Phenotype Of Disorder Research Articles

Momentary Dynamics Implicate Emotional Features in the ADHD Phenotype.

Emotional dysregulation is increasingly recognized as important to the attention-deficit/hyperactivity disorder (ADHD) phenotype alongside inattention and hyperactivity-impulsivity. Studies of ADHD have relied primarily on trait-based conceptualizations that emphasize stability of symptoms across moderate developmental timescales (i.e., months to years). Trait-based conceptualizations provide a critical view but fail to account for short-term dynamic variations in the expression of ADHD symptoms and emotion. This leaves a gap in our understanding of the short-term variation in ADHD symptom expression and the dynamic relationships among ADHD symptoms and emotion. Here, we assessed caregiver report of ADHD symptoms and positive and negative emotion using ecological momentary approaches over 2 weeks in a sample of 36 children with and without ADHD between the ages of 7-12 years old. Between-person (RKF) and within-person (RC) reliability were estimated. Multilevel models tested specific covariation hypotheses between ADHD symptoms and emotion. Analyses confirmed that ADHD and emotion ratings were reliable as individual differences (i.e., between-person; RKF range 0.93-1.0) and moment-to-moment change (i.e., within-person; Rc range 0.66-0.88) measures. Multilevel models found little evidence for lagged effects between domains, but consistently identified concurrent expression of ADHD symptoms and emotions; inattention covaried most strongly with negative emotion and hyperactivity-impulsivity covaried most strongly with positive emotion. Results demonstrate the importance of complementing trait-level conceptualizations with assessment of momentary dynamics. Momentary assessment suggests important covariation of ADHD symptoms and emotion as part of the ADHD phenotype.

Next generation sequencing panel as an effective approach to genetic testing in patients with a highly variable phenotype of neuromuscular disorders

Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2—8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals.

Modeling brain sex in the limbic system as phenotype for female-prevalent mental disorders

BackgroundSex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics.MethodsWe here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV).ResultsLimbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male–female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction.ConclusionsOverall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders.

COQ7 defect causes prenatal onset of mitochondrial CoQ10 deficiency with cardiomyopathy and gastrointestinal obstruction

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10 levels, and reduced basal and maximal respiration in patients’ fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.

Psychomotor delay: Expanding the neurological phenotype of ATP13A2-related disorders

Psychomotor delay: Expanding the neurological phenotype of ATP13A2-related disorders

Expanding the clinical phenotype and genetic spectrum of GEMIN5 disorders: Early-infantile developmental and epileptic encephalopathies.

Several biallelic truncating and missense variants of the gem nuclear organelle-associated protein 5 (GEMIN5) gene have been reported to cause neurodevelopmental disorders characterized by cerebellar atrophy, intellectual disability, and motor dysfunction. However, the association between biallelic GEMIN5 variants and early-infantile developmental and epileptic encephalopathies (EIDEEs) has not been reported. This study aimed to expand the phenotypic spectrum of GEMIN5 and explore the correlations between epilepsy and molecular sub-regional locations. We performed whole-exome sequencing in two patients with EIDEE with unexplained etiologies. The damaging effects of variants were predicted using multiple in silico tools and modeling. All reported patients with GEMIN5 pathogenic variants and detailed neurological phenotypes were analyzed to evaluate the genotype-phenotype relationship. Novel biallelic GEMIN5 variants were identified in two unrelated female patients with EIDEE, including a frameshift variant (Hg19, chr5:154284147-154284148delCT: NM_015465: c.2551_c.2552delCT: p.(Leu851fs*30)), a nonsense mutation (Hg19, chr5:154299603-154299603delTinsAGA: NM_015465: c.1523delTinsAGA: p.(Leu508*)), and two missense variants (Hg19, chr5:154282663T>A: NM_015465: c.2705T>A: p.(Leu902Gln) and Hg19, chr5:154281002C>G: NM_015465: c.2911C>G: p.(Gln971Glu)), which were inherited from asymptomatic parents and predicted to be damaging or probably damaging using in silico tools. Except p.Leu508*, all these mutations are located in tetratricopeptide repeat (TPR) domain. Our two female patients presented with seizures less than 1 month after birth, followed by clusters of spasms. Brain magnetic resonance imaging suggests dysgenesis of the corpus callosum and cerebellar hypoplasia. Video electroencephalogram showed suppression-bursts. Through a literature review, we found 5 published papers reporting 48 patients with biallelic variants in GEMIN5. Eight of 48 patients have epilepsy, and 5 patients started before 1 year old, which reminds us of the relevance between GEMIN5 variants and EIDEE. Further analysis of the 49 GEMIN5 variants in those 50 patients demonstrated that variants in TPR-like domain or RBS domain were more likely to be associated with epilepsy. We found novel biallelic variants of GEMIN5 in two individuals with EIDEE and expanded the clinical phenotypes of GEMIN5 variants. It is suggested that the GEMIN5 gene should be added to the EIDEE gene panel to aid in the clinical diagnosis of EIDEE and to help determine patient prognosis.

