Selective Loss Research Articles

Innovation of the protocol for the application of cryolipolysis: Effects and mechanisms of action.

In recent years, aesthetic procedures aiming at body remodeling and have grown exponentially. Cryolipolysis (CLL) has stood out as a noninvasive resource that acts directly on the subcutaneous adipose tissue promoting a significant reduction of adipose tissue through of cooling that could lead to the crystallization cytoplasmic lipids, loss of cellular integrity, apoptosis/necrosis of adipocytes, and local inflammation, producing selective loss of adipose tissue. Thus, the objective of the present study was to evaluate the effects of a specific technique of CLL application on the inflammatory reactions of the target tissue in different post-application times. This is a randomized, blind clinical study that evaluated the tissue sample of six patients after 45, 60, and 90 days of an innovative protocol for the application of CLL, with samples collected through abdominoplasty surgeries. The samples were evaluated by immunohistochemical analyses of several markers. A significantly greater increase in fibroblasts was observed at 45 days and greater phagocytic action at 60 days. Regarding the apoptosis process, the expression of caspase 3 and cleaved caspase 3 markers varied at different times, with cleaved caspase 3 being higher at 45 and 90 days after CLL application. The protocol of the CLL presented in this study was able to induce inflammatory responses in addition to confirming the selective apoptotic action at the different times studied.

Discovery of Tumor-Targeted 6-Methyl Substituted Pemetrexed and Related Antifolates with Selective Loss of RFC Transport.

Pemetrexed and related 5-substituted pyrrolo[2,3-d]pyrimidine antifolates are substrates for the ubiquitously expressed reduced folate carrier (RFC), and the proton-coupled folate transporter (PCFT) and folate receptors (FRs) which are more tumor-selective. A long-standing goal has been to discover tumor-targeted therapeutics that draw from one-carbon metabolic vulnerabilities of cancer cells and are selective for transport by FRs and PCFT over RFC. We discovered that a methyl group at the 6-position of the pyrrole ring in the bicyclic scaffold of 5-substituted 2-amino-4-oxo-pyrrolo[2,3-d]pyrimidine antifolates 1-4 (including pemetrexed) abolished transport by RFC with modest impacts on FRs or PCFT. From molecular modeling, loss of RFC transport involves steric repulsion in the scaffold binding site due to the 6-methyl moiety. 6-Methyl substitution preserved antiproliferative activities toward human tumor cells (KB, IGROV3) with selectivity over IOSE 7576 normal ovary cells and inhibition of de novo purine biosynthesis. Thus, adding a 6-methyl moiety to 5-substituted pyrrolo[2,3-d]pyrimidine antifolates affords tumor transport selectivity while preserving antitumor efficacy.

The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes.

The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in Nlrp1-/-, Casp1-/-, and GsdmD-/- knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

Cassia fistula galactomannan stabilized copper nanocatalyst as an efficient, recyclable heterogeneous catalyst for the fast clickable [3+2] Huisgen cycloadditions in water

In this study, we have first time investigated the synthesis of copper nanocatalyst by using biopolymer galactomannan, naturally extracted from Cassia fistula pods. The methodology involved for the preparation of copper nanocatalyst is economical, efficient, environment friendly, and did not involve further processing for stabilization or reduction of copper nanoparticles. The morphology and structural characterization of the nanocatalyst was performed by using different techniques such as FT-IR, 1H NMR, SEM, EDX, HR-TEM, XRD, XPS, ICP-MS, BET, and TGA analysis. The prepared copper nanocatalyst is applied for the click [3+2] Huisgen cycloadditions of various azides and alkynes, employing water as environmentally benign solvent. In comparison to earlier reported methods, our method requires lowest catalyst loading, less reaction time, excellent yields and have wide substrate scope. Additionally, the catalyst was easily recovered by simple filtration and recycled at least ten consecutive times without any appreciable loss of efficiency and selectivity. The effect of mannose and galactose (Man/Gal) ratio of Cassia fistula galactomannan on the catalytic activity were also investigated.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Smith–Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith–Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

