Full Syndrome Research Articles

Examining the multifaceted factors of night eating syndrome among adults in Saudi Arabia: A nursing perspective

BackgroundNight Eating Syndrome (NES) is a prevalent eating disorder that significantly impacts individuals' quality of life and well-being. However, most NES research has focused on adolescent populations, leaving a significant gap in our understanding of its prevalence and predictors among adults, particularly in the MENA region. This study, therefore, presents a novel contribution by filling this gap and determining the prevalence of NES and its predictors among adults in Abha, Saudi Arabia. DesignA descriptive correctional design was conducted on 714 adults randomly recruited from primary healthcare centers (PHCCs). MethodsA self-administered questionnaire, which comprised a demographic and lifestyle data sheet and the Arabic version of the NES questionnaire, was used for data collection. Results13.3 % of the participants reported having full syndrome of NES, with 16.1 % of males and 22.5 % of females reporting high NES awareness. Meanwhile, 14.4 % of the participants were non-emotional eaters. This finding is significant as it sheds light on the high prevalence of NES among Saudi adults. Significant differences were observed between NES and higher education, sleeping patterns, smoking habits, dietary type, and exercise routines, with an OR of 1.422, 40.78, 6.14, 66.70, and 4.47, respectively, and a p-value of <0.001. ConclusionNES was a common eating disorder among Saudi adults. Higher education, inadequate sleep, smoking, unhealthy diet, and lack of exercise were the most significant predictors of NES. These findings underline the importance of addressing these factors in preventing and managing NES. Social media campaigns, awareness campaigns, and cognitive behavioral and mindfulness therapies could effectively address NES. However, further research is necessary to identify underlying causes and assess their association with comorbidities, providing a clear direction for future studies.

Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion.

MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome. KEY MESSAGES: A missense AP1S1 c.269T > C (σ1A L90P) variant causes full MEDNIK syndrome. The σ1A L90P variant is largely unable to assemble into the AP-1 complex. The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs. The σ1A L90P variant results in loss-of-function of the protein.

#2555 C4d—a novel predictor of the disease progression and treatment failure in primary focal segmental glomerulosclerosis?

Abstract Background and Aims Complement system seems to play a role in the pathogenesis of primary focal segmental glomerulosclerosis (pFSGS) where, due to unpredictable clinical course and outcome, novel prognostic factors are sought. The split product of C4 and tissue marker of complement activation, C4d, is a potential candidate whose prognostic significance was determined in this study. Method Patients &amp;gt;18 years with features consistent with pFSGS (full blown nephrotic syndrome, diffuse podocyte foot processes effacement and exclusion of known causes of FSGS), were recruited from our Hospital registry of kidney biopsies, from 2003 to 2021. Patients with end-stage renal disease (ESRD) defined as eGFR &amp;lt;15 ml/min/1.73 m2 were not included. Every renal biopsy specimen was analyzed by light, immunofluorescence and electron microscopy with additional immunochemistry for C4d performed on paraffin-embedded tissue using monoclonal rabbit antibody (detection system Ventana BenchMark Ultra). Samples with at least one non-globally sclerosed glomerulus (GSG) were examined by two renal pathologists who classified every non-GSG into C4d positive and negative. Based on ratio of C4d+ non-GGS/total N of non-GSG and C4d+ nonsclerotic glomeruli (NSG)/total N of NSG, patients were stratified into two groups: &amp;lt;50% and ≥50%. Primary outcome was defined as composite of ESRD and initial eGFR declining &amp;gt;50%. Failure to meet criteria for at least partial remission at the last follow-up visit according to KDIGO 2021 Guidelines was defined as treatment failure. Numeric variables are shown as median with interquartile range (IQR) and P value &amp;lt;0.05 was considered as significant. Results Relevant data of 58 included patients with renal outcomes are shown in Table. Median follow up was 90.7 (IQR 48-167) months. Patients with ≥50% of C4d+ non-GSG had higher proportion of treatment failure (Table) and worse renal survival (log-rank test, p = 0.006). In multivariate Cox regression analysis, after inclusion of age, sex, initial eGFR and 24-h proteinuria, IFTA, serum albumin and C4d category, only C4d ≥50% (HR = 4.077, 95% CI 1.101-15.09, p = 0.035) and IFTA (HR = 1.052, 95% CI 1.019-1.085, p = 0.002) remained independent predictors of progression to defined endpoint. Likewise, patients with ≥50% of C4d+ NSG/total N of NSG had higher proportion of treatment failure (chi-square, p = 0.03) and worse renal survival (log-rank, p = 0.037). Conclusion C4d deposition is an independent predictor of disease progression, treatment failure and renal survival in pFSGS. Significant influence of NSG-C4d deposition on disease progression may indicate pathophysiological role of the complement system activation in pFSGS independently of the presence of glomerular sclerosis.

