Summary
Clinical characteristics.
Spastic paraplegia 11 (SPG11) is characterized by progressive spasticity and weakness of the lower limbs frequently associated with the following: mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs. Less frequent findings include: cerebellar signs (ataxia, nystagmus, saccadic pursuit); retinal degeneration; pes cavus; scoliosis; and parkinsonism with characteristic brain MRI features that include thinning of the corpus callosum. Onset occurs mainly during infancy or adolescence (range: age 1-31 years) and in rare cases as late as age 60 years. Most affected individuals become wheelchair bound one or two decades after disease onset.
Diagnosis/testing.
The diagnosis of SPG11 is established in a proband with characteristic clinical and MRI findings and biallelic pathogenic variants in SPG11 identified on molecular genetic testing.
Management.
Treatment of manifestations: Care by a multidisciplinary team; physiotherapy to stretch spastic muscles; antispastic drugs such as baclofen; botulin toxin and intrathecal baclofen for severe and disabling spasticity when oral drugs are ineffective. Urodynamic evaluation when bladder dysfunction is evident; anticholinergic drugs for urinary urgency. Treatment of psychiatric manifestations by standard protocols.
Prevention of secondary complications: Treatment of sphincter disturbances to prevent urinary tract infection secondary to bladder dysfunction.
Surveillance: Evaluation every six months to adjust physiotherapy and medications.
Genetic counseling.
SPG11 is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for an SPG11 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible once the pathogenic variants in a family are known.
Diagnosis
Suggestive Findings
Spastic paraplegia 11 (SPG11) should be suspected in individuals with the following clinical and imaging findings.
Frequent clinical findings
- Progressive spasticity and weakness of the lower limbs
- Mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline with onset in the first to third decade
- Axonal, motor, or sensorimotor peripheral neuropathy (>80% of individuals) [Stevanin et al 2008, Orlacchio et al 2010, Daoud et al 2012, Özoğuz et al 2015, Manole et al 2016, Montecchiani et al 2016]
- Pseudobulbar involvement with dysarthria and/or dysphagia
- Increased reflexes in the upper limbs
Less frequent clinical findings
- Cerebellar signs (ataxia or ocular signs including nystagmus and/or saccadic pursuit)
- Retinal degeneration (Kjellin syndrome) * [Puech et al 2011]
- Pes cavus
- Scoliosis
- Extrapyramidal signs such as parkinsonism [Anheim et al 2009, Faber et al 2018a]
* Kjellin syndrome is characterized by retinal degeneration, autosomal recessive hereditary spastic paraplegia, and thin corpus callosum initially associated with spastic paraplegia 15 (SPG15) but more often occurring in individuals with SPG11. See Spastic Paraplegia 15.
Imaging findings on brain and spinal cord MRI
- Thinning of the corpus callosum (TCC) (>90% of individuals) [Stevanin et al 2008] particularly with long T1 and T2 values in the forceps minor of the corpus callosum, the so-called "ear of the lynx" sign which appears hyperintense on FLAIR and hypointense on T1-weighted images [Pascual et al 2019]
- Cortical atrophy is frequently observed.
- White matter hyperintensities [França et al 2012]
- Only frontal and occipital periventricular hyperintensities may be seen initially.
- Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [Hehr et al 2007, Stevanin et al 2008].
- Atrophy of both the brain stem and the cerebellum can be observed [Stevanin et al 2007].
- The basal ganglia may also be affected [Faber et al 2018b].
Note: 60% of individuals with TCC, cognitive impairment, and spastic paraparesis were found to have biallelic SPG11 pathogenic variants [Stevanin et al 2008].
Establishing the Diagnosis
The diagnosis of spastic paraplegia 11 (SPG11) is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in SPG11 on molecular genetic testing (see Table 1).
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic SPG11 variants of uncertain significance (or identification of one known SPG11 pathogenic variant and one SPG11 variant of uncertain significance) does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene 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. Because the phenotype of SPG11 is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with spastic paraplegia are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic, imaging, and electrophysiology findings suggest the diagnosis of SPG11, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of SPG11 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Of note, 10%-20% of disease-associated variants are exon-sized or larger deletions and duplications [Günther et al 2016].
- A spastic paraplegia multigene panel that includes SPG11 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition 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).