CNSC-12. PATHOLOGY SPECIFIC, PHARMACOLOGICALLY REVERSIBLE LOSS OF NEURONAL FUNCTION IN HUMAN GLIOMAS

Abstract Prior evidence has demonstrated that neuronal activity is preserved within glioma-infiltrated cortex and maintains the ability to engage in task specific computations albeit with information loss. These findings support a potential therapeutic target to rescue cognitive impairments seen in nearly all afflicted patients if neuronal activity can be recovered. We developed an in vivo human behavioral and electrophysiological model to assess neuronal population tuning responses within primary sensory cortex including the decodability of stimuli and task-related changes in population spiking in a cohort of 14 human patients undergoing awake resection. We placed high-density electrode arrays to record human local field potentials from gliomas projecting to the cortical surface. We next designed a static sensory detection threshold task, stimulating with a tachometer at two different face and hand sites totaling 11,200 trials while recording from macroelectrode cortical contacts over both tumor-infiltrated (50 electrodes) and normal appearing cortex (52 electrodes). In tumor-infiltrated cortex, the ability to decode the site of stimulation using the oscillatory power in both theta (4-8 Hz) and gamma (32-70 Hz) bands was reduced compared to normal appearing cortex. However, tumor-infiltrated cortex-maintained selectivity between hand and face stimulation. Targeted next-generation tumor sequencing uncovered novel molecular targets of glioma-neuronal integration. The degree of loss of selectivity correlated with WHO grade and pathology. WHO grade 4 tumors and oligodendrogliomas compared to astrocytomas demonstrating greater loss of selectivity. Gabaergic agonist has been postulated to restore neuronal selectivity in aging and neurodegenerative disease. Therefore, we next computed GABA agonist dose (estimated by time off Propofol and beginning of behavioral testing). Higher concentrations of GABA agonist correlated with improved theta band selectivity and decodability. These results suggest that loss of neuronal computations in glioma-infiltrated cortex is caused by loss of neuronal selectivity and is both tumor selective and pharmacologically reversible.

Cone-driven strong flash electroretinograms in healthy adults: Prevalence of negative waveforms

PurposeBoth rod and cone-driven signals contribute to the electroretinogram (ERG) elicited by a standard strong flash in the dark. Negative ERGs usually reflect inner retinal dysfunction. However, in diseases where rod photoreceptor function is selectively lost, a negative waveform might represent the response of the dark-adapted cone system. To investigate the dark-adapted cone-driven waveform in healthy individuals, we delivered flashes on a dim blue background, designed to saturate the rods, but minimally adapt the cones.MethodsERGs were recorded, using conductive fibre electrodes, in adults from the TwinsUK cohort. Responses to 13 cd m−2 s white xenon flashes (similar to the standard DA 10 flash), delivered on a blue background, were analysed. Photopic and scotopic strengths of the background were 1.3 and 30 cd m−2, respectively; through a dilated pupil, this is expected to largely saturate the rods, but adapt the cones much less than the standard ISCEV background. ResultsMean (SD) participant age was 62.5 (11.3) years (93% female). ERGs from 203 right and 204 left eyes were included, with mean (SD) b/a ratios of 1.22 (0.28) and 1.18 (0.28), respectively (medians, 1.19 and 1.17). Proportions with negative waveforms were 23 and 26%, respectively. Right and left eye b/a ratios were strongly correlated (correlation coefficient 0.74, p < 0.0001). We found no significant correlation of b/a ratio with age.ConclusionsOver 20% of eyes showed b/a ratios less than 1, consistent with the notion that dark-adapted cone-driven responses to standard bright flashes can have negative waveforms. The majority had ratios greater than 1. Thus, whilst selective loss of rod function can yield a negative waveform (with reduced a-wave) in some, our findings also suggest that loss of rod function can occur without necessarily yielding a negative ERG. One potential limitation is possible mild cone system adaptation by the background.

Cohort profile: the United Kingdom Childhood Cancer Study (UKCCS) – a UK-wide population-based study examining the health of cancer survivors

PurposeThe United Kingdom Childhood Cancer Study’s (UKCCS’s) matched cohort was established to examine the longer term morbidity and mortality of individuals previously diagnosed with cancer before 15 years of age,...

