15q11-q13 Region Research Articles

Successful Electroconvulsive Therapy in a Patient With Catatonia and Maternal Duplication 15q11-13 Syndrome.

The 15q11-q13 chromosomal region contains genes encoding for GABA-A receptor subunits and is a known region of epigenetic modification associated with the development of neurodevelopmental disorders. The presence of at least one additional copy of the maternal 15q11-q13 results in a syndrome (maternal dup15q) characterized by intellectual disability, autism spectrum disorder, mood disorders, and epilepsy. Catatonia is a serious syndrome of behavioral and motor dysfunction, which occurs across a variety of psychiatric, neurologic, and general medical conditions, which has successfully been treated with benzodiazepines and electroconvulsive therapy. In this case report, we describe the treatment course of a patient with established maternal dup 15q with comorbid intellectual disability, autism spectrum disorder, bipolar mood disorder, and juvenile epilepsy who developed hypokinetic catatonia refractory to high-dose benzodiazepine therapy. In contrast with benzodiazepine treatment, electroconvulsive therapy resulted in rapid improvement in catatonic symptoms and return to premorbid baseline. This case suggests that electroconvulsive therapy can be safely delivered for some patients with maternal dup 15q and may be rapidly effective when benzodiazepine treatment results in inadequate symptom improvement.

Investigating the correlation between genotype and phenotype in Prader-Willi syndrome: a study of 45 cases from Brazil

BackgroundPrader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in PWS is crucial for improved genetic counseling and prognosis. In this study, we aimed to investigate the correlation between genotype and phenotype in 45 PWS patients who previously underwent methylation-sensitive high-resolution melting (MS-HRM) for diagnosis.ResultsWe employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and Sanger sequencing, along with collecting phenotypic data from the patients for comparison. Among the 45 patients, 29 (64%) exhibited a deletion of 15q11-q13, while the remaining 16 (36%) had uniparental disomy. No statistically significant differences were found in the main signs and symptoms of PWS. However, three clinical features showed significant differences between the groups. Deletion patients had a higher prevalence of myopia than those with uniparental disomy, as well as obstructive sleep apnea and an unusual skill with puzzles.ConclusionsThe diagnostic tests (MS-HRM, MS-MLPA, and Sanger sequencing) yielded positive results, supporting their applicability in PWS diagnosis. The study’s findings indicate a general similarity in the genotype-phenotype correlation across genetic subtypes of PWS.

Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome

Prader-Willi syndrome (PWS) is the prototypic genomic disorder resulting from deficiency of paternally expressed genes in the human chromosome 15q11-q13 region. The unique molecular mechanism involving epigenetic modifications renders PWS as the most attractive candidate to explore a proof-of-concept of epigenetic therapy in humans. The premise is that epigenetic modulations could reactivate the repressed PWS candidate genes from the maternal chromosome and offer therapeutic benefit. Our prior study identifies an EHMT2/G9a inhibitor, UNC0642, that reactivates the expression of PWS genes via reduction of H3K9me2. However, low brain permeability and poor oral bioavailability of UNC0642 preclude its advancement into translational studies in humans. In this study, a newly developed inhibitor, MS152, modified from the structure of UNC0642 has better brain penetration, more potency and selectivity against EHMT2/G9a. MS152 reactivated maternally silenced PWS genes in PWS patient fibroblasts and in brain and liver tissues of PWS mouse models. Importantly, the molecular efficacy of oral administration is comparable to intraperitoneal route. MS152 treatment in newborns ameliorated the perinatal lethality and poor growth, maintaining reactivation in a PWS mouse model at postnatal 90 days. Our findings provide strong support for MS152 as a first-in-class inhibitor to advance the epigenetic therapy of PWS in humans.

Behavioral changes in patients with Prader-Willi syndrome receiving diazoxide choline extended-release tablets compared to the PATH for PWS natural history study

BackgroundPrader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602.MethodsTo better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0–36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP).ResultsRelative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants.ConclusionLong-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families.Trial RegistrationClinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).

Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region.

The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome. Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.

UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies.

Published reports from the CDC's Autism and Development Disabilities Monitoring Networks have shown that an average of 1 in every 44 (2.3%) 8-year-old children were estimated to have ASD in 2018. Many of the ASDs exhibiting varying degrees of autism-like phenotypes have chromosomal anomalies in the Chr15q11-q13 region. Numerous potential candidate genes linked with ASD reside in this chromosomal segment. However, several clinical, in vivo, and in vitro studies selected one gene more frequently than others randomly and unbiasedly. This gene codes for UBE3A or Ubiquitin protein ligase E3A [also known as E6AP ubiquitin-protein ligase (E6AP)], an enzyme involved in the cellular degradation of proteins. This gene has been listed as one of the several genes with a high potential of causing ASD in the Autism Database. The gain of function mutations, triplication, or duplication in the UBE3A gene is also associated with ASDs like Angelman Syndrome (AS) and Dup15q Syndrome. The genetic imprinting of UBE3A in the brain and a preference for neuronal maternal-specific expression are the key features of various ASDs. Since the UBE3A gene is involved in two main important diseases associated with autism-like symptoms, there has been widespread research going on in understanding the link between this gene and autism. Additionally, since no universal methodology or mechanism exists for identifying UBE3A-mediated ASD, it continues to be challenging for neurobiologists, neuroscientists, and clinicians to design therapies or diagnostic tools. In this review, we focus on the structure and functional aspects of the UBE3A protein, discuss the primary relevance of the 15q11-q13 region in the cause of ASDs, and highlight the link between UBE3A and ASD. We try to broaden the knowledge of our readers by elaborating on the possible mechanisms underlying UBE3A-mediated ASDs, emphasizing the usage of UBE3A as a prospective biomarker in the preclinical diagnosis of ASDs and discuss the positive outcomes, advanced developments, and the hurdles in the field of therapeutic strategies against UBE3A-mediated ASDs. This review is novel as it lays a very detailed and comprehensive platform for one of the most important genes associated with diseases showing autistic-like symptoms. Additionally, this review also attempts to lay optimistic feedback on the possible steps for the diagnosis, prevention, and therapy of these UBE3A-mediated ASDs in the upcoming years.

Early onset critically ill infants with Schaaf-Yang syndrome: a retrospective study from the China neonatal genomes project and literature review.

Schaaf-Yang syndrome (SYS) is a recently identified rare neurodevelopmental disorder characterized by neonatal hypotonia, feeding difficulty, joint contractures, autism spectrum disorder and development delay/intellectual disability. It is mainly caused by truncating variants in maternally imprinted gene MAGEL2 within the Prader-Willi syndrome critical region 15q11-q13. Clinical diagnosis of SYS is difficult for clinicians due to its rarity and highly variable phenotypes, while unique inheritance patterns also complicate genetic diagnosis. To date, no published papers have analyzed the clinical consequences and molecular changes in Chinese patients. In this study, we retrospectively investigated the mutation spectrums and phenotypic features of 12 SYS infants. The data were from a cohort of critically ill infants from the China neonatal genomes project (CNGP), sponsored by Children's Hospital of Fudan University. We also reviewed relevant literature. Six previously reported mutations and six novel pathogenic variations of MAGEL2 were identified in 12 unrelated infants. Neonatal respiratory problems were the major complaint for hospitalization, which occurred in 91.7% (11/12) cases. All babies displayed feeding difficulties and a poor suck postnatally, and neonatal dystonia was present in 11 of the cases; joint contractures and multiple congenital defects were also observed. Interestingly, we found that 42.5% (57/134) of the reported SYS patients, including ours carried variants in the c.1996 site, particularly the c.1996dupC variant. The mortality rate was 17.2% (23/134), with the median age of death between 24 gestational weeks in fetuses and 1-month-old in infants. Respiratory failure was the leading cause of death in live-born patients (58.8%, 10/17), especially during the neonatal period. Our findings expanded the genotype and phenotype spectrum of neonatal SYS patients. The results demonstrated that respiratory dysfunction was a typical characteristic among Chinese SYS neonates that should attract physicians' attention. The early identification of such disorders allows early intervention and can further provide genetic counseling as well as reproductive options for the affected families.