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by spastic paraplegia, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
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
Onset of spastic paraplegia 11 (SPG11) occurs mainly during infancy or adolescence (age 1-31 years) and is characterized by gait disorders or less frequently by intellectual disability [Stevanin et al 2007, Stevanin et al 2008, Kara et al 2016]. Later onset (age 50-60 years) was reported in a few individuals [Rubegni et al 2015, Kawarai et al 2015].
Approximately ten years after onset, most affected individuals have the complete clinical picture of SPG11, including progressive lower-limb spasticity, atrophy of the corpus callosum with intellectual disability, and/or progressive cognitive decline. Thinning of the corpus callosum appears to correlate with disease severity [Kara et al 2016]. Most affected individuals become wheelchair bound one or two decades after disease onset [Stevanin et al 2008, Puech et al 2011].
Cognitive decline with low Mini Mental State Evaluation (MMSE) scores, found in the majority of affected individuals, worsens with time and includes severe short-term memory impairment, emotional lability, childish behavior, reduced verbal fluency, and attention deficit indicative of executive dysfunction [Hehr et al 2007, Stevanin et al 2008]. Psychiatric problems with behavioral disturbances are observed. Most individuals with SPG11 display little concern over the progression of their motor disease [Stevanin et al 2008]. All these findings correlate with the frontal atrophy detected on follow-up brain MRI.
Intellectual disability, found in most individuals with early onset, is characterized by learning difficulties in childhood and low IQ.
Eye findings can include the following:
- Macular excavation or degeneration as reported in the Kjellin syndrome [Orlén et al 2009, Puech et al 2011]
- Strabismus
- Cerebellar ocular signs such as abnormal saccadic pursuit and nystagmus in individuals with the longest disease duration
- Visual evoked potentials with increased latencies and decreased amplitudes [Stevanin et al 2008]
Additional features are severe weakness, dysarthria, distal or generalized muscle wasting, and less frequently, pes cavus, scoliosis, parkinsonism, epilepsy, and orthostatic hypotension [Kara et al 2016]. Individuals with the longest disease duration may have swallowing difficulties [Stevanin et al 2008].
Electromyography (EMG) and nerve conduction velocities (NCVs) frequently show signs of axonal sensorimotor neuropathy particularly when disease duration exceeds ten years [Stevanin et al 2008].
Sural nerve biopsies have shown loss of unmyelinated nerve fibers and accumulation of pleomorphic membranous material in unmyelinated axons [Hehr et al 2007].
Genotype-Phenotype Correlations
Missense and splice site variants are more often associated with later onset [Kawarai et al 2015, Rubegni et al 2015] and mild disease severity [Kara et al 2016].
Nomenclature
SPG11 is one of several autosomal recessive disorders in which hereditary spastic paraplegia is associated with thin corpus callosum (HSP-TCC).
Based on the EMG and NCV patterns and on anterior horn cell abnormalities seen in some affected individuals, several authors have characterized SPG11 as upper and lower motor neuron disease [Stevanin et al 2008], juvenile amyotrophic lateral sclerosis with long disease duration [Orlacchio et al 2010, Daoud et al 2012, Özoğuz et al 2015, Manole et al 2016], or Charcot-Marie-Tooth neuropathy [Montecchiani et al 2016].
Prevalence
The estimated prevalence for HSP of all types ranges from 1:100,000 to 10:100,000 depending on the country. Since SPG11 was found to account for 19%-31% of autosomal recessive HSP [Stevanin et al 2008, Kara et al, 2016], a prevalence of 1.25:100,000 for SPG11 can be estimated.
As expected in autosomal recessive disorders, most families with SPG11 originate from countries in which consanguinity is common, particularly the Mediterranean basin or the Middle East [Hehr et al 2007, Stevanin et al 2008, Boukhris et al 2009, Denora et al 2009, Özoğuz et al 2015, Kara et al 2016]. However, SPG11 has been reported in families worldwide [Hehr et al 2007, Stevanin et al 2007, Southgate et al 2010, Rajakulendran et al 2011, Özoğuz et al 2015, Kara et al 2016].