Infiltration of freshwater food chain by nanoplastics: An examination of trophic transfer and biological impact

The contamination of freshwater by nanoplastics (NPs) poses a significant threat to various organisms. However, the influence of food factors on the NPs toxicity and the associated risks to water safety remains poorly understood. In this study, we employed highly fluorescent NPs incorporating aggregation-induced emission fluorogens to quantify and visualize the interactions of NPs with freshwater phytoplanktonic alga Chlamydomonas reinhardtii and zooplankton Daphnia magna, including the uptake of NPs by algae and daphnids, as well as gut environment responses through both waterborne and foodborne routes. NPs at environmentally relevant concentrations were capable of aggregating and internalizing in planktonic algae, thus permeating the food chain and potentially causing ecological risks. Notably, positively charged NPs exhibited greater infiltration than the negatively charged NPs. Our findings indicated that NPs had a greater tendency to accumulate in Daphnia via the food chain rather than through direct exposure to water. This was attributed to the loss of selectivity, suggesting a potential mechanism for NP accumulation in aquatic food chains. However, daphnids exposed to NPs through waterborne route exhibited more gut pH acidification, esterase activity, and gut inflammation compared to those exposed via the foodborne route. Moreover, chronic exposure to NPs through waterborne routes significantly disrupted the growth, molting, and reproduction of Daphnia compared to the foodborne group. These findings provided valuable insights into the complexities of plastic pollution on primary trophic levels in aquatic environments.

Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics.

Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.

Mixture Adsorption in Nanoporous Zeolite and at Its External Surface: In-Pore and Surface Selectivity.

Using toluene, ethylene, and water as gas compounds with different representative molecular interactions, we perform atom-scale simulations for their mixtures to investigate the selectivity of the core nanoporosity and external surface in a prototypical zeolite. As expected, the overall behavior suggests that increasing the pressure of a given component promotes the desorption of the coadsorbing species. However, for water-toluene mixtures, we identify that the pseudohydrogen bonding between water and toluene leads to beneficial coadsorption as toluene adsorption in the low-pressure range promotes water adsorption. Moreover, when the zeolite is completely filled with water, toluene adsorption does not occur due to steric repulsion, and ethylene shows oversolubility as the amount of ethylene per water molecule is significantly larger than in bulk water. The underlying oversolubility mechanism is found to be due to localized ethylene adsorption in the density minima arising from the layering of water in nanoconfinement. Despite these specific effects, the relatively weak coadsorption effects in the zeolite nanoporosity, which are found to be reasonably captured using the ideal adsorbed solution theory, arise from the fact that adsorption of these gases having different molecular sizes occurs in distinct pore regions (channel type, channel intersection). Finally, in contrast to confinement in the nanoporosity, mixture adsorption at the external surface does not show coadsorption effects as it mostly follows the Henry regime. These results show that selectivity is mostly governed by the confinement effects as the external surface leads to a selectivity loss.

Copper phosphorylated cellulose nanofibers mediated azide-alkyne cycloaddition click reaction in water

Heterogenous copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC) was performed by using the phosphorylated carbohydrate-based cellulose nanofibers loaded with copper(II) ions. The copper-containing phosphorylated cellulose nanofibers (here after noted Cu(II)-PCNFs) were prepared in two different morphologies, namely the paper and foam ones and characterized by different techniques, including Scanning Electronic Microscopy (SEM), Energy Dispersive X-ray (EDX), Brauner-Emmett-Teller (BET), FT-IR spectroscopy (FTIR), Thermal Gravimetric Analysis (TGA), X-ray Photoelectron spectroscopy (XPS) and Atomic Force Microscopy (AFM). Cu(II)-PCNFs showed high activity in the CuAAC reaction when applied to the ligation of various organic azides and terminal alkynes without any reducing agent, resulting in the regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles in water at room temperature. These nanofibers were recovered and reused with no significant loss of catalytic activity or selectivity. A carbohydrate-based bio-support cellulose as reliable heterogenous catalyst was efficiently developed in view of taking the click chemistry concept to sustainable chemistry.