Exome Sequencing has a high diagnostic rate in sporadic congenital hypopituitarism and reveals novel candidate genes.

The pituitary gland is key for childhood growth, puberty, and metabolism. Pituitary dysfunction is associated with a spectrum of phenotypes, from mild to severe. Congenital Hypopituitarism (CH) is the most commonly reported pediatric endocrine dysfunction with an incidence of 1:4000, yet low rates of genetic diagnosis have been reported. We aimed to unveil the genetic etiology of CH in a large cohort of patients from Argentina. We performed whole exome sequencing of 137 unrelated cases of CH, the largest cohort examined with this method to date. Of the 137 cases, 19.1% and 16% carried pathogenic or likely pathogenic variants in known and new genes, respectively, while 28.2% carried variants of uncertain significance. This high yield was achieved through the integration of broad gene panels (genes described in animal models and/or other disorders), an unbiased candidate gene screen with a new bioinformatics pipeline (including genes high loss of function intolerance), and analysis of copy number variants. Three novel findings emerged. First, the most prevalent affected gene encodes the cell adhesion factor ROBO1. Affected children had a spectrum of phenotypes, consistent with a role beyond pituitary stalk interruption syndrome. Second, we found that CHD7 mutations also produce a phenotypic spectrum, not always associated with full CHARGE syndrome. Third, we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32, and report 13 novel candidate genes associated with CH (e.g. PTPN6, ARID5B). Overall, these results provide an unprecedented insight into the diverse genetic etiology of hypopituitarism.

Symposium 07: Early Development in Infants and Toddlers with Agenesis of the Corpus Callosum

Summary AbstractThe corpus callosum is the largest transverse white matter fiber tract connecting the two hemispheres of the brain. It plays an essential role in the interhemispheric transfer and bihemispheric coordination involved in perception and sensory-motor integration, as well as higher level cognition (e.g., memory, executive functioning). The corpus callosum forms prenatally (10-15 weeks gestation) and continues to develop through early adulthood. Damage to the corpus callosum throughout the lifespan, but especially later in life, can result in sensory and motor coordination deficits and produces disconnection syndromes.However, individuals born with a partial or fully absent corpus callosum, known as Agenesis of the Corpus Callosum (ACC), do not exhibit a full disconnection syndrome and may, in fact, demonstrate many intact skills including broadly average intellectual abilities. Agenesis of the corpus callosum (ACC) is a relatively common congenital brain malformation that occurs in 1 out of ∼4000 live births (Glass, Shaw, Ma, &amp; Sherr, 2008; Paul et al., 2007). There is significant heterogeneity in outcomes for these individuals, often related to the presence of additional neuropathology, and the presence of co-occurring medical and genetic conditions. In adults for whom ACC is the primary neurological finding, there is a core constellation of cognitive symptoms that include reduced interhemispheric transfer, slowed processing, and difficulty with complex novel problem solving (Brown &amp; Paul, 2019). There is also an elevated likelihood of autism spectrum disorders in this population as well (Paul et al, 2014).Modern ultrasound technology facilitates diagnosis of ACC in utero, offering a unique opportunity to study these individuals’ development from infancy. However, no studies to date have examined early development in this population using validated measures, leaving neuropsychologists, neurologists and primary care providers to make educated guesses about what families should expect and appropriate therapies/treatment.This symposium presents a series of studies examining the early development of individuals with primary ACC across domains including language, adaptive skills, autism symptomology, and temperament/anxiety. We will provide the first in-depth prospective characterization of development in ACC relative to typically developing children at 6, 12, 18 and 24 months and discuss what these findings reveal about brain development and plasticity more broadly (e.g. how does early disruption in interhemispheric connection impact cognitive development across key domains?).Finally, while ACC is defined specifically by corpus callosum anatomy, the corpus callosum has been implicated in other neurodevelopmental conditions (Paul, 2011). Utilizing extant comparison, we also assess how early development in ACC both overlaps and differs from two monogenic conditions (e.g. Fragile X and Down Syndrome) and a developmental behavioral diagnoses (e.g. autism) and discuss how early disruptions in interhemispheric transfer may contribute to shared behavioral phenotypes in these conditions.

A geospatial analysis of cardiometabolic diseases and their risk factors considering environmental features in a midsized city in Argentina.