Understanding metabolic patterns in polycystic ovary syndrome: Comparing lean and obese women at a family medicine clinic.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder and various phenotypes have been described. While most women with PCOS are obese, women who are lean also suffer from PCOS. Metabolic derangements often accompany this syndrome. Family physicians, being the first point of contact in the healthcare system, play a vital role in the early diagnosis and management of this condition through diet and lifestyle modifications. The present study was conducted at the Diet and Lifestyle Diseases Management Division of a Family Medicine Clinic. We conducted a retrospective analysis of the correlation between body mass index (BMI) and metabolic parameters in women diagnosed with PCOS. The case records of women with PCOS, diagnosed as per modified Rotterdam criteria and who attended the outpatient clinic from January 2020 to December 2022, were chosen. Data on BMI and metabolic parameters were retrieved and statistically analyzed. Upon analysis of 51 case records, 25.49% of women were in the lean group and 74.51% were overweight or obese. Triglycerides/HDL ratio (1.91 ± 0.47 vs 3.97 ± 5.89) and Vitamin D levels (Median 14.12 vs 16.10 ng/ml) were abnormal in both the obese and the lean women groups. However, there was no significant difference between the groups. Other metabolic parameters were within normal ranges. The present study indicates that metabolic derangements are associated with PCOS, irrespective of BMI. More robust studies in larger population samples are needed to elucidate the role of metabolic derangements and mainly insulin resistance in the pathophysiology of PCOS and its different phenotypes.

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation.

Background: CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. Methods and Results: We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. Conclusions: The present study highlights the importance of considering the investigation of the CACNA1C gene in children's neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.

Lethal phenotypes in Mendelian disorders

PurposeExisting resources that characterize the essentiality status of genes are based on either proliferation assessment in human cell lines, viability evaluation in mouse knockouts, or constraint metrics derived from human population sequencing studies. Several repositories document phenotypic annotations for rare disorders; however, there is a lack of comprehensive reporting on lethal phenotypes. MethodsWe queried Online Mendelian Inheritance in Man for terms related to lethality and classified all Mendelian genes according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. We characterized the genes across these lethality categories, examined the evidence on viability from mouse models and explored how this information could be used for novel gene discovery. ResultsWe developed the Lethal Phenotypes Portal to showcase this curated catalog of human essential genes. Differences in the mode of inheritance, physiological systems affected, and disease class were found for genes in different lethality categories, as well as discrepancies between the lethal phenotypes observed in mouse and human. ConclusionWe anticipate that this resource will aid clinicians in the diagnosis of early lethal conditions and assist researchers in investigating the properties that make these genes essential for human development.

Expanding the Phenotype of BCL11B-related Disorders: A Case Series of Primary Movement Disorders with Literature Review (P10-3.008)

Expanding the Phenotype of BCL11B-related Disorders: A Case Series of Primary Movement Disorders with Literature Review (P10-3.008)

Globus Pallidus Lesion With Iron Deposition and Dopaminergic Denervation in a Patient With a Pathogenic SLC6A1 Variant: A Case Report.