CD16+ monocytes are involved in the hyper-inflammatory state of Prader-Willi Syndrome by single-cell transcriptomic analysis.

Patients with Prader-Willi syndrome (PWS) have a reduced life expectancy due to inflammation-related disease including cardiovascular disease and diabetes. Abnormal activation of peripheral immune system is postulated as a contributor. However, detailed features of the peripheral immune cells in PWS have not been fully elucidated. Serum inflammatory cytokines were measured in healthy controls (n=13) and PWS patients (n=10) using a 65- multiplex cytokine assays. Changes of the peripheral immune cells in PWS was assessed by single-cell RNA sequencing (scRNA-seq) and high-dimensional mass cytometry (CyTOF) using peripheral blood mononuclear cells (PBMCs) from PWS patients (n=6) and healthy controls (n=12). PWS patients exhibited hyper-inflammatory signatures in PBMCs and monocytes were the most pronounced. Most inflammatory serum cytokines were increased in PWS, including IL-1β, IL-2R, IL-12p70, and TNF-α. The characteristics of monocytes evaluated by scRNA-seq and CyTOF showed that CD16+ monocytes were significantly increased in PWS patients. Functional pathway analysis revealed that CD16+ monocytes upregulated pathways in PWS were closely associated with TNF/IL-1β- driven inflammation signaling. The CellChat analysis identified CD16+ monocytes transmitted chemokine and cytokine signaling to drive inflammatory process in other cell types. Finally, we explored the PWS deletion region 15q11-q13 might be responsible for elevated levels of inflammation in the peripheral immune system. The study highlights that CD16+ monocytes contributor to the hyper-inflammatory state of PWS which provides potential targets for immunotherapy in the future and expands our knowledge of peripheral immune cells in PWS at the single cell level for the first time.

Hyperphagia in Prader-Willi syndrome with obesity: From development to pharmacological treatment.

Prader-Willi syndrome (PWS) is a rare genetic disorder due to lack of genes expression inherited from the paternal chromosome 15q11-q13 region usually from paternal deletions, maternal uniparental disomy 15 or imprinting defect. There are two different nutritional stages reported in an individual with PWS; first stage during infancy marked by feeding and growth difficulties and second stage where hyperphagia starts and leads to development of obesity. However, the exact mechanism of hyperphagia development, from having difficulties in feeding during early years to insatiable appetite after they grow is still unknown and is the focused in this review. The keywords used for literature search such as "Prader-Willi syndrome", "hyperphagia", "obesity", and "treatment" were used to create the search strings by using synonyms in order to retrieve the relevant records from PubMed, Scopus and Science Direct. The possible mechanism of hyperphagia can be classed into hormonal abnormalities such as increase in ghrelin and leptin from infancy to adulthood. Low level of hormones was observed in the thyroid, insulin and peptide YY at certain ages. Neuronal abnormalities contributed by Orexin A and brain structure alteration was documented at 4-30 years old. Treatment in the form of drugs such as livoletide, topiramate, and diazoxide could potentially alleviate these abnormalities and make hyperphagia less prominent in PWS. The approaches are important to regulate the hormonal changes and neuronal involvement as potentially controlling hyperphagia and obesity.

Prader-Willi and Angelman Syndromes: Mechanisms and Management.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition. Management should include a multidisciplinary team by various medical subspecialists and therapists. Developmental and behavioral management of PWS and AS in infancy and early childhood includes early intervention services and individualized education programs for school-aged children. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS.