New approaches to the study of cardiometabolic disease (CMD) distribution include analysis of built environment (BE), with spatial tools as suitable instruments. We aimed to characterize the spatial dissemination of CMD and the associated risk factors considering the BE for people attending the Non-Invasive Cardiology Service of Hospital Nacional de Clinicas in Córdoba City, Argentina during the period 2015-2020. We carried out an observational, descriptive, cross-sectional study performing non-probabilistic convenience sampling. The final sample included 345 people of both sexes older than 35 years. The CMD data were collected from medical records and validated techniques and BE information was extracted from Landsat-8 satellite products. A geographic information system (GIS) was constructed to assess the distribution of CMD and its risk factors in the area. Out of the people sampled, 41% showed the full metabolic syndrome and 22.6% only type-2 diabetes mellitus (DM2), a cluster of which was evidenced in north-western Córdoba. The risk of DM2 showed an association with high values of the normalized difference vegetation index (NDVI) (OR= 0.81; 95% CI: - 0.30 to 1.66; p=0.05) and low normalized difference built index (NDBI) values that reduced the probability of occurrence of DM2 (OR= -1.39; 95% CI: -2.62 to -0.17; p=0.03). Considering that the results were found to be linked to the environmental indexes, the study of BE should include investigation of physical space as a fundamental part of the context in which people develop medically within society. The novel collection of satellite-generated information on BE proved efficient.

#3512 GLOMERULOPATHIES DURING PREGNANCY: A TEN-YEAR SINGLE CENTER EXPERIENCE

Abstract Background and Aims Literature regarding pregnancy management and outcomes in women with glomerulopathies is still sparse. Specific guidelines for each glomerulopathy are still lacking which impairs a more homogeneous approach. The authors describe the multidisciplinary approach and the outcomes of pregnant women with primary and genetic glomerulopathies. Method Retrospective observational study in which the authors reviewed maternal, obstetric and perinatal outcomes in pregnant women with primary and genetic glomerulopathies surveilled at our nephro-obstetric clinic from 2011 to 2021. Results We evaluated 23 gestations in 20 patients (two pregnancies still ongoing). Mean age was 32.4±5.4 years (18-41), 17 women were caucasian, 3 black African, 10/23 nulliparous and 5/20 had chronic hypertension. Mean baseline SCr was 0.8±0.3mg/dl (0.5-1.8) and proteinuria was 1360±2199.6 mg/day (150-8615), with 13/6/2 patients being on CKD stage 1/2/3, before pregnancy, respectively (unknown in 2 patients). The most frequent CKD etiologies were IgA nephropathy (6/20), Focal Segmental Glomerulosclerosis (FSGS; 3/20) and Membranous nephropathy (2/20). Exposure to teratogenic therapy during the 1st trimester occurred in 5/23 gestations with a mean exposure of 7.0±3.6 weeks. De novo proteinuria and worsening proteinuria occurred in 3/23 and 16/23 patients, respectively, with full blown nephrotic syndrome in 4/23 patients. Renal function deteriorated in one patient (CKD G3). Kidney biopsy was performed in 1/20 and 3/20 patients during and post pregnancy, revealing IgA Nephropathy (2/20, 1 with superimposed FSGS), C3 glomerulonephritis (1/20) and FSGS (1/20). Genetic diagnosis was done during/post pregnancy in 3/1 patients. Aspirin and LMWH were started in 17/23 and 4/23 gestations, respectively. Immunosuppression consisted of cyclosporin or tacrolimus with or without low dose prednisolone in 6/23 patients with partial and complete remission in all patients. De novo and worsening hypertension occurred in 2/23 and 3/23 gestations, during the 3rd trimester. Preeclampsia developed in 1 patient at 32 weeks. Fetus malformation (trisomy 21) and severe nephrotic syndrome led to pregnancy termination during the 1st trimester in two pregnancies. Cesarean delivery was performed in 5 gestations mainly due to pelvic position. Mean gestation time was 38.9±2 weeks. There was one preterm delivery due to preeclampsia. Mean birth weight was 3076.6±630.7 mg (1500-3850), with 3 newborns having low birth weight (&amp;lt;2500g). Apgar scores at 1/5/10 minutes were 9/10/10, respectively. Neonatal intensive care was needed in 1 newborn. Conclusion In our series, glomerulopathies with proteinuria or nephrotic syndrome were not associated with poor renal and perinatal outcome, with only one patient developing PE and renal function deterioration, probably associated to with CKD stage 3. In patients with nephrotic syndrome, immunosuppression with calcineurin inhibitor and low dose prednisone was associated with complete or partial remission in all patients.