Genetically Related (Allelic) Disorders
SPG11 pathogenic variants are associated with a spectrum of clinical manifestations resulting from first and/or second motor neuron degeneration. This includes pure or complex HSP [Stevanin et al 2008], amyotrophic lateral sclerosis [Orlacchio et al 2010, Daoud et al 2012, Özoğuz et al 2015, Manole et al 2016] and Charcot-Marie-Tooth neuropathy [Montecchiani et al 2016], regardless of the nature of the pathogenic variants. Individuals with multiple sclerosis have also been found to have SPG11 pathogenic variants [Romagnolo et al 2014, Mukai et al 2018].
Differential Diagnosis
See Hereditary Spastic Paraplegia Overview. The relative frequency of spastic paraplegia 11 (SPG11) varies according to phenotype and geographic origin. In Portugal, it accounts for 13% of all forms of spastic paraplegia regardless of the inheritance mode [Morais et al 2017]. SPG11 accounts for 5%-20% of autosomal recessive spastic paraplegias [Stevanin et al 2008] and up to 30%-50% of autosomal recessive complex spastic paraplegia [Kara et al 2016, Morais et al 2017]. This frequency increases up to 59%-70% [Stevanin et al 2008, Boukhris et al 2009, Denora et al 2009] when mental impairment and thinning of the corpus callosum are associated. SPG11 pathogenic variants can be found in a small proportion of individuals with a pure spastic paraplegia (<10%) but disease duration usually fewer than five years [Denora et al 2009].
There are other forms of spastic paraplegia associated with thinning of the corpus callosum and mental impairment and it is often difficult to distinguish them from SPG11 on clinical grounds (Table 2).
Lower motor neuron degeneration may mimic amyotrophic lateral sclerosis (ALS) when wasting is marked [Stevanin et al 2008, Orlacchio et al 2010, Daoud et al 2012]. The continuum between spastic paraplegia and ALS has been evidenced by the finding of lesions common to ALS in the brain of individuals with SPG11 [Denora et al 2016].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 11 (SPG11), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Neuropsychological testing to assess the cognitive impairment and decline
- Neuro-urologic examination for those with sphincter disturbance
- Electrophysiologic investigations (e.g., ENMG, VEP, SEP)
- Ocular investigations (e.g., funduscopic examination, OCT)
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
No specific drug treatment or cure exists for SPG11.
Care by a multidisciplinary team that may include a general practitioner, neurologist, clinical geneticist, physiotherapist, physical therapist, social worker, and psychologist should be considered.
Symptomatic treatment to reduce pyramidal hyperactivity in the lower limbs includes the following:
- Physiotherapy for stretching of the spastic muscles to prevent contractures. Adapted dance or movements are also helpful to maintain strength (see www.clickanddance.com).
- Antispastic drugs such as baclofen and tizanidine
- Botulin toxin and intrathecal baclofen, which can be considered when oral drugs are ineffective and spasticity is severe and disabling
When sphincter disturbances become a problem, urodynamic evaluation should be performed in order to adapt treatment and monitor follow up. Anticholinergic drugs are indicated for urinary urgency.
Psychiatric manifestations should be treated in accordance with standard practice.
Prevention of Secondary Complications
Follow up of sphincter disturbances is important to prevent bladder dysfunction and infection.
Early regular physiotherapy helps to prevent contractures.
Surveillance
Specialized outpatient clinic evaluations are suggested every six months to adjust medication and physical rehabilitation that will depend on disease severity.
Annual brain MRI can be used to follow the atrophy of the corpus callosum, cerebellum, and brain stem, and to monitor increases in the size and intensity of white matter hyperintensities.
Annual electrophysiologic investigations (e.g., ENMG, VEP, SEP) are recommended to follow the extent of the disease.
Visual acuity should be assessed annually.
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 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 11 (SPG11) is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
- In almost all cases, the parents of an affected child are heterozygotes (i.e., carriers of one SPG11 pathogenic variant).
- Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a SPG11 pathogenic variant and allow for reliable recurrence risk assessment. De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].In one rare case, a proband inherited one SPG11 pathogenic variant from a heterozygous parent and the second pathogenic variant occurred de novo in the proband (i.e., only one parent was a carrier) [Denora et al 2010].
- Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [Puech et al 2011].
Sibs of a proband
- If each parent is known to be heterozygous for an SPG11 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Intrafamilial clinical variability is observed in SPG11; age at onset and associated clinical manifestations may vary among affected sibs.
- Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [Puech et al 2011].
Offspring of a proband. The offspring of an individual with SPG11 are obligate heterozygotes (carriers) of a pathogenic variant in SPG11.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in SPG11.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the SPG11 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/preimplantation genetic 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.
Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, 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 most centers would consider use of prenatal testing to be 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.
- EURO HSPPlateforme Maladies Rares99 Rue DidotParis 75014FrancePhone: 33 1 56 53 52 61Email: president@eurohsp.eu
- HSP Research FoundationAustraliaEmail: inquiries@hspersunite.org.au
- National Institute of Neurological Disorders and Stroke (NINDS)Phone: 800-352-9424
- Spastic Paraplegia Foundation, Inc.Phone: 877-773-4483
- Tom Wahlig-FoundationTom Wahlig StiftungGermany
- A.I. Vi.P.S.Associazione Italiana Vivere la Paraparesi SpasticaVia Tevere, 720020 Lainate (MI)ItalyPhone: 39 392 9825622Email: info@aivips.it
- EURORDIS-Rare Diseases EuropeEmail: eurordis@eurordis.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.
Molecular Pathogenesis
Introduction. SPG11 encodes spatacsin, a protein strongly conserved through evolution. Neither SPG11 nor spatacsin shows any significant sequence similarity to known cDNA or protein sequences. The spatacsin protein interacts with the SPG15 and SPG48 protein products [Słabicki et al 2010] and is an accessory protein of the adaptor protein 5 complex [Hirst et al 2011]. It is required for proper lysosomal tubulation and recycling [Chang et al 2014].
Mechanism of disease causation. Most pathogenic variants identified to date in SPG11 predict truncation of the protein, demonstrating that pathogenicity results from loss of spatacsin function. The few disease-associated missense variants are likely to result in partial loss of spatacsin function since the phenotype is often milder.
The loss of spatacsin function is associated with reduced clearance of lipids from lysosomes with accumulation of gangliosides and cholesterol [Boutry et al 2018, Boutry et al 2019]. Consequently, cholesterol levels on membranes and calcium homeostasis are altered [Boutry et al 2019]. Spatacsin is also required for neurite formation [Martin et al 2012] and the GSK3b signaling pathway [Pozner et al 2018]. These data provide potential targets for preclinical studies.
Chapter Notes
Author Notes
Giovanni Stevanin, PhD is a molecular biologist with expertise in spinocerebellar degeneration. He is Director of Research at INSERM and Professor at the Ecole Pratique des Hautes Etudes / Paris Sciences Lettres University. He co-leads a research team at the Institut du Cerveau et de la Moelle Epinière (Paris, France) and the international network on spastic paraplegias and ataxias (SPATAX; see below).
The author suggests the following organization for patient registries and information on ataxia and spastic paraparesis:
SPATAX Network
Institut du Cerveau et de la Moelle Epinière
Pitié-Salpêtrière Hospital
47 Bd de l’Hôpital
75013 Paris, France
Email: spatax@icm-institute.org
Web: www.spatax.wordpress.com
Acknowledgments
The author's work is financially supported by the French Agency for Research (ANR), the Spastic Paraplegia Foundation (US), the European Union through the H2020 program, the Erare program, and the French Strümpell Lorrain Association (ASL).
