Incontinence in Phelan‐McDermid Syndrome

Witmer, Claire P.; Mattingly, Aviva S.; D’Souza, Precilla; Thurm, Audrey; Hadigan, Colleen

doi:10.1097/mpg.0000000000002342

Cited by 6 publications

(20 citation statements)

References 18 publications

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“…Consistent with this idea, PMS and human KCNMA1/BK mutations are associated with several shared phenotypes including: autism, developmental delay, intellectual disability, hypotonia, seizures, and gastrointestinal defects (i.e. vomiting, constipation, or diarrhea) (Bailey et al, 2019;Laumonnier et al, 2006;Phelan and McDermid, 2012;Soorya et al, 2013;Witmer et al, 2019). Moreover, BK channels are regulated by two high confidence ASD genes (UBE3A and hnRNP U).…”

Section: Shank As a Regulator Of Ion Channel Densitymentioning

confidence: 72%

Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains

Gao

Zhao

Ardiel

et al. 2022

eLife

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Mutations altering the scaffolding protein Shank are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. Among its many binding partners, Shank directly binds CaV1 voltage activated calcium channels. Here we show that the C. elegans SHN-1/Shank promotes CaV1 coupling to calcium activated potassium channels. Mutations inactivating SHN-1, and those preventing SHN-1 binding to EGL-19/CaV1 all increase action potential durations in body muscles. Action potential repolarization is mediated by two classes of potassium channels: SHK-1/KCNA and SLO-1 and SLO-2 BK channels. BK channels are calcium-dependent, and their activation requires tight coupling to EGL-19/CaV1 channels. SHN-1's effects on AP duration are mediated by changes in BK channels. In shn-1 mutants, SLO-2 currents and channel clustering are significantly decreased in both body muscles and neurons. Finally, increased and decreased shn-1 gene copy number produce similar changes in AP width and SLO-2 current. Collectively, these results suggest that an important function of Shank is to promote microdomain coupling of BK with CaV1.

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Section: Shank As a Regulator Of Ion Channel Densitymentioning

confidence: 72%

Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains

Gao

Zhao

Ardiel

et al. 2022

eLife

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“…Rates of GER range from 42% to 59% (Sarasua et al, 2014; Soorya et al, 2013; Witmer et al, 2019). In a small cohort of 17 children with PMS studied at the National Institutes of Health (NIH), 4/17 had functional constipation, 13/17 had fecal incontinence, and 10/17 had GER, as assessed by Rome IV criteria (Witmer et al, 2019). Additionally, 13 cases had colonic transit studies using Sitz markers, which was abnormal in 2 of the 13 studies completed.…”

Section: Resultsmentioning

confidence: 99%

“…The most common nonstructural genitourinary abnormality is delayed or persistent incontinence, common in PMS (Hussong et al, 2020; Witmer et al, 2019). Individuals with large chromosomal deletions may be more likely to have urinary or bowel incontinence compared with those with small chromosomal deletions (Witmer et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Updated consensus guidelines on the management of Phelan–McDermid syndrome

Srivastava,

Sahin,

Buxbaum

et al. 2023

American J of Med Genetics Pt A

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Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and largescale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The For affiliations refer to page 2038

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“…Also referring to the abovementioned observation of an altered microbiome [ 161 , 211 , 212 ], the gastrointestinal system might be an interesting peripheral target for further investigation. Since ASD and also the PMDS are frequently associated with gastrointestinal alterations [ 221 – 223 ], and the insular cortex, which has often been described as visceroceptive hub and center of multisensory integration in general [ 208 , 224 , 225 ], is also affected in SHANK3-deficient mice, dysregulated visceral signals to the insula or other involved regions might contribute to the overall phenotype by affecting the gut-brain axis [ 208 ].…”

Section: Main Textmentioning

confidence: 99%

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

Delling

Boeckers

2021

J Neurodevelop Disord

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Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

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Incontinence in Phelan‐McDermid Syndrome

Cited by 6 publications

References 18 publications

Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains

Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains

Updated consensus guidelines on the management of Phelan–McDermid syndrome

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

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