#6598 STUNNING RENAL FUNCTION RECOVERY AFTER TREATMENT WITH DARATUMAMB IN A CASE OF C3 GLOMERULOPATHY WITH MONOCLONAL GAMMOPATHY

Abstract Background and Aims 38 years old man with C3GN linked to Monoclonal Gammopathy recovers from dialysis after treatment with Daratumamb. Case report C3 glomerulonephritis related to monoclonal gammopathy is a challenging entity and the efficacy of treatment with Daratumumab is not clearly defined yet. We would like to describe the case of a stunning renal response to Daratumumab in a young man with MGUS and C3 glomerulonephritis. In July 2021 a 38 years old man presented to our nephrology division with full nephrotic syndrome, creatinine 1.2 mg/dl, low C3 and little IgG lambda spike of 2 g/dL on serum electrophoresis. Kidney biopsy revealed a membranoproliferative GN with bright C3 staining by immunofluorescence, no other positive immune-reactant and no masked deposits on pronase digested tissue. Electron microscopy confirmed the presence of subendothelial electron dense deposits. The diagnosis was consistent with C3 glomerulonephritis. Complement genetic test and C3 nephritic factor were negative. Assuming a form of C3GN associated to monoclonal gammopathy (MGRS), a bone marrow biopsy was performed and revealed a small clonal plasma cells population. In November 2021 he was started on velcade/dexamethasone but unfortunately stopped early due to severe side effects. Subsequently he begun cyclophosphamide and steroids without clinical or serological response. In few months renal function rapidly worsened requiring dialysis since April 2022. A repeat kidney biopsy confirmed C3GN with still moderate activity and low chronicity. In May 2022 he was started on Daratumamab/Lenalidome/Dexamethasone. After eight months of dialysis the diuresis progressively increased and the renal function improved so remarkably that dialysis was discontinued since December 2022. At present the patient renal function is stable with creatinine 3.5 mg/dl, proteinuria 3g/L, and monoclonal component decreased to 1.1 g/L from 3.5 g/L. He continues Daratumumab single agent monthly and we have scheduled a further renal biopsy in the next week. To our knowledge this is the first time a patient recovers from dialysis after treatment with Daratumamb for a C3GN linked to a monoclonal gammopathy. It definitely makes this case unique and inspiring for further studies and considerations regardinf this intriguing field of MGRS.

Advancing heart failure research using machine learning

Advancing heart failure research using machine learning

Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors.

Segmental Membranous Glomerulopathy in Adults

Introduction: The clinicopathological features of segmental membranous glomerulopathy (SMGN) have not been well characterized. The aim of this study was to investigate the prevalence and clinicopathological features of SMGN in adults. Methods: Adult patients with biopsy-confirmed SMGN in the native kidney at our center between January 2017 to September 2020 were identified. The clinicopathological features of SMGN were collected. The glomerular deposition of IgG subclasses, M-type phospholipase A2 receptor 1 (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), and neural epidermal growth factor-like 1 protein (NELL1) were tested. Clinical and pathologic features were comparable between NELL1-positive and NELL1-negative SMGN. Results: A total of 167 patients with biopsy-proven SMGN were enrolled. During the same period, 32,640 (33.0%) out of 98,939 renal biopsies were diagnosed with membranous nephropathy (MN) in adults. SMGN accounted for 0.17% of total kidney biopsies and 0.51% of MN in adults. One hundred and fifty (89.8%) cases were isolated SMGN, and 17 (10.2%) cases were complicated with other kidney disease. Clinically, the median age of isolated SMGN patients was 41.5 years, with female (74%) predominance, and 33.1% had full nephrotic syndrome. Pathologically, IgG1 was the dominant subclass (92.5%), followed by IgG4 (45.0%). PLA2R and THSD7A staining were done in 142 and 136 isolated SMGN cases, respectively, in which, all the cases showed negative. NELL1 staining was done in 135 isolated SMGN cases; 58 cases (43.0%) showed positive. Fifty-eight patients (41.1%) had diffuse (≥90%) foot process effacement, and 119 patients (83.8%) had either stage I (38.0%) or stage II (45.8%) membranous alterations in patients with SMGN. Most patients with NELL1-positive SMGN were female. Patients with NELL1-positive SMGN were more likely with lower prevalence of full nephrotic syndrome than NELL1-negative SMGN. Conclusions: SMGN is a relatively rare pathological type. Majority of patients with isolated SMGN were female, with a median age of 41.5 years, 33.1% had full nephrotic syndrome, absence of PLA2R and THSD7A, 43.0% with NELL1-positive, and mainly stage I or II MN (83.8%). NELL1 is the major target antigen of SMGN in adults.

Adverse Events Related to SARS-CoV-2 Vaccine in a Nationwide Cohort of Patients With Inflammatory Bowel Disease.

There are limited data on the safety profile of the severe acute respiratory syndrome coronavirus-2 vaccine among patients taking immunosuppressive medications. Our aim was to evaluate the adverse events related to the vaccines in a nationwide cohort of patients with inflammatory bowel disease on diverse immunosuppressive medications. This was a retrospective cohort study using data from the Veterans Health Administration. The primary outcome was any adverse event of special interest (cerebrovascular accident, venous thromboembolism, acute myocardial infarction, Bell palsy) within 90 days of vaccination. A total of 17,201 patients were included, and 12,351 patients (71.8%) received at least 1 vaccine dose. The most common adverse events were acute myocardial infarction and venous thromboembolism. In inverse probability treatment weighting-adjusted logistic regression, full vaccination was not significantly associated with increased adverse events through 90 days, relative to unvaccinated patients. Full severe acute respiratory syndrome coronavirus-2 vaccination was not associated with an increased rate of key adverse events relative to unvaccinated individuals among patients with inflammatory bowel disease.

