An observational study of pediatric healthcare burden in Angelman syndrome: results from a real-world study.

BACKGROUND:The objective of this study is to describe variations in the healthcare resource utilization (HRU) among individuals with Angelman syndrome (AS) over the first 12 years of life. Data for this study were drawn from the AS Natural History study (ASNHS), which is an observational study on the developmental progress, behavior, and medical morbidity of individuals with AS conducted over eight years. Caregiver-reported information on hospitalization, surgery, and medication utilization was used to assess HRU. Repeated measures mixed effect models were used to assess the relationship between age and probability of hospitalization, surgery, and prescription medication utilization. RESULTS:Mean age at study enrollment was 6 years of age and both sexes were equally represented. The mean number of visits per participant was three. Results from this study suggest that individuals with AS have a high HRU burden. Hospitalization and surgery burden were highest in the first year of life. Use of medications for seizures and sleep disturbance increased over time. CONCLUSIONS:The study highlights the significant healthcare burden among individuals with AS. Future studies that estimate cost and caregiver burden associated with AS are needed to assess the lifelong economic impact of AS on families and healthcare system

X-linked Malformation and Infantile Lethality Syndrome (provisionally named Ogden Syndrome)

This is a lethal X-linked disorder of infancy comprising a distinct combination of distinctive craniofacial features producing an aged appearance, growth failure, hypotonia, global developmental delays, cryptorchidism, and acquired cardiac arrhythmias. The first family was identified in Ogden, Utah, with five affected boys in two generations of family members. A mutation was identified as a c.109T>C(p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NatA). This same mutation was identified in a second unrelated family, with three affected boys in two generations. This X-linked Malformation and Infantile Lethality Syndrome has provisionally been named Ogden Syndrome, in honor of the hometown where the first family resides

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

BackgroundAngelman 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.ResultsA 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.ConclusionsThis 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 registrationNCT00348933 . Registered 6 July 2006

Erratum to: Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis

After publication of our article [1], we became aware that there were two minor data loading and analysis scripting errors in the human EEG data processing pipeline. These errors affected the channel loading/grouping and sleep/ wake coding of EEG data. We have re-analysed all the data affected by these errors. The errors do not affect any interpretations or conclusions, thus no changes to the text are required apart from correcting p values and raw values affected by the errors. There are no changes to statistical significance or lack-thereof. The errors affect data presented in Fig. 3, Fig. 4, Fig. 5, and Additional file 3: Figure S3 and thus we have re-plotted these figures (see below)

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells

Diazoxide choline extended‐release tablet in people with Prader‐Willi syndrome: results from long‐term open‐label study

Objective: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). Methods: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. Results: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] −9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). Conclusions: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families