Retinal clues for selective neuronal loss in multiple sclerosis.

The relationship between the cell body layer and the dendritic network layer of the retina and cognitive performance (CP) in MS patients has not been examined separately. The objective of this study is to predict cognitive impairment (CI) in RRMS patients and to examine the relationship between CP and ganglion cell layer (GCL), inner plexiform layer (IPL), and GCL divided by IPL (GCL/IPL). Ophthalmological evaluation, retinal segmentation, and Symbol Digit Modalities Test (SDMT) were performed on 102 RRMS patients and 54 healthy subjects. The relationships of GCL, IPL, and GCL/IPL with CP in eyes without a history of optic neuritis were investigated using Spearman's correlation. Models were created by accepting 1 standard deviation less of the SDMT mean of the control group as the limit for CI. The cutoff value of the GCL/IPL variable that could predict CI was calculated by ROC analysis, and the ability to accurately predict CI was tested with binary logistic regression. No correlation was found between OCT parameters and CP in healthy subjects. Correlation was found between GCL thickness and GCL/IPL variable and CP in RRMS patients (r=0.235, r=0.667 respectively). A GCL/IPL value of 1.255 was able to identify CI with 81.8% sensitivity and 75.9% specificity (AUC=0.844, LR=3.38) and predicted CI with 74.5% accuracy (Nagelkerke R2=0.439). In RRMS patients, the IPL thickness is unrelated to CP. Therewithal, the GCL/IPL-CP relationship is stronger than the GCL-CP relationship and GCL/IPL can predict CI.

4‐OH‐TEMPO radical grafted onto a novel polyaromatic ether sulfone containing carboxyl side chains as solid catalyst for alcohol oxidation

Abstract2,2,6,6‐Tetramethylpiperidinium‐nitroxide (TEMPO) is a mild and efficient catalyst, which is important in the industrial production of selective oxidation of alcohols to the corresponding aldehyde or ketone compounds. However, it is a challenge to recover the expensive TEMPO catalyst in homogeneous catalytic systems. In this study, a novel polymer‐supported catalyst was prepared using 4‐hydroxy‐2,2,6,6‐tetramethylpiperidin‐1‐oxy (4‐OH‐TEMPO) and polyaromatic ether sulfone (PAES). The successful grafting of 4‐OH‐TEMPO in PAES‐C was demonstrated by 1H nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FT‐IR), load capacity can be calculated by elemental analysis (EA). BET and scanning electron microscopy (SEM) to depict the structure‐performance relationship. Herein, SEM images revealed the existence of porous structure. This structure can effectively adsorb NO molecules to form a PAES‐TEMPO/NOx catalytic system to selectively oxidize benzyl alcohol. The experimental results indicated the high activity, the subsequent benzyl alcohol oxidation cycle can reach more than 93% conversion without showing a large loss of selectivity. More importantly, the as‐prepared catalyst exhibited the attractive recyclability (recovery rate is 98%). After 10 consecutive runs, no significant loss of conversion and selectivity was observed (the conversion rate of benzyl alcohol was more than 93% and the selectivity was more than 95%). This study might provide some recommendation on the development of highly efficient catalysts for alcohol oxidation.

Research on catalytic application of Fe3O4@AAPA-AP-CuCl2 nanocomposite: First nanomagnetic copper catalyst for preparation of aryl nitriles from aldehydes

Nitrile derivatives play an important role in the synthesis of drugs and medicinal compounds; and use to treat diseases such as major depression, generalized anxiety, HIV and mild dementia-related anxiety in non-psychotic patients. In this paper, we found that CuCl2 supported on magnetic nanoparticles modified with 3-amino-2-(aminomethyl)propanoic acid and acylpyrrole [Fe3O4@AAPA-AP-CuCl2] is an ecofriendly and highly efficient catalyst for the preparation of nitriles from aldehydes under mild conditions. Based on our research, it is the first report on the utilization of magnetic copper nanocatalysts for the preparation of aryl nitriles from aldehydes (through radical-type cleavage of coordinated cyanide anion process). The structure of Fe3O4@AAPA-AP-CuCl2 nanocomposite was fully confirmed by many spectroscopic techniques. The Fe3O4@AAPA-AP-CuCl2 catalyst showed high activity and could be recovered and reused 7 times without significant loss in catalytic activity and selectivity. The advantages of this system can be mentioned: performing the reaction in environmentally friendly solvent, easy separation of the catalyst, high reusability, synthesis of products with high yields, providing NMR for all products.