Prader-Willi syndrome patient with atypical phenotypes caused by mosaic deletion in the paternal 15q11-q13 region: a case report

BackgroundPrader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by the loss of paternally expressed genes in the human chromosome region 15q11.2-q13. It is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity. Motor milestones and language development are delayed and most patients have intellectual disability.Case presentationHere we describe a rare PWS case caused by mosaic imprinting defect in the region 15q11.2-q13 of paternal origin. The proband was a male child with a clinical presentation of global developmental delay and hypotonia with specific facial features. Karyotype of the child was noted as mosaic: 45XY,der(15)?t(15;21),-21[26]/46,XY[24]. Whole-exome sequencing (WES) identified a deletion of 22.7 Mb in size at chr15q11.2q21.1 region and a deletion of 2.1 Mb in size at chr21q22.3 region. The Methylation-specific multiplex ligation-dependent probe amplification(MS-MLPA) of the 15q11.2-q13 region showed that the loading ratio of methylated alleles was 70% and that of unmethylated alleles was 30%(50% normal), which confirmed that the loss of mosaic imprinted defects in the paternal allele led to the diagnosis of PWS.ConclusionsWe propose that complete clinical criteria for PWS should not be considered sensitive in diagnosing partial atypical PWS due to mosaic imprinting defects. In contrast, clinical suspicion based on less restrictive criteria followed by multiple techniques is a more powerful approach.

Quality of Life in Children with Prader-Willi Syndrome and the Impact of the Disease on the Functioning of Families.

Objective: Prader−Willi (PWS; OMIM#176270) syndrome is a clinically distinct genetic disorder, caused by an abnormality in the 15q11-q13 region, referred to as the critical region. One of the most popular concepts existing in modern sciences, not only within psychology, but also in the aspect of all sciences that are related to human life and its course, is the quality of life (QoL). Though it is known that health-related quality of life in children with PWS can be reduced, less is understood about the impact on the family. We aimed to identify factors related to the quality of life of children with PWS and the impact of the disease on family functioning. Methods: A cross-sectional questionnaire survey. The subjects were 46 parents of children with PWS. The Computer Assisted Self-Interviewing (CASI) method was used; the Paediatric Quality of Life Inventory and the PedsQL Family Impact Module. Results: The PedsQL mean score was 49.0; (min−max: 5.6−90.8; SD = 16.8), with the highest scores in the Emotional Functioning (EF) (EF; 55.9; min−max: 5.0−100.0; SD = 22.0), and the lowest in the Social Functioning (SF) (SF; 42.7; min−max: 5.0−85.0; SD = 18.7) 56.4 (SD ± 14.7). The child’s age does not affect the quality of life, there were no statistically significant (p > 0.05). families have difficulties in performing daily activities (total score 27.6; SD 16.7), support family functioning (total score 28.9; SD 18.8) and effects physical domain (total score 27.7; SD 15.7). Conclusion: Research on the QoL of patients with PWS and their families is very important in order to assess the QoL, but also to provide the perspective of an active change in the perspective of a better treatment process, rehabilitation and communication in society.

Prader-Willy syndrome: heterogenous genetic mechanisms in a wide phenotypic spectrum

Prader-Willi syndrome (PWS) is an imprinted neuro-behavioral syndrome, affecting many organ systems, characterized by severe hypothalamic-pituitary dysfunction, severe hypotonia, feeding difficulties in the neonatal period, followed by hyperphagia with gradual development of morbid obesity since early childhood, short stature, hypogonadism, infertility, characteristic facial features, impaired motor and language development, cognitive impairment of varying degrees, delayed speech, increased risk of developing autism spectrum disorders (ASD), impaired social skills, and behavioral problems and / or severe psychiatric problems. Loss of expression of the preferentially paternally expressed of genes from the chromosomal region 15q11-q13 are the basis of pathogenesis of PWS, which occur through several mechanisms: deletion of 5-6 Mb DNA fragment from the 15q11-q13 region of the inherited paternal chromosome (65-75%), maternal uniparental disomy (mUPD) (in 20-30%) and Imprinting center (IC) defects, as microdeletions and epimutations (in 1-4%). In this paper, we present two cases diagnosed with PWS from our experience. The importance of diagnosis and familial recurrence risk will be discussed, as well as genotype-phenotype relationships in PWS. Patients with PWS should benefit from multidisciplinary management very early for greatly improving their quality of life, taking into consideration that obesity is a major factor influencing morbidity and mortality. In addition, a better understanding of the molecular basis of PWS pathogenesis offers hope for the development of new, revolutionary, epigenetic therapies in PWS, as well as in other genetic imprinting diseases.