Author History
Alexis Brice, MD; Hôpital Pitié-Salpêtrière (2008-2019)
Alexandra Durr, MD, PhD; Hôpital Pitié-Salpêtrière (2008-2019)
Giovanni Stevanin, PhD (2008-present)
Revision History
- 19 December 2019 (sw) Comprehensive update posted live
- 31 January 2013 (me) Comprehensive update posted live
- 3 September 2009 (cd) Revision: deletion/duplication analysis available clinically
- 27 March 2008 (me) Review posted live
- 26 November 2007 (gs) Original submission
References
Literature Cited
- Anheim M, Lagier-Tourenne C, Stevanin G, Fleury M, Durr A, Namer IJ, Denora P, Brice A, Mandel JL, Koenig M, Tranchant C. SPG11 spastic paraplegia. A new cause of juvenile parkinsonism. J Neurol. 2009;256:104–8. [PubMed: 19224311]
- Boukhris A, Stevanin G, Feki I, Denora P, Elleuch N, Miladi MI, Goizet C, Truchetto J, Belal S, Brice A, Mhiri C. Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity. Clin Genet. 2009;75:527–36. [PubMed: 19438933]
- Boutry M, Pierga A, Matusiak R, Branchu J, Houllegatte M, Ibrahim Y, Balse E, El Hachimi KH, Brice A, Stevanin G, Darios F. Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis. Commun Biol. 2019;2:380. [PMC free article: PMC6797781] [PubMed: 31637311]
- Boutry M, Branchu J, Lustremant C, Pujol C, Pernelle J, Matusiak R, Seyer A, Poirel M, Chu-Van E, Pierga A, Dobrenis K, Puech JP, Caillaud C, Durr A, Brice A, Colsch B, Mochel F, El Hachimi KH, Stevanin G, Darios F. Inhibition of lysosome membrane recycling causes accumulation of gangliosides that contribute to neurodegeneration. Cell Rep. 2018;23:3813–26. [PMC free article: PMC6045775] [PubMed: 29949766]
- Chang J, Lee S, Blackstone C. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest. 2014;124:5249–62. [PMC free article: PMC4348974] [PubMed: 25365221]
- Daoud H, Zhou S, Noreau A, Sabbagh M, Belzil V, Dionne-Laporte A, Tranchant C, Dion P, Rouleau GA. Exome sequencing reveals SPG11 mutations causing juvenile ALS. Neurobiol Aging. 2012;33:839.e5–9. [PubMed: 22154821]
- Denora PS, Smets K, Zolfanelli F, Ceuterick-de Groote C, Casali C, Deconinck T, Sieben A, Gonzales M, Zuchner S, Darios F, Peeters D, Brice A, Malandrini A, De Jonghe P, Santorelli FM, Stevanin G, Martin JJ, El Hachimi KH. Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions. Brain. 2016;139:1723–34. [PMC free article: PMC5839621] [PubMed: 27016404]
- Denora PS, Brockmann K, Ciccolella M, Truchetto J, Stevanin G, Santorelli FM. Identification of a de novo mutation in SPG11. Mov Disord. 2010;25:501–3. [PubMed: 20108361]
- Denora PS, Schlesinger D, Casali C, Kok F, Tessa A, Boukhris A, Azzedine H, Dotti MT, Bruno C, Truchetto J, Biancheri R, Fedirko E, Di Rocco M, Bueno C, Malandrini A, Battini R, Sickl E, de Leva MF, Boespflug-Tanguy O, Silvestri G, Simonati A, Said E, Ferbert A, Criscuolo C, Heinimann K, Modoni A, Weber P, Palmeri S, Plasilova M, Pauri F, Cassandrini D, Battisti C, Pini A, Tosetti M, Hauser E, Masciullo M, Di Fabio R, Piccolo F, Denis E, Cioni G, Massa R, Della Giustina E, Calabrese O, Melone MA, De Michele G, Federico A, Bertini E, Durr A, Brockmann K, van der Knaap MS, Zatz M, Filla A, Brice A, Stevanin G, Santorelli FM. Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion. Hum Mutat. 2009;30:E500–19. [PubMed: 19105190]
- Faber I, Martinez ARM, Martins CR Jr, Maia ML, Souza JP, Lourenço CM, Marques W Jr, Montecchiani C, Orlacchio A, Pedroso JL, Barsottini OGP, Ramos CD, Lopes-Cendes Í, Friedman JH, Amorim BJ, França MC Jr. SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response. Mov Disord. 2018a;33:1650–6. [PubMed: 30306626]
- Faber I, Martinez ARM, de Rezende TJR, Martins CR Jr, Martins MP, Lourenço CM, Marques W Jr, Montecchiani C, Orlacchio A, Pedroso JL, Barsottini OGP, Lopes-Cendes Í, França MC Jr. SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage. Neuroimage Clin. 2018b;19:848–57. [PMC free article: PMC6008284] [PubMed: 29946510]
