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Spastic Paraplegia 7

Synonym: Hereditary Spastic Paraplegia, Paraplegin Type

, PhD and , MD.

Author Information
, PhD
San Raffaele Scientific Institute and Vita-Salute San Raffaele University
Milan, Italy
, MD
Department of Neuroscience
Ospedale Misericordia
Grosseto, Italy

Initial Posting: ; Last Update: December 23, 2010.

Summary

Disease characteristics. 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 is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years. Additional features such as hyperreflexia in the arms, sphincter disturbances, spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, and amyotrophy may be observed.

Diagnosis/testing. The diagnosis of SPG7 is suspected in individuals with characteristic neurologic findings and is confirmed by detection of disease-causing mutations in SPG7, the gene encoding the protein paraplegin. SPG7 is the only gene in which mutations are known to cause SPG7.

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 helps 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 and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing alleles have been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of spastic paraplegia 7 (SPG7) is suspected in the presence of the following:

  • Insidiously progressive bilateral leg weakness
  • Spasticity
  • Decreased vibratory sense caused by degeneration of cortical spinal axons and dorsal columns
  • Neurologic examination demonstrating:
  • Family history consistent with autosomal recessive inheritance

The diagnosis is confirmed by detection of disease-causing mutations in SPG7.

Testing

Neuroimaging

Other investigations

Molecular Genetic Testing

Gene. SPG7, which encodes the protein paraplegin, is the only gene in which mutations are known to cause spastic paraplegia 7 (SPG7) [Casari et al 1998].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Spastic Paraplegia 7

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
SPG7Sequence analysisSequence variants 2100% 3
Deletion / duplication analysis 4Deletions, including the 9.5-kb deletion 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. The disease is defined by presence of an SPG7 mutation; therefore, the mutation detection rate is by definition 100%.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

5. See Table 4 (pdf).

Table 3 (pdf) shows PCR primers that can be used for molecular diagnosis.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband requires molecular genetic testing to identify SPG7 disease-causing mutations.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutations in the family.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk to develop the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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 is mostly in adulthood, 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].

Additional features such as hyperreflexia in the arms, sphincter disturbances, spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, and amyotrophy may be observed [Harding 1983, De Michele et al 1998, Fink 2003, Wilkinson et al 2004, Elleuch et al 2006, Brugman et al 2008, Salinas et al 2008, Warnecke et al 2010].

Progression of disease may be rapid with severe disability after eight years' duration [Elleuch et al 2006, Schüle et al 2006].

Serum creatine kinase activity may be slightly above the normal range in some cases.

Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.

Muscle biopsy may shed light on the pathogenic process and reveal 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 (SDH) and negative for cytochrome c oxidase (COX, the complex IV of the mitochondrial respiratory chain), indicating an oxidative phosphorylation (OXPHOS) 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 2-6:100,000 for most countries.

Autosomal recessive inheritance appears relatively uncommon outside regions with a high rate of consanguineous marriages. Of note, a significant proportion of individuals with autosomal recessive SPG7 may present as simplex cases (i.e., a single occurrence in a family).

SPG7 is estimated to account for 5%-12% of autosomal recessive HSP [McDermott et al 2001; Elleuch et al 2006, Brugman et al 2008; Salinas et al 2008; Casari, personal observation].

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 mutations are a frequent cause of spastic paraplegia in individuals representing simplex cases (i.e., a single occurrence in a family) with adult-onset disease who do not have an identifiable SPG4 mutation. They also noted that SPG7 mutations 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:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spastic paraplegia 7 (SPG7), evaluation by a multidisciplinary team that includes a general practitioner, neurologist, medical geneticist, physical therapist, social worker, and psychologist should be considered.

Treatment of Manifestations

No specific drug treatments or cures exist for SPG7.

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 [Young 1994].

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

Occupational therapy is often helpful in managing activities of daily living.