Synthesis and Modification of Magnetic Nanoparticles for Biosensing and Bioassay Applications: A Review

Biosensors are analytical devices that use biological interactions to detect and quantify single molecules, clinical biomarkers, contaminants, allergens, and microorganisms. By coupling bioreceptors with transducers, such as nucleic acids or proteins, biosensors convert biological interactions into electrical signals. Electrochemical and optical transductions are the most widely used methods due to their high detection capability and compatibility with miniaturization. Biosensors are valuable in analytical chemistry, especially for health diagnostics, as they offer simplicity and sensitivity. Despite their usefulness, challenges persist in immobilizing biorecognition elements on the transducer surface, leading to issues such as loss of sensitivity and selectivity. To address these problems, the introduction of nanomaterials, in particular magnetic nanoparticles (MNPs) and magnetic beads, has been implemented. MNPs combine their magnetic properties with other interesting characteristics, such as their small size, high surface-to-volume ratio, easy handling, and excellent biocompatibility, resulting in improved specificity and sensitivity and reduced matrix effects. They can be tailored to specific applications and have been extensively used in various fields, including biosensing and clinical diagnosis. In addition, MNPs simplify sample preparation by isolating the target analytes via magnetic separation, thus reducing the analysis time and interference phenomena and improving the analytical performance of detection. The synthesis and modification of MNPs play a crucial role in adjusting their properties for different applications. This review presents an overview of the synthesis and surface modifications of magnetic nanoparticles and their contributions to the development of biosensors and bioassays for their applications across different areas. The future challenges of MNP synthesis and integration in assays are focused on their stability, multiplex detection, simplification and portability of test platforms, and in vivo applications, among other areas of development.

Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

Huntington’s disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from patients with HD that is associated with the increased activation and localization of complement proteins, innate immune molecules, to these synaptic elements. We also found that levels of these secreted innate immune molecules are elevated in the cerebrospinal fluid of premanifest HD patients and correlate with established measures of disease burden.In preclinical genetic models of HD, we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis, marking them for removal by microglia, the brain’s resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons. Inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function-blocking antibody or genetic ablation of a complement receptor on microglia prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD; they also provide new preclinical data to support complement as a therapeutic target for early intervention.

THU241 Novel PPARG Pathogenic Gene Variant In Newly Diagnosed Familial Partial Lipodystrophy With Childhood Onset

