Atypical Angelman syndrome due to a mosaic imprinting defect: Case reports and review of the literature

Abstract

Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11-q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11-q13 imprinting defect on the maternal allele. These patients present with a milder phenotype, often with hyperphagia and obesity or non-specific intellectual disability. Unlike typical AS syndrome, they can have a vocabulary up to 100 words and speak in sentences. Ataxia and seizures may not be present, and the majority of individuals do not have microcephaly. Here we review the current literature and present three individuals with atypical AS caused by a mosaic imprinting defect to demonstrate why DNA methylation analysis at the SNRPN locus needs to be considered in a broader clinical context. © 2017 Wiley Periodicals, Inc.

Preserved expressive language as a phenotypic determinant of Mosaic Angelman Syndrome

“…Signs and symptoms of mAS were contrasted with the incidence of the core symptoms of AS (Williams et al, ) by chi‐square. Given the limitations of parental survey data, we additionally compared our findings to historical data in mAS patients described by Le Fevre et al (). Comparison between our cohort and the 28 patients described by Le Fevre et al () was with chi‐square.…”

“…Given the limitations of parental survey data, we additionally compared our findings to historical data in mAS patients described by Le Fevre et al (). Comparison between our cohort and the 28 patients described by Le Fevre et al () was with chi‐square. Comparison of specific behaviors from mAS patients and AS patients from within the NHS was with the student's t ‐test or with Fisher's exact test.…”

“…Cases of mosaic AS (mAS) have been described previously in the literature (Aypar et al, ; Camprubí et al, ; Fairbrother et al, ; Gillessen‐Kaesbach et al, ; Lawson‐Yuen, Wu, Lip, Sahoo, & Kimonis, ; Le Fevre et al, ; Nazlican et al, ). mAS is caused by cell populations with lack of expression of maternally inherited UBE3A and is detected by methylation studies that reveal partial methylation of the maternal allele (Aypar et al, ; Camprubí et al, ; Fairbrother et al, ; Le Fevre et al, ; Nazlican et al, ). In this case, somatic mosaicism with loss of maternal 15q11.2q13 ( SNRPN ) methylation pattern is caused by a post‐zygotic imprint maintenance error after primary cell division (Aypar et al, ; Camprubí et al, ; Fairbrother et al, ).…”

“…Another possible mechanism of mosaicism would include failed trisomy rescue in the case of uniparental disomy. Mosaic Angelman appears to be characterized by a milder phenotype; for example, the characteristic expressive language delay is milder with greater attainment of meaningful words (Le Fevre et al, ). We aim to profile the mAS phenotype in a larger collection of individuals to encourage clinicians to consider a lower threshold for adding this diagnosis to the differential and to discuss mAS in the context of piloting and developing meaningful outcome measures for upcoming clinical trials to impact the lives of individuals with Angelman syndrome.…”

Human cerebral organoids capture the spatiotemporal complexity and disease dynamics of UBE3A

“…We also note that topotecan treated samples appeared to have a compensatory rebound 10 days after treatment in which UBE3A-ATS increased beyond the original levels ( Figure 4F). In addition, both topotecan and indotecan were unable to fully rescue UBE3A to neurotypical levels, although studies suggest even partial rescue of UBE3A would have beneficial effects (Brockmann et al, 2002;Le Fevre et al, 2017;Meng et al, 2012). Collectively, these observations may inform the treatment window and regimen for potential future therapeutics.…”