scholarly journals Genotype–Phenotype Correlations in Angelman Syndrome

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 987
Author(s):  
Lili Yang ◽  
Xiaoli Shu ◽  
Shujiong Mao ◽  
Yi Wang ◽  
Xiaonan Du ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Cognitive Skills ◽  
Molecular Mechanisms ◽  
Uniparental Disomy ◽  
Treatment Modalities ◽  
Global Developmental Delay ◽  
Loss Of Function ◽  
Neurodevelopmental Disease ◽  
Severe Intellectual Disability ◽  
New Treatment

Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11–q13, paternal uniparental disomy of chromosome 15q11–q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11–13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype–phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype–phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype–phenotype correlations based on larger data should be carried out for identifying new treatment modalities.

Molecular Analysis of an Extra inv dup(15)(q13) Chromosome in Two Patients with Angelman Syndrome

1996 ◽  
Vol 45 (1-2) ◽  
pp. 217-220 ◽  
Author(s):  
T. Buchholz ◽  
S. Schuffenhauer ◽  
K. Evans ◽  
L. Robson ◽  
B. Appleton ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Angelman Syndrome ◽  
Uniparental Disomy ◽  
Molecular Data ◽  
Monoallelic Expression ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Maternal Allele ◽  
Molecular Defects

Angelman syndrome (AS) is caused by the loss of function of yet unidentified gene(s) which map within 15q 11-13 and show monoallelic expression from the maternal allele. Lack of the maternal allele(s), due to either a deletion on the maternal chromosome 15 (about 70% of AS patients) or a paternal uniparental disomy (UPD)15 (<5%), are the most common molecular defects in AS. Prader-Willi syndrome (PWS) also maps to proximal 15q, but is caused by the loss of function of paternally expressed gen(s) [1]. Here we describe clinical, cytogenetic and molecular data for two non-related patients with AS who carry a nonmosaic extra cromosome inv dup(15).

scholarly journals Prader-Willi syndrome: reflections on seminal studies and future therapies

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200195
Author(s):  
Michael S. Chung ◽  
Maéva Langouët ◽  
Stormy J. Chamberlain ◽  
Gordon G. Carmichael
Keyword(s):  
Genomic Imprinting ◽  
Angelman Syndrome ◽  
Cpg Island ◽  
Uniparental Disomy ◽  
Large Deletion ◽  
Paternal Allele ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Maternal Uniparental Disomy ◽  
Parental Allele

Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in which genes are expressed exclusively from one parental allele. The genomic imprinting of the 15q11-q13 locus is established in the germline and is largely controlled by a bipartite imprinting centre. One part, termed the Prader-Willi syndrome imprinting center (PWS-IC), comprises a CpG island that is unmethylated on the paternal allele and methylated on the maternal allele. The second part, termed the Angelman syndrome imprinting centre, is required to silence the PWS_IC in the maternal germline. The loss of the paternal contribution of the imprinted 15q11-q13 locus most frequently occurs owing to a large deletion of the entire imprinted region but can also occur through maternal uniparental disomy or an imprinting defect. While PWS is considered a contiguous gene syndrome based on large-deletion and uniparental disomy patients, the lack of expression of only non-coding RNA transcripts from the SNURF-SNRPN/SNHG14 may be the primary cause of PWS. Patients with small atypical deletions of the paternal SNORD116 cluster alone appear to have most of the PWS related clinical phenotypes. The loss of the maternal contribution of the 15q11-q13 locus causes a separate and distinct condition called Angelman syndrome. Importantly, while much has been learned about the regulation and expression of genes and transcripts deriving from the 15q11-q13 locus, there remains much to be learned about how these genes and transcripts contribute at the molecular level to the clinical traits and developmental aspects of PWS that have been observed.

scholarly journals A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Poh Hui Chia ◽  
Franklin Lei Zhong ◽  
Shinsuke Niwa ◽  
Carine Bonnard ◽  
Kagistia Hana Utami ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Germline Mutation ◽  
Growth Delay ◽  
Global Developmental Delay ◽  
Loss Of Function ◽  
C Elegans ◽  
Calcium Calmodulin Dependent ◽  
Severe Intellectual Disability

Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p.His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.In vivo, CAMK2AH477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.

scholarly journals A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Julia Han ◽  
Terry Jo Bichell ◽  
Stephanie Golden ◽  
Irina Anselm ◽  
Susan Waisbren ◽  
...  
Keyword(s):  
Folic Acid ◽  
Angelman Syndrome ◽  
Antisense Transcript ◽  
Controlled Trial ◽  
Neurodevelopmental Disorder ◽  
Uniparental Disomy ◽  
Identical Twins ◽  
Clinical Phenotypes ◽  
Severe Intellectual Disability ◽  
The Brain