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

In an SPG7 mouse model using intramuscular viral delivery of the gene to correct some of the defects, Pirozzi et al [2006] observed an improvement of neuropathologic changes and mitochondrial morphology, described by Ferreirinha et al [2004], in the peripheral nerves of parapegin-deficient mice. This approach may offer hope for future treatment strategies.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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

  • The parents of an affected child are obligate heterozygotes and, therefore, carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic. A single family in which an SPG7 mutation cosegregates with an HSP phenotype of apparent dominant inheritance has been identified [McDermott et al 2001].

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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with SPG7 are obligate heterozygotes (carriers) for a disease-causing mutation in SPG7.

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

Carrier Detection

Carrier testing for at-risk family members is possible once the SPG7 mutations have been identified in the family.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as SPG7 are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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.
    PO Box 1208
    Fortson GA 31808-1208
    Phone: 877-773-4483 (toll-free)
    Email: information@sp-foundation.org
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.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 7: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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

Normal allelic variants. SPG7 spans a physical distance of approximately 52 kb and is composed of 17 exons (Table 2).

Pathologic allelic variants. All types of DNA alterations are observed in almost every exon or splice site. Missense mutations are the most frequent subgroup. Missense mutations and truncating mutations have been reported within the paraplegin functional domain. See Table 3 (pdf) for primers that can be used in molecular genetic testing [McDermott et al 2001; Casari, unpublished data].

To date, 26 mutations have been confirmed in SPG7 (Table 4 - pdf).

Normal gene product. Paraplegin, comprising 795 amino acids, is in the AAA (ATPases associated with diverse cellular activities) family, as is spastin, encoded by SPAST, mutations in which cause SPG4, an autosomal dominant form of HSP [Hazan et al 1999] (see also Hereditary Spastic Paraplegia Overview). Paraplegin and spastin belong to different subclasses of the AAA family, since mitochondrial function of spastin has been excluded but demonstrated as a function of paraplegin.

Paraplegin is ubiquitously expressed in adult and fetal human tissues and in mouse brain [Sacco et al 2010].

Paraplegin shares its closest amino acid sequence homology with the yeast mitochondrial metalloproteases Afg3, Rca1, and Yme1 [Casari et al 1998, Settasatian et al 1999]. Yeast mitochondrial ATPases demonstrate both proteolytic and chaperone-like activities at the inner mitochondrial membrane, where they are involved in the assembly and degradation of proteins in the respiratory chain complex [Pearce 1999]. Two additional human genes encoding protein highly homologous to paraplegin, AFG3L2 and YME1L1, have been discovered [Banfi et al 1999, Coppola et al 2000]. 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 localized in the central part of paraplegin between amino acid residues 344 and 534.

Abnormal gene product. Atorino et al [2003] demonstrated that paraplegin co-assembles with a homologous protein, AFG3L2, in the mitochondrial inner membrane. The two proteins form a high molecular-weight complex that appears to be aberrant in fibroblasts of individuals affected with HSP. The inactivation of this complex causes reduced complex I activity in mitochondria that can be reversed by increased expression of wild type paraplegin. Furthermore, complementation studies in yeast demonstrate functional conservation of the human paraplegin/AFG3L2 complex with the yeast m-AAA protease and also assign proteolytic activity to this structure.

A study of AFG3L2 found that null or missense Afg3l2 mouse models had marked impairment of axonal development and transport 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 phenotype was reported to be more severe than that seen in paraplegin-deficient mice because of the higher neuronal expression of AFG3L2, but also serves to link mitochondria function with HSP. Despite coassembling in the same complex, mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28) [Di Bella et al 2010].

Biochemical analysis from two SPG7 mutation-positive individuals 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 [Wilkinson et al 2004].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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  31. Warnecke T, Duning T, Schirmacher A, Mohammadi S, Schwindt W, Lohmann H, Dziewas R, Deppe M, Ringelstein EB, Young P. A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects. Mov Disord. 2010;25:413–20. [PubMed: 20108356]
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Suggested Reading

  1. Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G. Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. J Neurosci. 2009;29:9244–54. [PubMed: 19625515]

Chapter Notes

Revision History

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