Notable ATL1 Pathogenic Variants

Reference
Sequences
DNA Nucleotide
Change (Alias 1)
Predicted
Protein Change
Comment [Reference]
NM_015915​.4
NP_056999​.2
c.470T>Gp.Leu157Trp Rainier et al [2006]
c.715C>T
(884C>T)
p.Arg239CysRecurrent variant, possibly caused by methylated CpG dinucleotide hot spot [Zhao et al 2001]
c.1243C>Tp.Arg415TrpThis variant shows incomplete penetrance [D'Amico et al 2004].

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

References

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 6-8-20.
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 6-8-20.

Literature Cited

  • Abel A, Fonknechten N, Hofer A, Dürr A, Cruaud C, Voit T, Weissenbach J, Brice A, Klimpe S, Auburger G, Hazan J. Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A. Neurogenetics. 2004;5:239–43. [PubMed: 15517445]
  • Andersen EW, Leventer RJ, Reddihough DS, Davis MR, Ryan MM. Cerebral palsy is not a diagnosis: a case report of a novel atlastin-1 mutation. J Paediatr Child Health. 2016;52:669–71. [PubMed: 27333849]
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Chapter Notes

Acknowledgments

P Hedera is supported by NIH (NINDS) grant K02NS057666

Revision History

  • 18 June 2020 (bp) Comprehensive update posted live
  • 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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