Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Stevanin, Giovanni; Santorelli, Filippo M.; Azzedine, Hamid; Coutinho, Paula; Chomilier, Jacques; Denora, Paola S.; Martin, Elodie; Ouvrard-Hernandez, Anne Marie; Tessa, Alessandra; Bouslam, Naïma; Lossos, Alexander; Charles, Perrine; Loureiro, José Leal; Elleuch, N.; Confavreux, Christian; Cruz, Vítor Tedim; Ruberg, Merle; LeGuern, Eric; Grid, Djamel; Tazir, Mériem; Fontaine, Bertrand; Filla, Alessandro; Bertini, Enrico; Dürr, Alexandra; Brice, Alexis

doi:10.1038/ng1980

Cited by 294 publications

(317 citation statements)

References 24 publications

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“…As gait impairment raises the suspicion of an HSP earlier, learning difficulties as the presenting symptom might have been under-represented in previous studies. 1,7,8 Most patients lost ambulation 1 to 2 decades after disease onset, regardless of supportive therapeutic strategies. The percentage of wheelchair-bound subjects was 67% after 15.9 years (mean) of gait impairment, which is only slightly higher than reported previously.…”

Section: Discussionmentioning

confidence: 99%

“…1,5,8,10,12 Finally, we found a much higher percentage of sphincter disturbances than previous studies (94% vs 42.9%), and urinary and fecal incontinence in particular (44% vs unknown), possibly due to under-reporting before. 7 Whether obesity, hallucinations and muscle atrophy are part of the SPG11 phenotype itself or are actually secondary to immobility, comorbidity or comedication, needs further attention in future studies, as well as the possibility of a more severe disease course in patients with retinal pigment epithelium lesions (Kjellin syndrome).…”

Section: Discussionmentioning

confidence: 99%

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Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

et al. 2013

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Although SPG11 is the most common complicated hereditary spastic paraplegia, our knowledge of the long-term prognosis and life expectancy is limited. We therefore studied the disease course of all patients with a proven SPG11 mutation as tested in our laboratory, the single Dutch laboratory providing SPG11 mutation analysis, between 1 January 2009 and 1 January 2011. We identified nine different SPG11 mutations, four of which are novel, in nine index patients. Eighteen SPG11 patients from these nine families were studied by means of a retrospective chart analysis and additional interview/examination. Ages at onset were between 4 months and 14 years; 39% started with learning difficulties rather than gait impairment. Brain magnetic resonance imaging showed a thin corpus callosum and typical periventricular white matter changes in the frontal horn region (known as the 'ears-of the lynx'-sign) in all. Most patients became wheelchair bound after a disease duration of 1 to 2 decades. End-stage disease consisted of loss of spontaneous speech, severe dysphagia, spastic tetraplegia with peripheral nerve involvement and contractures. Several patients died of complications between ages 30 and 48 years, 3-4 decades after onset of gait impairment. Other relevant features during the disease were urinary and fecal incontinence, obesity and psychosis. Our study of 18 Dutch SPG11-patients shows the potential serious long-term consequences of SPG11 including a possibly restricted life span.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

et al. 2013

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“…Disease causing variants in SPG11 (KIAA1840) (OMIM phenotype #604360) constitute the most frequent cause of TCCassociated HSP (41-77%) and up to for 10-20% of all AR HSP, particularly in the Mediterranean basin. 6,10,[12][13][14][15][16] Next-generation sequencing aided in the identification of many rare HSP genes. 1,17 TFG/SPG57 stands as an example of this genetic surge.…”

Section: Introductionmentioning

confidence: 99%

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSPrelated genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C4T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C4T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

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“…SPG11 encodes the 2,443 amino acid protein spatacsin 9. Because of the lack of relevant disease models, the underlying molecular mechanisms and, in particular, the neuronal functions of spatacsin are still unclear.…”

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confidence: 99%

GSK3ß‐dependent dysregulation of neurodevelopment in SPG11‐patient induced pluripotent stem cell model

Mishra

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Havlicek

et al. 2016

Annals of Neurology

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ObjectiveMutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal‐recessive complex hereditary spastic paraplegia (HSP) and juvenile‐onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient‐specific induced pluripotent stem cell (iPSC)‐derived cortical neural progenitor cells (NPCs).MethodsWe generated and characterized iPSC‐derived NPCs and neurons from 3 SPG11 patients and 2 age‐matched controls.ResultsGene expression profiling of SPG11‐NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell‐cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3ß‐signaling pathway was found to be dysregulated in SPG11‐NPCs. Impaired proliferation of SPG11‐NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11‐NPCs was rescued by GSK3 modulation.InterpretationThis iPSC‐derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ß as a potential novel target to reverse the disease phenotype. Ann Neurol 2016;79:826–840

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Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Cited by 294 publications

References 24 publications

Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

GSK3ß‐dependent dysregulation of neurodevelopment in SPG11‐patient induced pluripotent stem cell model

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