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Spastic Paraplegia 7

Synonym: Hereditary Spastic Paraplegia, Paraplegin Type

, PhD and , MD.

Author Information

Initial Posting: ; Last Update: October 25, 2018.

Summary

Clinical characteristics.

Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral leg weakness and spasticity. Most affected individuals have decreased vibration sense and cerebellar signs. Onset is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years. Additional features including ataxia (gait and limbs), spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, ptosis, hearing loss, motor and sensory neuropathy, amyotrophy, scoliosis, pes cavus, and urinary sphincter disturbances may be observed.

Diagnosis/testing.

The diagnosis of SPG7 is established in a proband with typical clinical findings and biallelic pathogenic variants in SPG7 identified by molecular genetic testing.

Management.

Treatment of manifestations: Drugs that may reduce spasticity and muscle tightness include baclofen, tizanidine, dantrolene, and diazepam. Physical therapy and assistive walking devices often reduce contractures, provide support, and promote stability. Occupational therapy and speech therapy help with activities of daily living.

Surveillance: Annual neurologic evaluation to identify potential complications of spasticity, such as contractures.

Genetic counseling.

SPG7 is inherited in an autosomal recessive manner. Heterozygotes (carriers) are usually asymptomatic. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal diagnosis for pregnancies at increased risk and preimplantation genetic diagnosis are possible if both pathogenic alleles have been identified in the family.

Diagnosis

Suggestive Findings

Spastic paraplegia 7 (SPG7) should be suspected in individuals with the following:

  • Insidiously progressive bilateral leg weakness
  • Spasticity
  • Decreased vibratory sense
  • Cerebellar signs
  • Neurologic examination demonstrating EITHER of the following:
    • A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
    • A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, and amyotrophy [Brugman et al 2008, Salinas et al 2008, Warnecke et al 2010, Pfeffer et al 2014]
  • Neuroimaging findings of cerebellar atrophy (MRI) or white matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem
  • Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of SPG 7 is established in a proband with typical clinical findings and identification of biallelic pathogenic variants in SPG7 by molecular genetic testing (see Table 1).

Note: A single SPG7 pathogenic variant (p.Leu78*) was identified in a proband with a pure HSP phenotype suggesting that heterozygosity for an SPG7 pathogenic variant may be sufficient to cause disease (i.e., autosomal dominant inheritance). However, this conclusion is challenged by the finding of unaffected p.Leu78* heterozygotes in other families as well as the possibility that the affected heterozygous individual had a second SPG7 pathogenic variant which was not detected due to testing limitations [Sánchez-Ferrero et al 2013].

Because the phenotype of SPG7 is indistinguishable from many other forms of hereditary spastic paraplegia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of SPG7, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

  • A multigene panel that includes SPG7 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
    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 7

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
SPG7Sequence analysis 3>98% 4
Gene-targeted deletion/duplication analysis 5<2% 6
1.
2.

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

3.

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.

4.
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 7 (SPG7) is characterized by insidiously progressive bilateral lower-limb weakness and spasticity. Most affected individuals have proximal or generalized weakness in the legs and impaired vibration sense.

Onset typically occurs in adulthood, around age 30-45 years, although symptoms may start as early as age 11 years and as late as age 72 years [De Michele et al 1998, McDermott et al 2001, Wilkinson et al 2004].

Presentation. The first sign is typically insidiously progressive bilateral leg weakness.

Additional features. Other signs and symptoms can be observed [Brugman et al 2008, Salinas et al 2008, Warnecke et al 2010, Almontashiri et al 2014, Pfeffer et al 2014] including the following:

  • Cerebellar and motor signs
    • Ataxia (gait and limbs)
    • Spastic dysarthria
    • Dysphagia
  • Ophthalmic findings
    • Pale optic disks
    • Nystagmus
    • Strabismus
    • Ptosis
  • Hearing loss of conductive/neurosensory /mixed type
  • Peripheral neuromuscular findings
    • Motor and sensory neuropathy
    • Amyotrophy
  • Orthopedic issues
    • Scoliosis
    • Pes cavus
  • Urinary sphincter disturbances

Progression. Severe disability of gait due to leg spasticity may develop as soon as eight years after onset of symptoms, and some individuals are confined to a wheelchair [Elleuch et al 2006, Schüle et al 2006].