Online Platform for SAMD9 and SAMD9L Variant Annotation and Phenotype Correlation

SAMD9 and SAMD9L (SAMD9/9L) syndromes are new bone marrow failure (BMF) disorders with multisystem involvement (neurological, endocrine, urogenital, and others) and a propensity to develop myelodysplasia (MDS) with monosomy 7 (-7). The SAMD9/9L genes are located on chromosome 7q and are implicated in antiviral immunity, cellular growth, and protein translation. Since the discovery of germline SAMD9L mutations (SAMD9Lmut) in patients with ataxia-pancytopenia and SAMD9 mutations (SAMD9mut) in MIRAGE syndrome, several reports expanded the clinical spectrum to non-syndromic familial MDS, CANDLE syndrome, B-cell aplasia, and steroid-resistant nephrotic syndrome. Because SAMD9/9Lmut proteins enhance the growth-inhibitory effect of wildtype proteins, they are considered gain-of-function (GOF). Clonal rescue hematopoiesis is common: loss or inactivation of the mutant allele occurs by developing -7 clones, via compensatory somatic SAMD9/9Lmut, or uniparental isodisomy 7q (UPD7q). Major challenges for variant interpretation are: i) most germline mutations are novel, ii) ~70% of the mutations are classified as variants of uncertain significance (VUS), iii) the expressivity and penetrance are variable, iv) the associated phenotypes are still emerging (Sahoo, Nat Med 2021). To address these obstacles, we established a comprehensive database of SAMD9/9L variants with detailed phenotype ascertainment. We accumulated reports of SAMD9/9Lmut from literature until July 2022 (n=223) and unpublished cases in our registries (n=83). We extracted patient phenotypes, categorized them anatomically and physiologically, and evaluated correlation with genotypes and somatic events. Germline mutations were mapped using ProteinPaint (Fig 1). Genotypes: We assessed 306 cases with 187 unique SAMD9/9Lmut. For SAMD9 genotype 161 patients carried 122 unique germline mutations with R1293 (n=7), R982 (n=6), and E974 (n=6) discerned as frequently mutated amino acid (aa) positions. In comparison, for SAMD9L genotype, 145 SAMD9L patients had 65 unique mutations, and 3 aa residues were recurrently affected in one-third of the patients: R986 (n=22), R1281 (n=12), and H880 (n=12). Phenotypes and clinical status: Hematological abnormalities were described in 92.5% (149/161) of SAMD9mut and 83% (121/145) of SAMD9Lmut cases. The leading non-hematologic phenotypes for SAMD9mut were genitourinary (47.6%, 51/107), endocrine (36.4%, 39/107), gastrointestinal (35.5%, 38/107), neurological (20.5%, 22/107), and cardiac (11.2%, 12/107); in SAMD9Lmut patients, neurological abnormalities were predominant and found in 36% (42/116) of patients, followed by immunological abnormalities (15.5%, 18/116), while typical MIRAGE phenotypes were also observed (n=2). Within published SAMD9mut or SAMD9Lmut cases, 53% (52/98) or 75.0% (87/116) were alive at last follow-up, respectively. Of note, 63% (29/46) of the deceased SAMD9mut patients had full MIRAGE syndrome spectrum. Clonal rescue hematopoiesis: Somatic genetic rescue (SGR) with UPD7q was reported in 11.7% (26/223) of patients (SAMD9mut 5.6%; SAMD9Lmut 17.2%), SGR with somatic SAMD9/9Lmut in 22.0% (49/223) of cases (SAMD9mut 17.8%; SAMD9Lmut 25.9%), while -7 clones were present in 46.6% (104/223) of the cohort (SAMD9mut 50.5%; SAMD9Lmut 43.1%). UPD7q was more frequent in SAMD9Lmut compared to SAMD9mut (p<0.01). Moreover, 60% (24/41) of SAMD9Lmut cases with SGR (UPD7q and somatic SAMD9/9Lmut) were associated with germline mutations affecting only 4 aa residues (H880, R986, R1281, and V1512). Lastly, we defined the population minor allelic frequency (MAF) thresholds for germline mutations based on the presence of -7 clones and adaptive SGR. We found that specific MAF thresholds were lower than the generic 0.1% and gene-specific: for -7 vs SGR in SAMD9 (0.002 vs 0.0004)and SAMD9L(0.01 vs 0.002) (Fig. 1). Our study (www.stjude.org/samd9) represents the first effort to develop a genotype-phenotype database of SAMD9/9L syndromes which will allow investigators to deposit variants and compare them with published and unpublished data. In newly discovered predisposition syndromes, databases like the one presented here, will be instrumental in gathering crucial clinical data for variant interpretation, identify new phenotypic and prognostic correlates, and improving patients’ clinical care. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Ayurvedic Review on Poly-Cystic Ovarian Disease