Abstract Background Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 − 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain. Results A potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events. Conclusions This study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies. Trial registration NCT00348933. Registered 6 July 2006.

scholarly journals Pathogenic SPTBN1 variants cause a novel autosomal dominant neurodevelopmental syndrome

2020 ◽  
Author(s):  
Margot A Cousin ◽  
Keith A. Breau ◽  
Blake A. Creighton ◽  
Rebecca C. Spillman ◽  
Erin Torti ◽  
...  
Keyword(s):  
Neural Development ◽  
Plasma Membranes ◽  
Neuronal Development ◽  
Critical Role ◽  
Dominant Negative ◽  
Global Developmental Delay ◽  
Loss Of Function ◽  
Cytoskeleton Organization ◽  
Severe Intellectual Disability ◽  
The Brain

SPTBN1 encodes βII-spectrin, the ubiquitously expressed member of the β-spectrin family that forms micrometer-scale networks associated with plasma membranes. βII-spectrin is abundantly expressed in the brain, where it is essential for neuronal development and connectivity. Mice deficient in neuronal βII-spectrin expression have defects in cortical organization, global developmental delay, dysmorphisms, and behavioral deficiencies of corresponding severity. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous variants in this gene may also present with measurable compromise of neural development and function. Here we report the identification of heterozygous SPTBN1 variants in 29 individuals who present with global developmental, language and motor delays, mild to severe intellectual disability, autistic features, seizures, behavioral and movement abnormalities, hypotonia, and variable dysmorphic facial features. We show that these SPTBN1 variants lead to loss-of-function, gain-of-function, and dominant negative effects that affect protein stability, disrupt binding to key protein partners, and affect cytoskeleton organization and dynamics. Our studies define the genetic basis of this new neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and neural development, and underscore the critical role of βII-spectrin in the central nervous system.

scholarly journals Molecular-Genetic Diagnostics of Angelman Syndrome – The Bulgarian Experience

2020 ◽  
Vol 47 (1) ◽  
pp. 9-16
Author(s):  
B. Georgieva ◽  
S. Atemin ◽  
A. Todorova ◽  
T. Todorov ◽  
A. Miteva ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Angelman Syndrome ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Molecular Genetic ◽  
Regulatory Region ◽  
Uniparental Disomy ◽  
Pcr Multiplex ◽  
Ube3a Gene ◽  
Mechanisms Of Mutagenesis

AbstractObjective: The aim of the study was to determine the molecular mechanisms of mutagenesis in Bulgarian patients with Angelman syndrome (AS). AS is a severe neurodevelopmental disorder caused by loss of expression in brain of the maternally inherited UBE3A gene as a result of various 15q11.2-q13 alterations.Material and Methods: In total 24 patients (11 boys, 13 girls) from 22 unrelated families with suspected clinical diagnosis AS were analysed. We used methylation specific PCR, multiplex ligation-dependent probe amplification, methylation sensitive MLPA, and direct sequencing of the UBE3A gene.Results: In 9 families (41%) pathogenic mutations were detected, which confirmed the clinical diagnosis on а molecular-genetic level. In 4 (44%) of these families we found 15q11-q13 region deletion with breakpoints BP1-BP3 or BP2-BP3. In 1 (11%) of the families we found imprinting defect: deletion of the AS-SRO regulatory region (part of the PWS-AS imprinting center). In 1 (11%) of the families we detected a rare finding – paternal uniparental disomy of chromosome 15. In 3 (33%) of the families diff erent point mutations in the UBE3A gene were detected: two novel missence mutations c.488T > C; p.Leu163Ser and c.1832A > T; p.Gln611Leu, and one known frameshift mutation c.2576_2579delAAGA; p.Lys859Argfs*4.Conclusion: The obtained results helped us to develop a systematic diagnostic algorithm in order to provide proper diagnosis for the patients with AS. Combining excellent knowledge of the molecular mechanisms of mutagenesis and proper molecular-genetic testing approaches is a cornerstone in the management of AS patients, ensuring AS families would receive both adequate genetic counseling and prophylaxis of the disease in the future.