Findings on Neuroimaging and Other Investigations

Neuroimaging

  • In a few individuals, conventional cerebral MRI may show cerebellar (or, less frequently, cortical) atrophy [Salinas et al 2008, Hourani et al 2009, Warnecke et al 2010].
  • White matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem are specific to SPG7.
  • Spinal imaging studies are useful in the differential diagnosis to exclude other anomalies of the pontomedullary junction and of the cervical and dorsolumbar medulla.

Other investigations

  • Spinal evoked potentials may reveal delayed prolongation of the central conduction time [Nielsen et al 2001].
  • Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.
  • Paired transcranial magnetic stimulation may show delayed prolongation of the central motor conduction time and motor threshold in some affected individuals in lower limb muscles [Warnecke et al 2010]. Intracortical inhibition appears normal in SPG7 [Nardone & Tezzon 2003].
  • Optical coherence tomography is useful for detecting subclinical optic neuropathy [Klebe et al 2012].
  • A battery of neuropsychological tests may reveal mild impairment of visuoconstructive and executive functions in some individuals [Warnecke et al 2010].
  • Serum creatine kinase activity may be slightly above the normal range in some cases.
  • Muscle biopsy has revealed the following:
    • Changes of denervation with partial reinnervation
    • Atrophic, angulated fibers, predominantly type II
    • Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome c oxidase (COX, the complex IV of the mitochondrial respiratory chain), indicating an oxidative phosphorylation defect [Casari et al 1998, McDermott et al 2001, Wilkinson et al 2004, Tzoulis et al 2008].

Genotype-Phenotype Correlations

No genotype-phenotype correlations can be proposed based on published studies.

Prevalence

The prevalence of SPG7 is estimated at between 1:100,000 and 9:100,000 for most countries (www.orpha.net).

Differential Diagnosis

No significant differences exist between spastic paraplegia 7 (SPG7) and other types of pure autosomal dominant and autosomal recessive spastic paraplegia [Fink 2002, Fink 2003, Salinas et al 2008] (see Hereditary Spastic Paraplegia Overview for a review). However, Brugman et al [2008] reported that SPG7 pathogenic variants are less likely to be found in adult-onset cases in which upper motor neuron symptoms (UMN) are present in the arms and in adult-onset cases with UMN symptoms involving the bulbar region.

Other conditions that need to be considered in the differential diagnosis of SPG7 are summarized in Table 2.

Table 2.

Other Disorders to Consider in the Differential Diagnosis of SPG7

DisorderGene(s)MOIClinical Features of This Disorder
Overlapping w/SPG7Distinguishing from SPG7
Adrenomyeloneuropathy
and other leukodystrophies
(e.g., Krabbe disease,
arylsulfatase A deficiency
[metachromatic
leukodystrophy])
ABCD1
GALC
ARSA
XL
AR
Paraplegia neuropathy
  • Dementia
  • On MRI: leukodystrophy, adrenal dysfunction, long-chain fatty acid accumulation
Spinocerebellar ataxia type 28AFG3L2AD
  • Paraplegia
  • Ataxia
Rare dystonia or parkinsonism
Dopa-responsive dystoniaGCH1AD
  • Brisk reflexes
  • Spasticity
  • Extensor plantar responses
  • Young-onset dystonia parkinsonism responsive to levodopa
  • Diurnal variation
Amyotrophic lateral sclerosisSee footnote 1AD
AR
XL
SpasticityMuscle atrophy, weakness & fasciculations
Primary lateral sclerosis 2UnknownN/ASpasticitySurvival 15-20 years
Arginase deficiencyARG1ARSpasticity
  • Epileptic seizures
  • Severe mental retardation
  • Elevated plasma arginine
  • Hyperammonemia
Structural abnormalities of the brain or spinal cordN/AN/AGait difficultiesOn MRI: spine abnormalities
Vitamin B12 deficiencyN/AN/AUnsteady gait
  • Subacute combined degeneration
  • Improvement after vitamin B12 supplementation
Primary progressive multiple sclerosisN/AN/ASpasticity
  • MRI white matter changes
  • Oligoclonal IgG bands
  • Elevated IgG index
Progressive external ophthalmoplegiaVariousAR
AD
Eyelid ptosis
  • External ophthalmoplegia
  • Proximal myopathy
  • No pyramidal signs
Tropical spastic paraplegia (caused by HTLV1 infection)N/AN/AParaplegiaHTLV-1 serology
Optic neuropathyKLC2 3
MFN2 4
AR
AD
Pale optic disksNo pyramidal signs