PCOD is the most common endocrine disorder in women of reproductive age group, affecting 5% to 10% of women exhibiting, the full blown syndrome of hyperandrogenism, chronic anovulation and polycystic ovaries. PCOD is a disease which is related to the cystic changes in the ovary. It is the most common cause of Menstrual Irregularities, Obesity, anovulatory infertility and hyperandrogenism, etc. PCOD are not compiled as a disease or syndrome in Ayurveda, most of them have been described as symptoms of separate diseases or conditions. Ayurvedic management principles Samshodhana, Agneya dravya, Nidan parivarjana as well as modern treatment describe here. The present article is an attempt to highlighting on details of Ayurvedic review on poly cystic ovarian diseases.

Prodromal α-Synucleinopathies.

This article describes prodromal α-synucleinopathies. The pathology underlying α-synucleinopathies, which include Parkinson disease, multiple system atrophy, and dementia with Lewy bodies, begins years before the presence of the full syndrome that is the basis for the clinical diagnosis of each of these disorders. This "prodromal" phase may manifest with various signs or symptoms. In addition to individuals in the prodromal phase, some individuals are asymptomatic but are at risk for α-synucleinopathies owing to genetic predisposition or other risk factors. Clinicians are increasingly seeing patients in the clinical setting who are prodromal or at risk for α-synucleinopathies, and this article reviews the approach to these patient populations, which includes identifying clinical features, assessment, and counseling.

Variation in TAF1 expression in female carrier induced pluripotent stem cells and human brain ontogeny has implications for adult neostriatum vulnerability in X-linked Dystonia Parkinsonism.

X-linked dystonia-parkinsonism (XDP) is an inherited, X-linked, adult-onset movement disorder characterized by degeneration in the neostriatum. No therapeutics alter disease progression. The mechanisms underlying regional differences in degeneration and adult onset are unknown. Developing therapeutics requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is possibly due, in part, to a partial loss of TAF1 function. A disease-specific SINE-VNTR-Alu (SVA) retrotransposon insertion occurs within intron 32 of TAF1, a subunit of TFIID involved in transcription initiation. While all XDP males are usually clinically affected, females are heterozygous carriers generally not manifesting the full syndrome. As a resource for disease modeling, we characterized eight iPSC lines from three XDP female carrier individuals for X chromosome inactivation (XCI) status and identified clonal lines that express either the wild-type X or XDP haplotype. Furthermore, we characterized XDP-relevant transcript expression in neurotypical humans, and found that SVA-F expression decreases after 30 years of age in the brain and that TAF1 is decreased in most female samples. Uniquely in the caudate nucleus, TAF1 expression is not sexually dimorphic and decreased after adolescence. These findings indicate that regional-specific, age-specific, and sex-specific mechanisms regulate TAF1, highlighting the importance of disease-relevant models and postmortem tissue. We propose that the decreased TAF1 expression in the adult caudate may synergize with the XDP-specific partial loss of TAF1 function in patients, thereby passing a minimum threshold of TAF1 function, and triggering degeneration in the neostriatum.

COMPARISON OF DIET INDUCED METABOLIC SYNDROME WITH ARTIFICIALLY INDUCED METABOLIC SYNDROME IN A RAT MODEL

Background: Metabolic syndrome is an emerging health problem. The diets rich in fats and refined carbohydrates and monosodium glutamate are considered major risk factors for this emerging epidemic. The aim of this study was to determine whether high fat high carbohydrate (HFHC) diet, Monosodium glutamate (MSG) diet or their combination is faster/more potent inducer of MS. Methods: Twenty male Sprague Dawley rats were randomly divided into four groups. Group 1 was given normal rat chow, group 2 was given HFHC diet, group 3 was given MSG in diet and group 4 was given both HFHC and MSG in their diet for 20 weeks. Body weight, blood pressure, lipid profile and glycaemic indices were determined at the end of study. Results: After 20 weeks of study, HFHC and MSG groups showed full blown Metabolic syndrome (MS) with development of obesity, hypertension, hyperglycaemia and dyslipidemia. However, group 4 which was given combination diet did not develop features of MS. Conclusion: Both HFHC and MSG containing diets when given alone are potent inducers of MS in rat model rather than their combination. Pak J Physiol 2022;18(2):6?9

