Long‐term course and mutational spectrum of <i>spatacsin</i>‐linked spastic paraplegia

Hehr, Ute; Bauer, Péter; Winner, Beate; Schüle, Rebecca; Ölmez, Akgün; Köehler, Wolfgang; Uyanık, G.; Engel, Anna; Lenz, Daniela; Seibel, A.; Hehr, Andreas; Ploetz, Sonja; Gamez, Josep; Rolfs, Arndt; Weis, Joachim; Ringer, Thomas; Bonin, Michael; Schuierer, Gerhard; Marienhagen, J.; Bogdahn, Ulrich; Weber, Bernhard H. F.; Topaloǧlu, Haluk; Schöls, Ludger; Rieß, Olaf; Winkler, Juergen

doi:10.1002/ana.21310

Cited by 112 publications

(151 citation statements)

References 35 publications

(44 reference statements)

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“…In other reports progression to nonambulation varied from 1 or 2 decades to intact ambulation after 24 years. 6,9 Our study underscores the potential serious long-term consequences of SPG11 including a restricted life span.…”

Section: Discussionmentioning

confidence: 63%

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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: 63%

“…[3][4][5] Onset of SPG11 usually occurs within the second decade of life and the disease progresses relatively rapidly as compared with other HSPs. 6 Most patients become wheelchair bound after 1 or 2 decades.…”

Section: Introductionmentioning

confidence: 99%

Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

et al. 2013

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“…Our data point toward distinct temporal functions of spatacsin, causing axonal transport deficits in corticospinal projections in mature neurons in vitro, and most likely during adulthood, in patients 12. It is imperative to speculate that the cortical changes (TCC and cortical atrophy) in SPG11 patients, when they first present with spastic paraplegia, are rather the results of defects in proliferation during cortical development,5, 6, 7 thereby highlighting a novel role for spatacsin in early neural development. Our current model of SPG11 disease pathology starts with an early‐onset neurodevelopmental phenotype (first two decades), consisting of a proliferation deficit and cortical neurogenesis defects.…”

Section: Discussionmentioning

confidence: 81%

“…SPG11‐1 and SPG11‐2 are sisters (Fig 1A,B) with a heterozygous nonsense mutation at c.3036C>A/p.Tyr1012X in exon 16 and a c.5798 delC/p.Ala1933ValfsX18 mutation in exon 30 7, 18. SPG11‐3 has a heterozygous nonsense mutation at c.267G>A/p.…”

Section: Methodsmentioning

confidence: 99%

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

Mishra

Prots

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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Molecular Genetics of Hereditary Spastic Paraplegias

Stevanin

2010

Encyclopedia of Life Sciences

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Hereditary spastic paraplegias (HSPs), also known as Strümpell–Lorrain disease, are rare neurological conditions characterised by gradual spasticity and weakness of the lower limbs usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. The course is generally slowly progressive, with considerable variation in age at onset and severity of spasticity. There are also complex forms of HSP, with additional neurological features or extra‐neurological signs. HSPs are transmitted according to all modes of inheritance, and 21 of the 43 genes localised have been identified. In recent years, genetic studies have shown abnormal membrane trafficking, axonal transport, cholesterol homeostasis and mitochondrial dysfunction to be the major physiopathological mechanisms in HSP. A new classification is now emerging taking into account clinical, genetic and pathological mechanisms. Key Concepts: Hereditary spastic paraplegias are among the most highly heterogeneous neurodegenerative disorders. The clinical presentation in patients can be pure or complex, variably associating additional, neurological and non‐neurological signs. Mutations or genomic rearrangements in at least 43 genes can lead to spastic paraplegia. Intracellular trafficking and maintenance of axon/myelin are the main systems altered in these diseases.

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Long‐term course and mutational spectrum of spatacsin‐linked spastic paraplegia

Cited by 112 publications

References 35 publications

Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

Rapidly deteriorating course in Dutch hereditary spastic paraplegia type 11 patients

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

Molecular Genetics of Hereditary Spastic Paraplegias

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