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role...

Interstitial duplication syndrome in the chromosomic region 15q11q13: a case report

Introduction: The chromosomal region 15q11-13 contains a group of genes essential for normal neurodevelopment and alterations in this region result in different syndromes. Among the most frequent alterations, there are chromosomal deletions and duplications. Duplications of chromosome region 15q11q13 occur as a supernumerary chromosome 15, and may occur as interstitial duplications. The main clinical manifestations are intellectual impairment, problems with vision, hearing, teething and in bones and joints. Currently, there are few cases reported in the literature about this genetic condition, which justifies the relevance of this study. Objective: To report a case of duplication in the chromosomal region 15q11q13 and describe the clinical manifestations. Methodology: This is a case report of a qualitative nature. Case report: J.V.A.S., male, eight years old, attended at the Associação de Pais e Amigos dos Excepcionais (APAE), in Anápolis, Goiás, Brazil, in 2017, diagnosed with neuropsychomotor developmental delay (ADNPM) and macrocrania. No complications during childbirth. The patient had head support at six months, sat up at nine months, walked and talked at one year and ten months. He attends school and has good interaction, but has learning difficulties. In 2018, the CGH – ARRAY (aCGH) revealed the presence of a duplication in 15q11.2q13.1 of approximately 6.1Mb classified as pathogenic. Results and discussion: Due to the rarity of this syndrome, we did not find a satisfactory number of articles that specifically addressed this duplication. Conclusion: It is necessary to carry out more studies, in the long term and through satisfactory samples, in order to elucidate the main aspects involved in this pathology.

Reference Genes across Nine Brain Areas of Wild Type and Prader-Willi Syndrome Mice: Assessing Differences in Igfbp7, Pcsk1, Nhlh2 and Nlgn3 Expression.

Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by the deletion or inactivation of paternally expressed imprinted genes at the chromosomal region 15q11–q13. The PWS-critical region (PWScr) harbors tandemly repeated non-protein coding IPW-A exons hosting the intronic SNORD116 snoRNA gene array that is predominantly expressed in brain. Paternal deletion of PWScr is associated with key PWS symptoms in humans and growth retardation in mice (PWScr model). Dysregulation of the hypothalamic–pituitary axis (HPA) is thought to be causally involved in the PWS phenotype. Here we performed a comprehensive reverse transcription quantitative PCR (RT-qPCR) analysis across nine different brain regions of wild-type (WT) and PWScr mice to identify stably expressed reference genes. Four methods (Delta Ct, BestKeeper, Normfinder and Genorm) were applied to rank 11 selected reference gene candidates according to their expression stability. The resulting panel consists of the top three most stably expressed genes suitable for gene-expression profiling and comparative transcriptome analysis of WT and/or PWScr mouse brain regions. Using these reference genes, we revealed significant differences in the expression patterns of Igfbp7, Nlgn3 and three HPA associated genes: Pcsk1, Pcsk2 and Nhlh2 across investigated brain regions of wild-type and PWScr mice. Our results raise a reasonable doubt on the involvement of the Snord116 in posttranscriptional regulation of Nlgn3 and Nhlh2 genes. We provide a valuable tool for expression analysis of specific genes across different areas of the mouse brain and for comparative investigation of PWScr mouse models to discover and verify different regulatory pathways affecting this complex disorder.