SLC6A1-related disorders encompass heterogeneous neuropsychiatric manifestations through GABAergic dysregulation, without any specific abnormalities on brain MRI, nor evidence of dopaminergic cell loss on I123-FP-β-CIT SPECT. We report here a case of globus pallidus lesions and dopaminergic denervation in a patient with a pathogenic SLC6A1 variant. A 26-year-old female patient with intellectual disability, behavioral, and psychiatric disorders treated by neuroleptics for many years developed a parkinsonian syndrome associated with mild hand dystonia and chorea. A 3T brain MRI and I123-FP-β-CIT SPECT were performed. MRI of the brain found bilateral pallidal lesions consistent with neurodegeneration with iron accumulation. The I123-FP-β-CIT SPECT showed bilateral striatal presynaptic dopaminergic denervation. Whole-genome sequencing revealed a pathogenic SLC6A1 de novo variant. No additional variant was found in any of the genes responsible for Neurodegeneration with Brain Iron Accumulation (NBIA). This is a description of dopaminergic denervation and globus pallidus lesions with iron accumulation related to a SLC6A1 pathogenic variant. These findings expand the phenotype of SLC6A1-related disorder and suggest that it could be considered as a differential diagnosis of NBIA.

Childhood trauma as a transdiagnostic risk factor: clinical implications and preventive interventions

AbstractAbstract: This presentation seeks to explore the interplay between various types of psychological traumas and their potential correlation with the development of distinct types and severities of eating disorders. Emphasis will be placed on elucidating the underlying biological underpinnings and psychological and developmental factors that contribute to the manifestation of diverse eating disorder phenotypes in individuals who have experienced childhood maltreatment. Drawing upon existing research and novel insights, I will present some data from studies investigating the notion that the observed variations in eating disorder presentations may be linked especially to environmental influences. Contrary to the conventional focus on genetic determinants, our findings suggest that the differential ecophenotypic expression of eating disorders may not solely be attributed to DNA variants but rather to the complex interplay between genetic predispositions and environmental contexts.In particular, I will expose the concept of an ecophenotype characteristic of eating disorders associated with childhood maltreatment, positing that the unique ecological context in which an individual is raised significantly influences the trajectory and severity of their eating disorder. This exploration extends beyond a mere examination of genetic markers, shedding light on the environmental and ecosystemic factors that shape the development of an individual’s relationship with food and body image.Disclosure of InterestNone Declared

PET and SPECT imaging as a solid guide to detect and discriminate atypical phenotypes of neurodegenerative disorders

Introduction and aim. Atypical or mixed presentations of neurodegenerative disorders may postpone or confound the final diagnosis. Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) radioligands provide target-specific information and may anticipate the diagnosis by “in vivo” detection of the neuro pathological substrate, as Aβ deposition, nigrostriatal dopaminergic depletion or tau inclusions. This concise review will dis cuss the potential of PET and SPECT imaging as a solid guide to better characterize atypical phenotypes of neurodegeneration in the clinical routine, with the potential to drive personalized interventions, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies. Material and methods. Literature search was performed focusing on the role of PET and SPECT imaging in assessing atypical phenotypes of neurodegeneration, using the electronic source of database PubMed/MEDLINE and the web-based search engines Google, Google Scholar. Analysis of the literature. New disease-modifying drugs may increase their effect with early initiation, which is especially im portant in working persons and younger subjects presenting atypical symptoms. In older individuals, the coexistence of neu rodegeneration, age-related changes, cerebrovascular lesions, or depression makes challenging a definitive diagnosis. Quantitative tools able to measure tracer distribution increase the accuracy of molecular neuroimaging creating topographic maps that compare subject’s data with healthy controls databases. Conclusion. Atypical phenotypes may be associated with quantitative key-pattern allowing a more precise and early diagnosis of the neurodegenerative disorder. Finally, quantitative assessment of the pathological substrates allows us to track the disease process and measure treatment response.