- França MC Jr, Yasuda CL, Pereira FR, D'Abreu A, Lopes-Ramos CM, Rosa MV, Cendes F, Lopes-Cendes I. White and grey matter abnormalities in patients with SPG11 mutations. J Neurol Neurosurg Psychiatry. 2012;83:828–33. [PubMed: 22696581]
- Günther S, Elert-Dobkowska E, Soehn AS, Hinreiner S, Yoon G, Heller R, Hellenbroich Y, Hübner CA, Ray PN, Hehr U, Bauer P, Sulek A, Beetz C. High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles. Hum Mutat. 2016;37:703–9. [PubMed: 27071356]
- Hehr U, Bauer P, Winner B, Schule R, Olmez A, Koehler W, Uyanik G, Engel A, Lenz D, Seibel A, Hehr A, Ploetz S, Gamez J, Rolfs A, Weis J, Ringer TM, Bonin M, Schuierer G, Marienhagen J, Bogdahn U, Weber BH, Topaloglu H, Schols L, Riess O, Winkler J. Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. Ann Neurol. 2007;62:656–65. [PubMed: 18067136]
- Hirst J, Barlow LD, Francisco GC, Sahlender DA, Seaman MN, Dacks JB, Robinson MS. The fifth adaptor protein complex. PLoS Biol. 2011;9:e1001170. [PMC free article: PMC3191125] [PubMed: 22022230]
- Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
- Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016;139:1904–18. [PMC free article: PMC4939695] [PubMed: 27217339]
- Kawarai T, Miyamoto R, Mori A, Oki R, Tsukamoto-Miyashiro A, Matsui N, Miyazaki Y, Orlacchio A, Izumi Y, Nishida Y, Kaji R. Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation. J Neurol Sci. 2015;359:250–5. [PubMed: 26671123]
- Manole A, Chelban V, Haridy NA, Hamed SA, Berardo A, Reilly MM, Houlden H. Severe axonal neuropathy is a late manifestation of SPG11. J Neurol. 2016;263:2278–86. [PMC free article: PMC5065903] [PubMed: 27544499]
- Martin E, Yanicostas C, Rastetter A, Naini SM, Maouedj A, Kabashi E, Rivaud-Péchoux S, Brice A, Stevanin G, Soussi-Yanicostas N. Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish. Neurobiol Dis. 2012;48:299–308. [PubMed: 22801083]
- Montecchiani C, Pedace L, Lo Giudice T, Casella A, Mearini M, Gaudiello F, Pedroso JL, Terracciano C, Caltagirone C, Massa R, St George-Hyslop PH, Barsottini OG, Kawarai T, Orlacchio A. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016;139:73–85. [PMC free article: PMC5839554] [PubMed: 26556829]
- Morais S, Raymond L, Mairey M, Coutinho P, Brandão E, Ribeiro P, Loureiro JL, Sequeiros J, Brice A, Alonso I, Stevanin G. Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias. Eur J Hum Genet. 2017;25:1217–28. [PMC free article: PMC5643959] [PubMed: 28832565]
- Mukai M, Koh K, Ohnuki Y, Nagata E, Takiyama Y, Takizawa S. Novel SPG11 mutations in a patient with symptoms mimicking multiple sclerosis. Intern Med. 2018;57:3183–6. [PMC free article: PMC6262711] [PubMed: 29877287]
- Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S, Munhoz RP, Rogaeva EA, St George-Hyslop PH, Bernardi G, Kawarai T. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133:591–8. [PMC free article: PMC2822627] [PubMed: 20110243]
- Orlén H, Melberg A, Raininko R, Kumlien E, Entesarian M, Söderberg P, Påhlman M, Darin N, Kyllerman M, Holmberg E, Engler H, Eriksson U, Dahl N. SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:984–92. [PubMed: 19194956]
- Özoğuz A, Uyan Ö, Birdal G, Iskender C, Kartal E, Lahut S, Ömür Ö, Agim ZS, Eken AG, Sen NE, Kavak P, Saygı C, Sapp PC, Keagle P, Parman Y, Tan E, Koç F, Deymeer F, Oflazer P, Hanağası H, Gürvit H, Bilgiç B, Durmuş H, Ertaş M, Kotan D, Akalın MA, Güllüoğlu H, Zarifoğlu M, Aysal F, Döşoğlu N, Bilguvar K, Günel M, Keskin Ö, Akgün T, Özçelik H, Landers JE, Brown RH, Başak AN. The distinct genetic pattern of ALS in Turkey and novel mutations. Neurobiol Aging. 2015;36:1764.e9–1764.e18. [PMC free article: PMC6591733] [PubMed: 25681989]
