Movement Disorder Phenotypes in Children With 22q11.2 Deletion Syndrome

Cunningham, Adam; Fung, Wilson; Massey, Thomas; Hall, Jérémy; Bree, Marianne B. M. van den; Peall, Kathryn J.

doi:10.1002/mds.28078

Cited by 12 publications

(6 citation statements)

References 7 publications

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“…14,52 These functional hubs may be highly sensitive to a broad range of genetic risks for neuropsychiatric conditions. This is consistent with the fact that (i) most if not all rare CNVs, and rare deleterious variants in general, that increase the risk for psychiatric conditions are also associated with delayed gross motor milestones 10,53 and development coordination disorders 54 ; and (ii) delay in motor milestones has been demonstrated in individuals with SZ 55 and ASD. 56 Of note, functional and structural measures of the thalamus, basal ganglia 57 and unimodal regions (i.e.…”

Section: Genetic Risks Converge On the Thalamus And Somatomotor Networksupporting

confidence: 86%

Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Moreau

Kumar

Harvey

et al. 2022

Brain

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Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behavior. We processed nine resting-state functional MRI datasets including 32,726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism, and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of nineteen pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic - rFunctional connectivity= 0.71 [0.40-0.87] and rTranscriptomic - rFunctional connectivity= 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms - amenable to intervention - across psychiatric conditions and genetic risks.

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Section: Genetic Risks Converge On the Thalamus And Somatomotor Networksupporting

confidence: 86%

Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Moreau

Kumar

Harvey

et al. 2022

Brain

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“…Development delays need to be checked at every step of infancy and childhood, as early intervention can help provide support for children with the deletion [ 69 , 70 ]. The most common problems are motor delays and speech difficulty, which can be connected with very frequent conductive hearing impairment (HP:0000405) and muscular hypotonia (HP:0001252) [ 61 , 71 , 72 , 73 , 74 ]. Delays in reaching motor milestones and the emergence of language are common in children with 22q11.2DS.…”

Section: Individual Levelmentioning

confidence: 99%

“…Children with 22q11.2 deletion syndrome are able to button their clothes at 6.2 years (median) and to do up their laces at 9.75. Upon examination, 95% show evidence of movement disorders and dystonia [ 71 ]. The mean IQ of such individuals is about 70, and 22q11.2DS children have problems with mathematics and other skills that require abstract reasoning [ 76 , 77 , 78 , 79 ].…”

Section: Individual Levelmentioning

confidence: 99%

Consequences of 22q11.2 Microdeletion on the Genome, Individual and Population Levels

Karbarz

2020

Genes

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Chromosomal 22q11.2 deletion syndrome (22q11.2DS) (ORPHA: 567) caused by microdeletion in chromosome 22 is the most common chromosomal microdeletion disorder in humans. Despite the same change on the genome level, like in the case of monozygotic twins, phenotypes are expressed differently in 22q11.2 deletion individuals. The rest of the genome, as well as epigenome and environmental factors, are not without influence on the variability of phenotypes. The penetrance seems to be more genotype specific than deleted locus specific. The transcript levels of deleted genes are not usually reduced by 50% as assumed due to haploinsufficiency. 22q11.2DS is often an undiagnosed condition, as each patient may have a different set out of 180 possible clinical manifestations. Diverse dysmorphic traits are present in patients from different ethnicities, which makes diagnosis even more difficult. 22q11.2 deletion syndrome serves as an example of a genetic syndrome that is not easy to manage at all stages: diagnosis, consulting and dealing with.

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“… 2 As well as representing a primary disorder, dystonia is also a phenotypic component of many neurodevelopmental and neurodegenerative disorders. 3 , 4 In excess of 25 Mendelian inherited, dystonia-causing genes have now been identified, with these predominantly resulting in the early-onset motor symptoms. 5 One such disorder is myoclonus dystonia, caused by mutations in the autosomal dominantly inherited ε-sarcoglycan ( SGCE ) gene, encoding the ε-sarcoglycan protein, and whose penetrance is reduced owing to maternal imprinting.…”

Section: Introductionmentioning

confidence: 99%

Cortical neuronal hyperexcitability and synaptic changes in SGCE mutation-positive myoclonus dystonia

Sperandeo

Tamburini

Noakes

et al. 2022

Brain

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Myoclonus Dystonia is a childhood-onset hyperkinetic movement disorder with a combined motor and psychiatric phenotype. It represents one of the few autosomal dominant inherited dystonic disorders and is caused by mutations in the ε-sarcoglycan (SGCE) gene. Work to date suggests that dystonia is caused by disruption of neuronal networks, principally basal ganglia-cerebello-thalamo-cortical circuits. Investigation of cortical involvement has primarily focused on disruption to interneuron inhibitory activity, rather than the excitatory activity of cortical pyramidal neurons. Here, we have sought to examine excitatory cortical glutamatergic activity using two approaches; the CRISPR/Cas9 editing of a human embryonic cell line, generating an SGCE compound heterozygous mutation, and three patient-derived induced pluripotent stem cell lines (iPSC) each gene edited to generate matched wild-type SGCE control lines. Differentiation towards a cortical neuronal phenotype demonstrated no significant differences in neither early- (PAX6, FOXG1) nor late-stage (CTIP2, TBR1) neurodevelopmental markers. However, functional characterisation using Ca2+ imaging and MEA approaches identified an increase in network activity, while single-cell patch clamp studies found a greater propensity towards action potential generation with larger amplitudes and shorter half-widths associated with SGCE-mutations. Bulk-RNA-seq analysis identified gene ontological enrichment for neuron projection development, synaptic signalling, and synaptic transmission. Examination of dendritic morphology found SGCE-mutations to be associated with a significantly higher number of branches and longer branch lengths, together with longer ion-channel dense axon initial segments, particularly towards the latter stages of differentiation (D80 and D100). Gene expression and protein quantification of key synaptic proteins (synaptophysin, synapsin and PSD95), AMPA and NMDA receptor subunits found no significant differences between the SGCE-mutation and matched wild-type lines. By contrast, significant changes to synaptic adhesion molecule expression were identified, namely higher pre-synaptic neurexin-1 and lower post-synaptic neuroligin-4 levels in the SGCE mutation carrying lines. Our study demonstrates an increased intrinsic excitability of cortical glutamatergic neuronal cells in the context of SGCE mutations, coupled with a more complex neurite morphology and disruption to synaptic adhesion molecules. These changes potentially represent key components to the development of the hyperkinetic clinical phenotype observed in Myoclonus Dystonia, as well a central feature to the wider spectrum of dystonic disorders, potentially providing targets for future therapeutic development.

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Movement Disorder Phenotypes in Children With 22q11.2 Deletion Syndrome

Cited by 12 publications

References 7 publications

Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Consequences of 22q11.2 Microdeletion on the Genome, Individual and Population Levels

Cortical neuronal hyperexcitability and synaptic changes in SGCE mutation-positive myoclonus dystonia

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