SnoRNAs in plasma extracellular vesicles of AD patients are differentially associated with APOE genotype

AbstractBackgroundStandardized disease specific PET patterns correctly classify 95% of AD MCI patients. The cost of PET, however, is still prohibitive as a widespread AD diagnostic test. Diagnostic tests using CSF have also been established to measure the levels of Aβ and hyperphosphorylated tau for early diagnosis of AD or to monitor the effects of therapeutics and progression of the disease. CSF biomarkers show a good agreement with amyloid imaging and a combination of CSF Aβ42/Aβ40 increases the agreement between markers of amyloid pathology. Plasma extracellular vesicles (EVs) and their cargo present an opportunity to isolate and profile molecules associated with human pathological conditions. We have recently found small nucleolar non‐coding RNAs (snoRNAs) of box C/D (SNORDs), transcribed from imprinted chromosomal domains SNURF‐SNRPN at human chromosomal region 15q11q13 and DLK1‐DIO3 at region 14q32, highly enriched in plasma EVs of AD patients compared to non‐demented individuals.MethodDuring the discovery phase of the study, using RNA‐seq we profiled four major classes of ncRNAs in EVs isolated from early stage AD patients and control non‐demented individuals: miRNAs, snoRNAs, tRNAs and piRNAs. We verified the results by Digital Droplet PCR in plasma samples of independent group of AD and control plasma samples.ResultWe report a significant enrichment of SNORDs in AD samples compared to controls. Through verification assays we confirmed these results and identified SNORD115s &amp; SNORD116s with the highest discriminatory power to differentiate AD samples against Controls.ConclusionThe results of our study present evidence that AD is associated with changes in enrichment of SNORDs, transcribed from imprinted genomic loci, in plasma EVs and provide a rationale to further explore validity of snoRNAs as plasma biomarkers for AD.

The Spectrum of the Prader-Willi-like Pheno- and Genotype: A Review of the Literature.

Prader-Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader-Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf-Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion, 15q duplication, 19p deletion, fragile X syndrome, and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%), and psychobehavioral problems (53%). In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.

EEG Patterns in Patients with Prader-Willi Syndrome.

Prader–Willi syndrome (PWS) is a rare disease determined by the loss of the paternal copy of the 15q11-q13 region, and it is characterized by hypotonia, hyperphagia, obesity, short stature, hypogonadism, craniofacial dysmorphisms, and cognitive and behavioral disturbances. The aims of this retrospective study were to analyze interictal EEG findings in a group of PWS patients and to correlate them with genetic, clinical, and neuroimaging data. The demographic, clinical, genetic, EEG, and neuroimaging data of seventy-four patients were collected. Associations among the presence of paroxysmal EEG abnormalities, genotype, and clinical and neuroimaging features were investigated. Four patients (5.4%) presented drug-sensitive epilepsy. Interictal paroxysmal EEG abnormalities—focal or multifocal—were present in 25.7% of the cases, and the normalization of the EEG occurred in about 25% of the cases. In 63.2% of the cases, the paroxysmal abnormalities were bilaterally localized over the middle–posterior regions. Brain magnetic resonance imaging (MRI) was performed on 39 patients (abnormal in 59%). No relevant associations were found between paroxysmal EEG abnormalities and all of the other variables considered. Interictal paroxysmal EEG abnormalities—in particular, with a bilateral middle–posterior localization—could represent an important neurological feature of PWS that is not associated with genotype, cognitive or behavioral endophenotypes, MRI anomalies, or prognosis.

A case of 15q11‐q13 duplication syndrome and literature review

BackgroundThe chromosomal 15q11‐q13 regions are structurally complex, and their abnormalities are associated with various neuropsychiatric disorders, including autism spectrum disorder (ASD), epilepsy, Angelman syndrome, and Prader–Willi syndrome.Case descriptionA 6‐year‐old child was admitted to the hospital as a result of an “epileptic status” showing ASD, intractable epilepsy, and total developmental retardation. Chromosome gene detection showed repetitive variation in the 15q11‐q13 regions, and the video electroencephalogram was abnormal. Although children are currently given antiepileptic treatment and rehabilitation training, intermittent seizures can still occur.ConclusionThe clinical phenotypes of 15q11‐q13 repetitive syndrome are complex, and vary in severity. Children with intractable epilepsy, ASD, and language and motor retardation should be considered to have this syndrome, which requires confirmation by multiplex ligation‐dependent probe amplification and gene detection. These approaches can enable early rehabilitation treatment and improve the patients’ quality of life.