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 7 (SPG7), the following evaluations are recommended if they have not already been completed:

  • Ophthalmologic evaluation
  • Hearing testing
  • Urologic evaluation in case of bladder dysfunction
  • Consultation with a clinical geneticist and/or genetic counselor

Evaluation by a multidisciplinary team that includes a general practitioner, neurologist, physical therapist, social worker, and psychologist should be considered.

Neuropsychological testing may be suggested.

Treatment of Manifestations

No specific drug treatments or cures for SPG7 exist.

Drugs to reduce spasticity and muscle tightness include baclofen, tizanidine, dantrolene, and diazepam – preferably administered one at a time.

Management of spasticity by intrathecal baclofen or intramuscular botulinum toxin injections may be an option in selected individuals [Kawano et al 2018].

A combination of physical therapy and assistive walking devices are often used to reduce contractures, provide support, and promote stability.

Occupational therapy and speech therapy are often helpful in managing activities of daily living.

Prevention of Secondary Complications

Because individuals with advanced disease are bedridden they are at major risk of aspiration pneumonia, urinary tract infections and pulmonary embolism; careful monitoring is recommended to help avoid these complications.

Surveillance

Annual neurologic evaluation can help identify potential complications of spasticity that develop over time (e.g., contractures).

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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 7 (SPG7) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and typically are not at risk of developing the disorder (see Parents of a proband).

Offspring of a proband. The offspring of an individual with SPG7 are obligate heterozygotes (carriers) for a pathogenic variant in SPG7.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SPG7 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SPG7 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being carriers.

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 SPG7 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for SPG7 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 most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • 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
  • A.I. Vi.P.S.
    Associazione Italiana Vivere la Paraparesi Spastica Onlus
    Via Tevere, 7
    20020 Lainate (MI)
    Italy
    Phone: 39 392 9825622
    Email: nfo@vipsonlus.it
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Tom Wahlig-Foundation
    Tom Wahlig Stiftung
    Büro Veghestrasse 22
    Germany
    Phone: 49 (0) 251 - 20 07 91 20
    Email: nfo@hsp-info.de

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 7: 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 7 (View All in OMIM)

602783SPG7 GENE; SPG7
607259SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE; SPG7

Gene structure. SPG7 spans a physical distance of approximately 52 kb and comprises 17 exons. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Pathogenic missense, nonsense, frameshift, and splice site variants have been observed throughout SPG7. Missense variants occur most frequently. Missense and truncating variants, such as c.1454_1462del9 (reported as c.1450_1458del9 [McDermott et al 2001]), deletion of 9.5 kb [Casari et al 1998] and 2228insA [Casari et al 1998] have been reported to delete main protein functional domains.

Twenty-seven pathogenic variants have been reported in SPG7 [Casari et al 1998, Arnoldi et al 2008, Brugman et al 2008, Klebe et al 2012, van Gassen et al 2012, Sánchez-Ferrero et al 2013, Pfeffer et al 2015]. The SPG7 c.1529C>T (p.Ala510Val) variant is the most frequent variant found across populations [Sánchez-Ferrero et al 2013, Pfeffer et al 2015, Choquet et al 2016]. Although this variant and most others identified have been associated with an ataxic phenotype, recent efforts have focused on associating SPG7 variants with additional clinical features. Recent studies suggest that cerebellar ataxia is a frequent feature among individuals with SPG7-related disease [Pfeffer et al 2015, Synofzik & Schule 2017]. The ataxic syndrome could even be a predominant feature over spasticity, as observed in a Japanese family segregating p.Arg398Ter [Yahikozawa et al 2015].