Insight into Insulin-like Growth Factor-1 Receptor (IGF-1R) gene mutations: Implications for growth disorders and treatment: A review of the literature and case report

Background: Insulin-like Growth Factor -1 Receptor (IGF-1R) and its ligand, IGF-1, are crucial for human tissue growth and development. Mutations in IGF-1R and, to a lesser extent, IGF-1 genes lead to diverse growth disorders, characterized by intrauterine growth retardation and postnatal growth challenges. Case report: We present a case of a 6-year-old girl with speech and mild cognitive delays, exhibiting normal motor skills, no neurological issues, and standard vital signs. Her growth parameters indicated significant retardation, with a height standard deviation score (Ht-SDS) of -2 and an IGF-1 level of +1.8 SDS, normal thyroid function and delayed bone age. Genetic analysis identified a 3335 mbp interstitial loss in 15q26.1, encompassing the IGF-1R gene, critical for growth and development. Literature review: Analysis of 34 papers provided insight into the genetic complexities of IGF-1R and IGF-1 mutations. Studies ranged from familial cases to cohort studies, uncovering mutations including missense mutations, deletions, and copy number variations (CNVs), each associated with unique growth disorder phenotypes. Advances in diagnostic techniques like multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES) have been pivotal in identifying these mutations, facilitating more targeted management approaches. Conclusions: This case and review of literature underscore the importance of an integrated genetic, endocrine, and developmental approach in managing growth hormone deficiency (GHD) and IGF-1 resistance. The variability in growth disorders and response to therapy highlights the need for personalized treatment plans, informed by genetic insights, to optimize outcomes for patients with these complex conditions.

Genetics of gambling disorder and related phenotypes: The potential uses of polygenic and multifactorial risk models to enable early detection and improve clinical outcomes.

Gambling Disorder (GD) is an impactful behavioural addiction for which there appear to be underpinning genetic contributors. Twin studies show significant GD heritability results and intergenerational transmission show high rates of transmission. Recent developments in polygenic and multifactorial risk prediction modelling provide promising opportunities to enable early identification and intervention for at risk individuals. People with GD often have significant delays in diagnosis and subsequent help-seeking that can compromise their recovery. In this paper we advocate for more research into the utility of polygenic and multifactorial risk modelling in GD research and treatment programs and rigorous evaluation of its costs and benefits.

Low Overlap and High Heterogeneity Across Common Measures of Eating Disorder Pathology: A Content Analysis.

This study evaluated symptoms assessed in common measures of eating disorder pathology and tested overlap to evaluate the extent to which measures may be interchangeable. Six measures were included: Bulimia Test-Revised, Eating Attitudes Test-26, Eating Disorder Diagnostic Scale, Eating Disorder Examination Questionnaire, Eating Pathology Symptoms Inventory, and Questionnaire for Eating Disorder Diagnoses. Content overlap was quantitatively estimated using the Jaccard Index. Mean overlap was low (.195), likely due to the wide range of symptoms (87) assessed. The mean overlap of each measure with all others was .117 - .267, and the overlap among individual measures was .083 - .382. Implications of low overlap among measures include variable characterization of eating disorder phenotypes and the risk for lower generalizability of findings due to measurement variability.

The autism spectrum disorder phenotype in children with tuberous sclerosis complex: A systematic review and meta-analysis.

https://onlinelibrary.wiley.com/doi/10.1111/dmcn.15307

Abnormal Calcium Accumulation and ROS Homeostasis-Induced Tapetal Programmed Cell Death Lead to Pollen Abortion of Petaloid-Type Cytoplasmic Male Sterility in Camellia oleifera