MO256: IGM in Fibrillary Glomerulopathy Linked to Monoclonal Gammopathy

Abstract BACKGROUND AND AIMS Fibrillary glomerulopathy (FGN) is a rare glomerular deposit disease accounting for less than 1% of annual native kidney biopsies. Its pathogenesis is still not fully understood. Immunofluorescence (IF) techniques in the vast majority of cases reveal the presence of smudgy polytypic IgG deposits associated with C3 and, anecdotally, of scarce IgM or IgA. The majority of cases are idiopathic, but up to one-third of patients may present with a secondary cause including monoclonal gammopathy, which in previously reported series ranged from 4% to 16% of the cases. The association of FGN and monoclonal gammopathy remains controversial, nonetheless monotypic cases in the absence of multiple myeloma, wäldestrom macroglobulinemia or high-grade lymphoma are currently included in the spectrum of monoclonal gammopathy of renal significance (MGRS). The aim of the study was to describe the role of IgM in FGN as a possible marker of an underlying MGRS. METHOD A single-center, retrospective and observational study of FGN cases diagnosed during the period of 2012–2019 was performed. Kidney biopsies were retrospectively reviewed. All cases had a confirmatory diagnosis made with electron microscopy (EM). Due to a lack of material and the novelty of the marker, DNAJB9 was not performed in all samples. IF on frozen tissue was done in all cases; digestion with proteinase K was done in cases of light chain restriction to unmask possible deposits. Demographics, clinical presentations, associated conditions and outcomes were reviewed. Data were expressed as mean standard deviation (SD). RESULTS Our cohort consisted of 17 patients, all but 2 caucasians, 9 males and 8 women, with a mean age of 63.1 ± 13.2. The mean follow-up was of 34.6 months. At the time of the diagnosis, most patients presented with hypertension 70% (12). All patients had proteinuria (mean 24-h protein excretion of 4.84 g ± 5.2) and renal impairment with a medium creatinine of 203.8 ± 202. Full nephrotic syndrome was present in 29% (5) of the cases and microhematuria in 52.9% (9); complement was normal in all cases. As for related medical conditions: 23% (4) had history of autoimmune diseases, 17% (3) had diagnosis of a solid tumor, 76.5% (13) were smokers (2 with diagnosed chronic obstructive pulmonary disease) and 29% (5) had diabetes mellitus. Monoclonal gammopathy was present in 35.3% (6/17) of the cases, all of which had an identified monoclonal component detected by electrophoresis with immunofixation (SPEPE/SIF). Three of them (50%) progressed (2 to multiple myeloma, 1 to amyloidosis AL) (Fig. 1). Light microscopic study showed three distinct patterns of glomerular injury, being mesangial pattern the most common 82% (14/17). Staining with congo red was negative in all cases, 17 cases. By immunofluorescence only 82% (13) showed glomerular positivity for IgG. Unexpectedly 23% (4) showed exclusively IgM deposits; three of them had monoclonal gammopathy. Looking in depth, 5/6 of the patients with monoclonal gammopathy showed IgM deposits in contrast to the non-associated FGN cases (3/10) (Fig. 2). No cases of GNF with IgM deposits had underlying cryoglobulinemia; there was one case of diabetes mellitus. A total of 41% (7) end up needing renal replacement therapy (RRT). No differences in the rate of RRT were observed between patients with monoclonal gammopathy and without. CONCLUSION IgM deposits were observed in patients with FGN cases associated with monoclonal gammopathy. IgM deposition is a finding rarely described in the literature up to the date. In this regard, we hypothesize that IgM monoclonal gammopathy due to a conformational alteration in the protein could generate deposits in the form of fibrils triggering a possible GNF. Thus, IgM deposition in the context of GNF could be a marker of a possible underlying MGRS. Future studies proving IgM conformational alterations in these patients could corroborate our hypothesis.

Effectiveness of Cognitive Behavioral Therapy–Based Intervention in Preventing Gaming Disorder and Unspecified Internet Use Disorder in Adolescents