Management of thoracic aortic lesions - the future is endovascular

VASA ◽  
2012 ◽  
Vol 41 (3) ◽  
pp. 163-176 ◽  
Author(s):  
Weidenhagen ◽  
Bombien ◽  
Meimarakis ◽  
Geisler ◽  
A. Koeppel
Keyword(s):  
Thoracic Aorta ◽  
Clinical Decision Making ◽  
Treatment Options ◽  
Clinical Decision ◽  
Clinical Results ◽  
Treatment Modalities ◽  
Traumatic Rupture ◽  
Descending Thoracic Aorta ◽  
New Treatment ◽  
Aneurysm Dissection

Open surgical repair of lesions of the descending thoracic aorta, such as aneurysm, dissection and traumatic rupture, has been the “state-of-the-art” treatment for many decades. However, in specialized cardiovascular centers, thoracic endovascular aortic repair and hybrid aortic procedures have been implemented as novel treatment options. The current clinical results show that these procedures can be performed with low morbidity and mortality rates. However, due to a lack of randomized trials, the level of reliability of these new treatment modalities remains a matter of discussion. Clinical decision-making is generally based on the experience of the vascular center as well as on individual factors, such as life expectancy, comorbidity, aneurysm aetiology, aortic diameter and morphology. This article will review and discuss recent publications of open surgical, hybrid thoracic aortic (in case of aortic arch involvement) and endovascular repair in complex pathologies of the descending thoracic aorta.

Role of Phytochemicals in the Treatment of Breast Cancer: Natural Swords battling Cancer Cells

2021 ◽  
Vol 16 ◽  
Author(s):  
Rajni Sawanny ◽  
Sheersha Pramanik ◽  
Unnati Agarwal
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Low Cost ◽  
Epigallocatechin Gallate ◽  
Cancer Therapeutics ◽  
Treatment Modalities ◽  
Breast Cancer Patients ◽  
Scientific Validity ◽  
Phytochemical Study ◽  
Treat Breast Cancer

: Breast cancer is the most common type of malignancy among ladies (around 30% of newly diagnosed patients every year). To date, various modern treatment modalities for breast cancer, such as radiotherapy, surgical method, hormonal therapy, and chemotherapeutic drug utilisation, are available. However, adverse drug reactions, therapeutic resistance, metastasis, or cancer reoccurrence chances remain the primary causes of mortality for breast cancer patients. To overcome all the potential drawbacks, we need to investigate novel techniques and strategies previously not considered and treat breast cancer effectively with safety and efficacy. For centuries, we utilise phytochemicals to treat various diseases because of their safety, low-cost & least or no side effects. Recently, naturally produced phytochemicals gain immense attention as potential breast cancer therapeutics because of their ideal characteristics; for instance, they operate via modulating molecular pathways associated with cancer growth and progression. The primary mechanism involves inhibition of cell proliferation, angiogenesis, migration, invasion, increasing anti-oxidant status, initiation of the arrest of the cell cycle, and apoptosis. Remedial viability gets effectively enhanced when phytochemicals work as adjuvants with chemotherapeutic drugs. This comprehensive review revolves around the latest chemopreventive, chemotherapeutic, and chemoprotective treatments with their molecular mechanisms to treat breast cancer by utilising phytochemicals such as vinca alkaloids, resveratrol, curcumin, paclitaxel, silibinin, quercetin, genistein and epigallocatechin gallate. The authors wish to extend the field of phytochemical study for its scientific validity and its druggability.

Systematic literature review of clinical outcomes in adults with metastatic or advanced synovial sarcoma

2020 ◽  
Vol 16 (35) ◽  
pp. 2997-3013
Author(s):  
Kentaro Kogushi ◽  
Michael LoPresti ◽  
Shunya Ikeda
Keyword(s):  
Synovial Sarcoma ◽  
High Frequency ◽  
Clinical Evidence ◽  
Systemic Treatment ◽  
Progression Free Survival ◽  
Treatment Modalities ◽  
Free Survival ◽  
New Treatment ◽  
Poor Outcomes

Background: Synovial sarcoma (SS) is a rare, aggressive soft tissue sarcoma with a poor prognosis after metastasis. The objective of this study was to conduct a systematic review of the clinical evidence for therapeutic options for adults with metastatic or advanced SS. Materials & methods: Relevant databases were searched with predefined keywords. Results: Thirty-nine publications reported clinical data for systemic treatment and other interventions. Data on survival outcomes varied but were generally poor (progression-free survival: 1.0–7.7 months; overall survival: 6.7–29.2 months) for adults with metastatic and advanced SS. A high frequency of neutropenia with systemic treatment and low quality of life post-progression were reported. Conclusion: Reported evidence suggests poor outcomes in adults with metastatic and advanced SS and the need for the development of new treatment modalities.

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