- Pascual B, de Bot ST, Daniels MR, França MC Jr, Toro C, Riverol M, Hedera P, Bassi MT, Bresolin N, van de Warrenburg BP, Kremer B, Nicolai J, Charles P, Xu J, Singh S, Patronas NJ, Fung SH, Gregory MD, Masdeu JC. "Ears of the lynx" MRI sign is associated with SPG11 and SPG15 hereditary spastic paraplegia. Am J Neuroradiol. 2019;40:199–203. [PMC free article: PMC7048588] [PubMed: 30606727]
- Pozner T, Schray A, Regensburger M, Lie DC, Schlötzer-Schrehardt U, Winkler J, Turan S, Winner B. Tideglusib rescues neurite pathology of SPG11 iPSC derived cortical neurons. Front Neurosci. 2018;12:914. [PMC free article: PMC6291617] [PubMed: 30574063]
- Puech B, Lacour A, Stevanin G, Sautiere BG, Devos D, Depienne C, Denis E, Mundwiller E, Ferriby D, Vermersch P, Defoort-Dhellemmes S. Kjellin syndrome: long-term neuro-ophthalmologic follow-up and novel mutations in the SPG11 gene. Ophthalmology. 2011;118:564–73. [PubMed: 21035867]
- Rajakulendran S, Paisán-Ruiz C, Houlden H. Thinning of the corpus callosum and cerebellar atrophy is correlated with phenotypic severity in a family with spastic paraplegia type 11. J Clin Neurol. 2011;7:102–4. [PMC free article: PMC3131536] [PubMed: 21779300]
- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
- Romagnolo A, Masera S, Mattioda A, Superti G, Santorelli FM, Mongini T, Pinessi L, Cavalla P. Atypical hereditary spastic paraplegia mimicking multiple sclerosis associated with a novel SPG11 mutation. Eur J Neurol. 2014;21:e14–5. [PubMed: 24571105]
- Rubegni A, Storti E, Tessa A, Federico A, Santorelli FM. Hereditary spastic paraplegia type 11 with a very late onset. J Neurol. 2015;262:1987–9. [PubMed: 26183056]
- Southgate L, Dafou D, Hoyle J, Li N, Kinning E, Critchley P, Németh AH, Talbot K, Bindu PS, Sinha S, Taly AB, Raghavendra S, Müller F, Maher ER, Trembath RC. Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish. Neurogenetics. 2010;11:379–89. [PMC free article: PMC2944959] [PubMed: 20390432]
- Słabicki M, Theis M, Krastev DB, Samsonov S, Mundwiller E, Junqueira M, Paszkowski-Rogacz M, Teyra J, Heninger AK, Poser I, Prieur F, Truchetto J, Confavreux C, Marelli C, Durr A, Camdessanche JP, Brice A, Shevchenko A, Pisabarro MT, Stevanin G, Buchholz F. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 2010;8:e1000408. [PMC free article: PMC2893954] [PubMed: 20613862]
- Stevanin G, Azzedine H, Denora P, Boukhris A, Tazir M, Lossos A, Rosa AL, Lerer I, Hamri A, Alegria P, Loureiro J, Tada M, Hannequin D, Anheim M, Goizet C, Gonzalez-Martinez V, Le Ber I, Forlani S, Iwabuchi K, Meiner V, Uyanik G, Erichsen AK, Feki I, Pasquier F, Belarbi S, Cruz VT, Depienne C, Truchetto J, Garrigues G, Tallaksen C, Tranchant C, Nishizawa M, Vale J, Coutinho P, Santorelli FM, Mhiri C, Brice A, Durr A. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain. 2008;131:772–84. [PubMed: 18079167]
- Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS, Martin E, Ouvrard-Hernandez AM, Tessa A, Bouslam N, Lossos A, Charles P, Loureiro JL, Elleuch N, Confavreux C, Cruz VT, Ruberg M, Leguern E, Grid D, Tazir M, Fontaine B, Filla A, Bertini E, Durr A, Brice A. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39:366–72. [PubMed: 17322883]
Publication Details
Author Information and Affiliations
INSERM, CNRS
Sorbonne University;
École Pratique des Hautes Études
Paris Sciences et Lettres Research University
Hôpital Pitié-Salpêtrière
Paris, France
Publication History
Initial Posting: March 27, 2008; Last Update: December 19, 2019.
Copyright
GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.
For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.
For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.
Publisher
University of Washington, Seattle, Seattle (WA)
NLM Citation
Stevanin G. Spastic Paraplegia 11. 2008 Mar 27 [Updated 2019 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.