Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting

Klebe, Stephan; Stevanin, Giovanni; Depienne, Christel

doi:10.1016/j.neurol.2015.02.017

Cited by 150 publications

(150 citation statements)

References 210 publications

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“…More than 75 different loci and 59 HSP genes, denoted as spastic paraplegia gene ( SPG ), have so far been identified 3. Mutations in SPG11 cause the most frequent form of autosomal‐recessive (AR)‐complex HSP,4, 5 and these patients, besides spastic paraparesis, present with cognitive impairment, cortical atrophy, a thin corpus callosum (TCC), and sensorimotor peripheral neuropathy,6, 7 indicative of a multisystem neurodegeneration.…”

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confidence: 99%

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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confidence: 99%

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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“…Hereditary spastic paraplegia (HSP) is a group of neurodegenerative monogenic disorders characterized by dysfunction of the longer tracts of the spinal cord: the corticospinal tract and, to a lesser extent, the posterior columns 1,2,3,4 . This culminates in the key clinical aspects of HSP: spasticity of the lower limbs, followed by a -usually less severe -weakness, urinary urgency and decreased vibration sense 1,2,3,4 .…”

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confidence: 99%

“…This culminates in the key clinical aspects of HSP: spasticity of the lower limbs, followed by a -usually less severe -weakness, urinary urgency and decreased vibration sense 1,2,3,4 . The HSP may segregate as autosomal dominant (AD-HSP), autosomal recessive (AR-HSP), X-linked or mitochondrial traits 1,2,3,4 . On clinical grounds, one may present with a pure form of the disease, which is more frequent in families with an autosomal dominant inheritance pattern.…”

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confidence: 99%

“…On the other hand, a complex or complicated clinical picture, characterized by the presence of other neurological or non-neurological dysfunctions, is more frequently found in AR-HSP or X-linked HSP 1, 2, 3, 4 . These features encompass, for example, ataxia, parkinsonism, peripheral neuropathy, cognitive dysfunction, cataracts, and icthyosis 1,2,3,4,5,6,7 . The diagnosis of an inherited spastic paraplegia is based essentially on the clinical picture, together with the investigation of other, potentially affected, members of the kindred.…”

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confidence: 99%

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Hereditary spastic paraplegia from 1880 to 2017: an historical review

Faber

Pereira

Martínez

et al. 2017

Arq. Neuro-Psiquiatr.

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“…In this situation traditional mutation screening, based on consecutive "searching" for a plurality of coding sequences, is too time consuming and unreasonably expensive. Furthermore, for hereditary neurodegenerations, explicit inter-and intra-familial phenotypical polymorphism is typical, it being manifested by various neurological syndromes within one nosological form among members of the same family [9][10][11][12].…”

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confidence: 99%

An Original Target Genetic Panel to Diagnose Neurodegenerative Diseases on the Basis of Next-Generation Sequencing: First Experience

Abramycheva¹,

Fedotova²,

Klyushnikov³

et al. 2016

Sovrem Tehnol Med

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The aim of the study was to assess the efficacy of a diagnostic panel based on next-generation sequencing (NGS) and developed by our team, to diagnose a wide range of socially significant hereditary degenerative diseases of the brain.Materials and Methods. Using the diagnostic target NGS panel (powered by Illumina MiSeq, USA), designed to sequence the encoding area of 300 genes related to neurodegenerative diseases manifesting with movement and cognitive disorders, we performed a mutation screening of the DNA of 32 patients with an otherwise obscure diagnosis.Results. The application of the original genetic panel revealed a number of rare hereditary neurodegenerative pathologies with mutations in genes for spinocerebellar ataxias and paraplegias, parkinsonism, dystonias, and neurometabolic diseases, identified by NGS and confirmed by direct sequencing. In 11 patients, 12 mutations were found in 10 different genes, causing the development of three autosomal recessive diseases (genes DDHD1, NPC1 and RARS) and eight diseases associated with autosomal dominant inheritance (genes SPAST, SPTBN2, GRN, GCH1, LRRK2, NOTCH3 and AGER).Conclusion. Panel screening of uncertain cases of neurodegenerative diseases using this bespoke target model enabled us to reveal and subsequently confirm mutations in various genes for more than a quarter of the examined patients.

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Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting

Cited by 150 publications

References 210 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

Hereditary spastic paraplegia from 1880 to 2017: an historical review

An Original Target Genetic Panel to Diagnose Neurodegenerative Diseases on the Basis of Next-Generation Sequencing: First Experience

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