Cytoplasmic male sterility (CMS) plays a crucial role in the utilization of heterosis. The petaloid anther abortion in oil tea (Camellia oleifera Abel.) constitutes a CMS phenomenon, which is of great value for the hybrid breeding of oil tea. However, as the mechanism of its CMS is still poorly understood, it is necessary to study the cytology and physiological characteristics of anther abortion. In this study, a C. oleifera cultivar, Huashuo (HS), and its petalized CMS mutant (HSP) were used as materials to explore this mechanism. Compared with HS, cytological analysis demonstrated that HSP showed early-onset tapetum programmed cell death (PCD) and an organelle disorder phenotype during the tetrad stage. In HSP, anthers exhibited elevated levels of calcium deposition in anther wall tissues, tapetum layers, and microspores, and yet calcium accumulation was abnormal at the later stage. The contents of hydrogen peroxide and MDA in HSP anthers were higher, and the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were lower than those of HS, which resulted in an excessive accumulation of reactive oxygen species (ROS). Real-time quantitative PCR confirmed that the transcription levels of CoPOD and CoCAT genes encoding key antioxidant enzymes in HSP were downregulated compared with HS in early pollen development; the gene CoCPK, which encodes a calcium-dependent protein kinase associated with antioxidase, was upregulated during the critical period. Thus, we suggest that excessive ROS as a signal breaks the balance of the antioxidant system, and along with an abnormal distribution of calcium ions, leads to the early initiation of PCD in the tapetum, and ultimately leads to pollen abortion for HSP. These results lay a cytological and physiological foundation for further studies on the CMS mechanism, and provide information for breeding male-sterile lines of C. oleifera.

Paraneoplastic neurological syndromes: upgraded approaches to diagnosis

Paraneoplastic neurological syndromes (PNNS) are neurological disorders due to autoimmune attack on the nervous system, induced by a tumor remote from these structures. The existence of relatively stable associations between the neurological syndrome, the type of antineuronal antibodies (Ab) and the nature of tumor has been proven. At the same time, there are no pathognomonic combinations of this kind: the same antibodies can be detected in diff erent types of tumors and in diff erent syndromes. In addition, level of reliability of the diagnosis of PNNS is considered, taking into account the phenotype of the neurological disorder, the presence of certain antibodies in the blood serum, the verifi cation of oncopathology and the duration of the observation for the patient.

Complement C5a Receptor Signaling Alters Stress Responsiveness and Modulates Microglia Following Chronic Stress Exposure

BackgroundAccumulating evidence underscores the pivotal role of heightened inflammation in the pathophysiology of stress-related diseases, but the underlying mechanisms remain elusive. The complement system, a key effector of the innate immune system, produces the C5–cleaved activation product C5a upon activation, initiating inflammatory responses through the canonical C5a receptor 1 (C5aR1). While C5aR1 is expressed in stress-responsive brain regions, its role in stress responsiveness remains unknown. MethodsTo investigate C5a-C5aR1 signaling in stress responses, mice underwent acute and chronic stress paradigms. Circulating C5a levels and messenger RNA expression of C5aR1 in the hippocampus and adrenal gland were measured. C5aR1-deficient mice were used to elucidate the effects of disrupted C5a-C5aR1 signaling across behavioral, hormonal, metabolic, and inflammation parameters. ResultsChronic restraint stress elevated circulating C5a levels while reducing C5aR1 messenger RNA expression in the hippocampus and adrenal gland. Notably, the absence of C5aR1 signaling enhanced adrenal sensitivity to adrenocorticotropic hormone, concurrently reducing pituitary adrenocorticotropic hormone production and enhancing the response to acute stress. C5aR1-deficient mice exhibited attenuated reductions in locomotor activity and body weight under chronic stress. Additionally, these mice displayed increased glucocorticoid receptor sensitivity and disrupted glucose and insulin homeostasis. Chronic stress induced an increase in C5aR1-expressing microglia in the hippocampus, a response mitigated in C5aR1-deficient mice. ConclusionsC5a-C5aR1 signaling emerges as a key metabolic regulator during stress, suggesting that complement activation and dysfunctional C5aR1 signaling may contribute to neuroinflammatory phenotypes in stress-related disorders. The results advocate for further exploration of complement C5aR1 as a potential therapeutic target for stress-related conditions.