Behavioral addictions were introduced as novel mental disorders in the International Classification of Diseases, 11th Revision, based on evidence that human behavior itself can become addictive, similar to addiction to substances. However, previous studies on prevention of gaming disorder and unspecified internet use disorder lacked randomization, follow-up measurements, and diagnostic interviews that assessed incidence rates; this trial was intended to fill this gap. To investigate whether the PROTECT (Professioneller Umgang mit technischen Medien [Professional Use of Technical Media]) intervention can reduce the symptom severity and prevent full syndrome and subthreshold onset of gaming disorder and unspecified internet use disorder in at-risk adolescents. A multicenter cluster randomized clinical trial conducted recruitment, screening, intervention delivery, and data collection among at-risk adolescents aged 12 to 18 years in 33 high schools in Germany. Inclusion criteria for the study and symptom severity analyses were elevated symptoms of gaming disorder and unspecified internet use disorder. A subsample that met the inclusion criteria for incidence analyses (no full syndrome of gaming disorder or unspecified internet use disorder, depression, or anxiety at baseline) was analyzed for illness onset. Participants were randomized to either the PROTECT intervention group or the assessment-only control group. Participants were assessed at baseline, 1-month follow-up, 4-month follow-up, and 12-month follow-up between October 1, 2015, and September 30, 2018. Based on intent-to-treat principle, data analyses were conducted from February 8, 2019, to May 7, 2021. PROTECT, a theory-driven, manualized, cognitive behavioral therapy-based indicated preventive group intervention that is delivered in 4 sessions by trained psychologists. It targets changes in addictive reward processing and pathological cognitive mechanisms. The primary outcome was symptom severity (measured by CSAS [Computerspielabhängigkeitsskala], a modified German video game dependency scale with a score range of 0-56 [higher scores indicating greater pathology]) along with incidence rates (assessed by a structured clinical interview) after 12 months. Secondary outcomes were comorbid psychopathology and problem behaviors. A total of 422 at-risk adolescents (mean [SD] age, 15.11 [2.01] years; 229 female participants [54.3%]) were randomized to either the PROTECT intervention group (n = 167; mean [SD] risk score, 29.05 [6.98]) or the assessment-only control group (n = 255; mean [SD] risk score, 26.21 [5.01]) and were included in the symptom severity analyses. Compared with the control group, the PROTECT group showed a significantly greater reduction in symptom severity of gaming disorder or unspecified internet use disorder (γ11 = -0.128; 95% CI, -0.246 to -0.011; P = .03), reflecting a 39.8% vs 27.7% reduction of symptoms with an effect size of Cohen d = 0.67 (baseline vs 12-month follow-up) for the PROTECT group. Differences in incidence rates did not reach statistical significance. The PROTECT group showed a significantly greater decrease in procrastination (γ11 = -0.458; 95% CI, -0.735 to -0.180; P < .001) over 12 months, but no significant differences were found for other secondary outcomes. Results of this trial showed that the PROTECT intervention effectively reduced symptoms of gaming disorder and unspecified internet use disorder over 12 months. The intervention did not change incidence rates of gaming disorder or unspecified internet use disorder. ClinicalTrials.gov Identifier: NCT02907658.

Humoral- and T-Cell-Specific Immune Responses to SARS-CoV-2 mRNA Vaccination in Patients With MS Using Different Disease-Modifying Therapies.

Background and ObjectivesTo evaluate the immune-specific response after full severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination of patients with multiple sclerosis (MS) treated with different disease-modifying drugs by the detection of both serologic and T-cell responses.MethodsHealthcare workers (HCWs) and patients with MS, having completed the 2-dose schedule of an mRNA-based vaccine against SARS-CoV-2 in the past 2–4 weeks, were enrolled from 2 parallel prospective studies conducted in Rome, Italy, at the National Institute for Infectious diseases Spallanzani–IRCSS and San Camillo Forlanini Hospital. Serologic response was evaluated by quantifying the region-binding domain (RBD) and neutralizing antibodies. Cell-mediated response was analyzed by a whole-blood test quantifying interferon (IFN)–γ response to spike peptides. Cells responding to spike stimulation were identified by fluorescence-activated cell sorting analysis.ResultsWe prospectively enrolled 186 vaccinated individuals: 78 HCWs and 108 patients with MS. Twenty-eight patients with MS were treated with IFN-β, 35 with fingolimod, 20 with cladribine, and 25 with ocrelizumab. A lower anti-RBD antibody response rate was found in patients treated with ocrelizumab (40%, p < 0.0001) and fingolimod (85.7%, p = 0.0023) compared to HCWs and patients treated with cladribine or IFN-β. Anti-RBD antibody median titer was lower in patients treated with ocrelizumab (p < 0.0001), fingolimod (p < 0.0001), and cladribine (p = 0.010) compared to HCWs and IFN-β–treated patients. Serum neutralizing activity was present in all the HCWs tested and in only a minority of the fingolimod-treated patients (16.6%). T-cell–specific response was detected in the majority of patients with MS (62%), albeit with significantly lower IFN-γ levels compared to HCWs. The lowest frequency of T-cell response was found in fingolimod-treated patients (14.3%). T-cell–specific response correlated with lymphocyte count and anti-RBD antibody titer (ρ = 0.554, p < 0.0001 and ρ = 0.255, p = 0.0078 respectively). IFN-γ T-cell response was mediated by both CD4+ and CD8+ T cells.DiscussionmRNA vaccines induce both humoral and cell-mediated specific immune responses against spike peptides in all HCWs and in the majority of patients with MS. These results carry relevant implications for managing vaccinations, suggesting promoting vaccination in all treated patients with MS.Classification of EvidenceThis study provides Class III data that SARS-CoV-2 mRNA vaccination induces both humoral and cell-mediated specific immune responses against viral spike proteins in a majority of patients with MS.