Table 3.

SPG7 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias) 1
Predicted Protein ChangeReference Sequences
del9.5 kb--NM_003119​.3
NP_003110​.1
c.1053dupC--
c.1192C>Tp.Arg398Ter
c.1454_1462del9p.Arg485_Glu487del
c.1529C>Tp.Ala510Val
c.2102A>Cp.His701Pro
c.2216insA
(2228insA 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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Normal gene product. Paraplegin is a mitochondrial inner membrane protein that exerts protein quality control in a high molecular complex with AFG3L2. Both paraplegin and AFG3L2 belong to the AAA protein family (ATPases associated with diverse cellular activities) (see also Hereditary Spastic Paraplegia Overview). Paraplegin and AFG3L2 coassemble in the mitochondrial inner membrane, forming a high molecular-weight complex [Atorino et al 2003]. Paraplegin is ubiquitously expressed in adult and fetal human tissues. The presence of two hydrophobic regions, which have the characteristics of transmembrane domains, allows identification of both paraplegin and AFG3L2 as integral membrane proteins. The AAA domain is in the central part of paraplegin between amino acid residues 344 and 534, while a coil-coil domain in the carboxy-terminal part of the molecule promotes assembly in the hexameric complex. In order to achieve maturation, paraplegin undergoes several cleavages upon its import in the mitochondria inner membrane by the mitochondrial processing peptidase and by the m-AAA protease complex itself [Koppen et al 2009]. Thus, the final processing of paraplegin in a mature form depends on its coassembly with AFG3L2 and, as recently demonstrated, the un-phosphorylation of AFG3L2 in position p.Tyr179 [Almontashiri et al 2014].

In a recent paper paraplegin was identified as a molecular component/regulator of the mitochondrial permeability transition pore [Shanmughapriya et al 2015]; however another study demonstrated conflicting results [König et al 2016].

Abnormal gene product. Inactivation of the paraplegin-AFG3L2 complex causes reduced complex I activity in mitochondria. Loss of AFG3L2 function is associated with autosomal recessive spastic ataxia 5 and spinocerebellar ataxia 28 (see Differential Diagnosis).

Biochemical analysis from two individuals with confirmed SPG7 pathogenic variants revealed a reduction in citrate synthase-corrected complex I and complex II/III activities in muscle and complex I activity in mitochondrial-enriched fractions from cultured myoblasts. Mitochondrial DNA damage has been observed in muscle biopsies of affected individuals with SPG7 variants c.2102A>C and c.1053dupC [Tzoulis et al 2008, Wedding et al 2014]. Further studies should clarify how paraplegin can alter mitochondrial DNA; however, this could be an indirect effect of the dysfunction of the mAAA-protease complex, as paraplegin does not interact directly with the DNA.

In mouse, AFG3L2 homozygous pathogenic variants appear more severe than paraplegin variants; null or missense Afg3l2 mouse models developed marked impairment of axonal development leading to neonatal death [Maltecca et al 2008]. The mice developed a severe early-onset tetraparesis and were found to have reduced myelinated fibers in the spinal cord and impaired respiratory chain complex I and III activity. The increased severity of the phenotype is explained by the higher neuronal expression of AFG3L2, but also the ability of AFG3L2 to form homocomplexes, while paraplegin requires coassembly with AFG3L2 to form functional complexes. Heterozygous pathogenic variants of AFG3L2 have been associated with a dominant form of spinocerebellar ataxia (SCA28) [Di Bella et al 2010].

Gene expression regulation. SPG7 is one of the targets of miR-224, which is located in an intron of the GABA A receptor ε subunit (GABRE) and produced in several models of cancer proliferation [Fu et al 2016].

References

Literature Cited

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Chapter Notes

Revision History

  • 25 October 2018 (ha) Comprehensive update posted live
  • 23 December 2010 (me) Comprehensive update posted live
  • 25 February 2008 (cd) Revision: deletion/duplication analysis available clinically
  • 24 August 2006 (me) Review posted live
  • 7 March 2005 (gc) Original submission
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