Abstract Disclosure: E.K. Chang: None. K. Greve: None. L. Escobar: None. Background: Familial partial lipodystrophy (FPL) is characterized by progressive, selective body fat loss and is often associated with various metabolic complications including insulin resistance. In particular, FPL Type 3 due to PPARG (peroxisome proliferator-activated receptor gamma) mutations is a very rare subtype with a prevalence of less than 1 per 1,000,000 people overall. This case report describes a clinical case of a child presenting with genetic testing revealing a novel PPARG pathogenic gene variant. Clinical Case: A 9 year old female with history of adoption and unknown family history presented with severe abdominal pain and intractable emesis in the setting of COVID19 infection. Her hospital CT scan of the abdomen was remarkable for pancreatitis and hepatosplenomegaly. Glucose was elevated at 356 mg/dL with normal liver function tests. HgA1c was 11%. Triglycerides were above 4425 mg/dL. Her overall clinical picture was consistent with new onset diabetes mellitus and acute pancreatitis. Physical exam was notable for xanthomatosis and acanthosis nigricans. She was later noted to have partial subcutaneous fat loss of the upper and lower extremities, with preserved fat in the face, neck, and truncal region. She was initiated on insulin therapy and discharged to home once symptomatically improved from her pancreatitis with downtrending triglycerides to less than 450 mg/dL. Her diabetes autoantibodies (Glutamic acid decarboxylase, Islet Antigen-2, Zinc transporter 8 antibodies) resulted as normal, and she was able to discontinue insulin with HgA1c trending down to 4.8% within 4 months of hospital discharge. She underwent whole exome sequencing per recommendation of her lipid specialist and geneticist, which identified a likely pathogenic, previously undescribed variant of PPARG: c.1050_1054dup, p.(Glu352Alafs*12) and a variant of uncertain significance for MC4R: c.409A&amp;gt;G, p.(Ile137Val). This particular variant of PPARG represents a frameshift mutation, resulting in a premature stop codon, likely leading to a loss of normal PPARG function. PPARG mutations are specific to FPL Type 3, which is reportedly associated with atypical fat distribution, diabetes mellitus, hypertriglyceridemia, hypertension, and pancreatitis, consistent with many features of this case. Conclusion: This is the first case to describe the unique PPARG variant c.1050_1054dup, p.(Glu352Alafs*12) which is associated with FPL Type 3. This child's clinical course and evaluation can help with identifying affected individuals of this very rare type of FPL. Presentation: Thursday, June 15, 2023

SAT274 Multilocus Imprinting Disorder Due To Genome-wide Paternal Uniparental Disomy Associated With Adrenocortical Tumors

Abstract Disclosure: E.M. Pinto: None. E. Lalli: None. G. Wu: None. R. Ribeiro: None. G. Zambetti: None. Pediatric adrenocortical tumor (ACT) is an uncommon malignancy frequently associated with Li-Fraumeni syndrome, a familial cancer predisposition disorder caused by germline mutations in the tumor suppressor TP53. ACT is also associated with other genetic constitutional disorders, such as Beckwith-Wiedemann syndrome (BWS) which results from the deregulation of a gene cluster on chromosome 11p15. We report here the identification of three pediatric patients with ACT and additional tumors, two of which received a clinical diagnosis of BWS. Family histories of these two probands include multiple unsuccessful pregnancies. All patients have wild-type TP53 sequence and no evidence for germline chromosome 11p15 alterations. Molecular analyses by whole genome sequencing revealed genome-wide copy neutral loss of heterozygosity (cnLOH) in all tumors. Microsatellite STR and MS-MLPA confirmed genome-wide cnLOH with the selective loss of all maternal chromosomes and duplication of paternal chromosomes in each tumor. Analysis of skin fibroblasts showed mosaic paternal uniparental disomy with partial LOH for all chromosomes, while no LOH was detected in blood DNA. The most prominent clinical feature of genome-wide cnLOH is an unbalanced monoallelic and parent-of-origin specific expression of imprinted genes known as multilocus imprinting disorder (MID). MID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (DMRs) in early embryogenesis. In addition, causative trans-acting factors in imprinting disorders, including the subcortical maternal complex (SCMC), have the potential to affect multiple DMRs across the genome, resulting in a multilocus imprinting disorder. Our study identifies three pediatric patients who developed ACT and other tumors that have undergone genome wide cnLOH that specifically selected against all maternal chromosomes. None of three patients presented with germline alterations in TP53 or 11p15, typical of pediatric ACT. WGS data revealed a germline mutation (p.M573T) in the histone methyltransferase NSD1 in the mother of patient #2. NSD1 mutations are reportedly associated with recurrent miscarriages, tissue overgrowth and increased cancer risk. Alterations in other epigenetic regulators, such as SETD1B (p.R226C), a component of a histone methyltransferase complex and TNRC18 (p.P454L), that enables chromatin binding activity were observed in both mother and child in each family. Further analysis of maternal-effect variants associated with abnormal pregnancies and MID will be important for understanding the mechanisms underlying genome-wide cnLOH. Our results support the molecular testing of multiple loci in atypical clinical presentations of patients with pediatric ACT. Presentation: Saturday, June 17, 2023