Clinical Progression and Genetic Analysis in Hereditary Spastic Paraplegia With Thin Corpus Callosum in Spastic Gait Gene 11 (SPG11)

Winner, Beate; Uyanık, G.; Groß, Claudia; Lange, Max; Schulte‐Mattler, Wilhelm J.; Schuierer, Gerhard; Marienhagen, J.; Hehr, Ute; Winkler, Juergen

doi:10.1001/archneur.61.1.117

Cited by 74 publications

(65 citation statements)

References 20 publications

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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%

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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Section: Discussionmentioning

confidence: 81%

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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“…31 A longitudinal clinical and neuroradiologic follow-up demonstrated further decrease of relative cerebral blood flow in the thalamus or cerebral cortex suggestive of progressive thalamic and cerebral cortical involvement. 21,32 At the level of the spinal cord, studies by Sperfeld et al 33,34 showed significant atrophy of the upper spinal cord in patients with HSP compared with the controls, both at the cervical and thoracic levels.…”

Section: Discussionmentioning

confidence: 97%

MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

Hourani

El-Hajj²,

Barada³

et al. 2009

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:Hereditary spastic paraplegia (HSP) is a disorder characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord. Previously described radiologic findings included nonspecific brain abnormalities such as brain atrophy and white matter lesions, as well as atrophy of the spinal cord. In our study, we aimed to better characterize brain and spine MR imaging findings in a series of patients with HSP.

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“…There are several reports in the literature of white matter hyperintensities (diffuse or patchy) and corpus callosum abnormalities in association with HSP. 9,10,17,19,20,[26][27][28][29][30] Thinning of the cervical and thoracic spinal cord has been noted in HSP. 31 Volume loss is an expected finding as there is a degeneration of the longer corticospinal tracts to the spinal cord (mainly to the lower limbs) and dorsal column pathway within the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Clinical Spectrum of Hereditary Spastic Paraplegia in Children : A Study of 74 Cases = الطيف السريري للشلل السفلي التشنجي الوراثي في الأطفال : دراسة 74 حالة

Koul¹,

Al-Murshedi²,

Al-Azri³

et al. 2013

SQUMJ

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abstract:Objectives: The aim of the study was to explore the spectrum of hereditary spastic paraplegia (HSP) in children in Oman. Methods: This retrospective study was carried out between January 1994 and August 2011 on children with delayed development, gait disorders and motor handicaps, with signs of symmetrical pyramidal tract involvement. A detailed perinatal and family history, including the age of onset of symptoms, was recorded. The children were labelled as having either the pure or complicated form of HSP based on the established diagnostic criteria. In families with more than one affected child, parents and all other siblings were also examined. Results: Within the study, 74 children from 31 families were diagnosed with HSP. Parental consanguinity was seen in 91% of cases, with 44 children (59.4%) experiencing onset of the disease under one year of age. Complicated HSP was the most common type, seen in 81.1%. Speech involvement, mental retardation, and epilepsy were the most common associated abnormalities. Nonspecific white matter changes and corpus callosum abnormalities were noted in 24.3% of cases on magnetic resonance imaging. Conclusion: The study described clinical features of 74 children with HSP. Autosomal recessive complicated HSP was seen in 81.1% of cases. Keywords

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Clinical Progression and Genetic Analysis in Hereditary Spastic Paraplegia With Thin Corpus Callosum in Spastic Gait Gene 11 (SPG11)

Abstract: Progressive axonal degeneration occurs in the corticocortical projections, corticospinal tract, and peripheral nerves in HSP with thin CC linking to chromosome 15q13-15 in a German pedigree.

Cited by 74 publications

References 20 publications

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

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

MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

Clinical Spectrum of Hereditary Spastic Paraplegia in Children : A Study of 74 Cases = الطيف السريري للشلل السفلي التشنجي الوراثي في الأطفال : دراسة 74 حالة

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