Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment

Keute, Marius; Miller, Meghan T.; Krishnan, Michelle L.; Sadhwani, Anjali; Chamberlain, Stormy J.; Thibert, Ronald L.; Tan, Wen‐Hann; Bird, Lynne M.; Hipp, Joerg F.

doi:10.1038/s41380-020-0858-6

Cited by 55 publications

(43 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a genomic imprinting disorder, AS has featured presentations that include global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile [ 1 , 5 , 6 , 7 ]. This rare neurodevelopment disorder has a prevalence of 1 in 10,000–24,000 births [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Genotype–Phenotype Correlations in Angelman Syndrome

Yang

Shu

Mao

et al. 2021

Genes

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Genotype–Phenotype Correlations in Angelman Syndrome

Yang

Shu

Mao

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…Angelman syndrome (OMIM: 105830) is a neurogenetic imprinting disorder with an estimated incidence of 1 in 10,000‐24,000 births. (Keute et al, 2020; Thibert et al, 2013). AS is caused by the loss or mutation of regional imprinting and maternal genes especially influences on the UBE3A gene.…”

Section: Discussionmentioning

confidence: 99%

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

Huang

Chen

et al. 2021

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background The 15q11‐q13 region contains three breakpoints (BP1 to BP3), and copy number variations often occur in the region. Aims 15q11‐q13 microdeletion and microduplication are usually associated with Prader‐Willi and Angelman syndromes, respectively. It is not yet clear to what extent microdeletion and microduplication affect the physical health of the fetus and the child. In this study, we examined seven fetuses ranging in gestational age from 15 to 27 weeks. Materials & Methods Detailed prenatal screening and laboratory examinations were performed, while karyotype analysis and chromosomal microarray analysis (CMA) of the amniotic fluid and umbilical cord blood were applied for genetic analysis. Results CMA analysis showed that four fetuses harbored a microdeletion and one fetus showed a microduplication at 15q11.2 BP1‐BP2, two fetuses had a microdeletion at 15q11‐q13 BP2‐BP3, and one fetus had an additional microdeletion at 16p13.11. Discussion There is no clear standard for the clinical diagnosis of 15q11‐q13 microdeletion and microduplication, some of them have clinical phenotypes or are clinically affected. Conclusion Therefore, parents of such fetuses should be informed of the possibility of microdeletions or microduplications to mitigate the psychological burden, and medical consultation and assistance should be provided when communicating the results of the mid‐gestation screening.

show abstract

“…Individuals with Angelman syndrome can have developmental delay, almost universal loss of speech (with the majority of the patient population being completely non-verbal), gross motor dysfunction, ataxia/balance issues, fine motor limitations, severe sleep disturbances, and debilitating seizures [ 28 , 29 ]. The expression of these manifestations can be widely variable between patients [ 28 – 30 ]. Some individuals with Angelman syndrome have difficulty with walking and balance, some do not respond to their name, and most do not speak any words.…”

Section: Summary Of Key Learnings From the Phase 3 Laronidase Studymentioning

confidence: 99%

The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases

Tandon

Kakkis

2021

Orphanet J Rare Dis

View full text Add to dashboard Cite

In traditional clinical trial design, efficacy is typically assessed using a single primary endpoint in a randomized controlled trial to detect an expected treatment effect of a therapy in a narrowly selected patient population. This accepted paradigm is based on clinical evaluations that may not actually capture the breadth of the impact of a disease, which is especially true in the setting of complex, multisystem, rare diseases with small, extremely heterogeneous patient populations. The multi-domain responder index (MDRI) is a novel approach that accommodates complex and heterogeneous disease manifestations and evaluates a broad array of clinical disease without impairing the power or rigor of a study to fully understand a treatment. The MDRI sums the scores corresponding to clinically significant thresholds of change for each component domain in each individual patient, capturing the mean clinically meaningful change across multiple domains within individuals. This novel approach combines and then sums the results of independent domain endpoint responder analyses into one responder score to provide a broad basis for the assessment of efficacy. The impact of a treatment across multiple, physiologically independent domains, can be assessed clinically, reducing the adverse impact of heterogeneity on trial outcomes and allowing eligibility criteria to enroll a wider range of patients, ultimately resulting in efficacy and safety assessments of a therapy across a broad group of heterogeneous patients in rare disease programs.Trial registration The following studies are referenced within this manuscript (CLINICALTRIALS.GOV registration numbers): NCT00912925; NCT00146770; NCT00067470; NCT00104234; NCT00069641; NCT02230566; NCT02377921; NCT02432144.

show abstract

Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment

Cited by 55 publications

References 33 publications

Genotype–Phenotype Correlations in Angelman Syndrome

Genotype–Phenotype Correlations in Angelman Syndrome

A report on seven fetal cases associated with 15q11‐q13 microdeletion and microduplication

The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases

Contact Info

Product

Resources

About