Phenotype Of Disorder Research Articles

Clinical and diagnostic imaging profile of three anterior segment dysgenesis disorders presenting with infantile corneal opacities.

To describe three anterior segment dysgenesis disorders with infantile corneal opacities, namely, congenital hereditary endothelial dystrophy (CHED), primary congenital glaucoma (PCG), and Peters anomaly (PA) in terms of clinical characteristics, histopathology, genetic association, and diagnostic imaging profiles using imaging modalities such as ultrasound biomicroscopy (UBM) and microscope-integrated intraoperative optical coherence tomography (i-OCT). Seventy-four eyes with 22 eyes of CHED, 28 eyes of PA, and 24 eyes of PCG were clinically evaluated and underwent imaging using UBM and i-OCT. Corneal buttons of 16 operated patients underwent histopathological analysis, while genetic analysis was done in 23 patients using whole-exome sequencing. Corneal diameters (CD) and UBM parameters like anterior chamber depth (ACD), iris thickness (IT), and ciliary body (CB) thickness revealed a statistically significant difference between the three categories. In PA, 9 eyes had a third rare phenotype with only a posterior corneal defect with no iris adhesions. Genetic mutations were seen in all tested patients with CHED, in 83.3% of patients with PCG, and in 80% of patients with the third type of PA. i-OCT helped in the characterization of corneal opacity, identification of posterior corneal defects, iridocorneal adhesions, and contour of Descemet's membrane. Overlapping phenotypes of the above disorders cause a diagnostic dilemma and parameters like CDs, UBM ACD, IT, and CB thickness help differentiate between them. i-OCT can help in classifying the diseases in a high resolution, non-contact manner, and can better delineate corneal characteristics. The rare third type of PA phenotype may have a genetic association.

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder.

Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as "borderline." Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the "borderline" individual with moderate anxiety and obsessive-compulsive traits. The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a "borderline" phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.

Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders

BackgroundPrenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth.MethodsWe performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro.ResultsDPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered—particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development.ConclusionsOur study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.

Withdrawal and tolerance as related to compulsive sexual behavior disorder and problematic pornography use - Preregistered study based on a nationally representative sample in Poland.

The addiction model of compulsive sexual behavior disorder (CSBD) and problematic pornography use (PPU) predicts the presence of withdrawal symptoms and increased tolerance for sexual stimuli in the disorder phenotype. However, clear empirical evidence supporting this claim has largely been lacking. In the preregistered, nationally representative survey (n = 1,541, 51.2% women, age: M = 42.99, SD = 14.38), we investigated the role of self-reported withdrawal symptoms and tolerance with respect to CSBD and PPU severity. Bothwithdrawal and tolerance were significantly associated with the severities of CSBD (β = 0.34; P< 0.001 and β = 0.38; P < 0.001, respectively) and PPU (β = 0.24; P < 0.001 and β = 0.27; P<0.001, respectively). Of the 21 withdrawal symptom types investigated, the most often reported symptoms were frequent sexual thoughts that were difficult to stop (for participants with CSBD: 65.2% and with PPU: 43.3%), increased overall arousal (37.9%; 29.2%), difficult to control level of sexual desire (57.6%; 31.0%), irritability (37.9%; 25.4%), frequent mood changes (33.3%; 22.6%), and sleep problems (36.4%; 24.5%). Changes related to mood and general arousal noted inthe current study were similar to the cluster of symptoms in a withdrawal syndrome proposed forgambling disorder and internet gaming disorder in DSM-5. The study provides preliminary evidence on an understudied topic, and present findings can have significant implications for understanding the etiology and classification of CSBD and PPU. Simultaneously, drawing conclusions about clinical importance, diagnostic utility and detailed characteristics of withdrawal symptoms andtolerance as a part of CSBD and PPU, as well as other behavioral addictions, requires further research efforts.

Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

Perinatal manifestations of congenital disorders of glycosylation-A clue to early diagnosis.

N-glycosylation defects-isolated or mixed with other glycosylation defects-are the most frequent congenital disorders of glycosylation and present mostly in childhood, with a specific combination of non-specific phenotypic features. The diagnosis, however, is often delayed. The aim of this study is to describe the perinatal phenotype of congenital disorders of N-glycosylation. We present an analysis of perinatal symptoms in a group of 24 one-center Polish patients with N-glycosylation defects-isolated or mixed. The paper expands the perinatal phenotype of CDGs and shows that some distinctive combinations of symptoms present in the perinatal period should raise a suspicion of CDGs in a differential diagnosis.

ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA

Pathogenic ATP1A3 variants play an essential role in the pathogenesis of Sodium-Potassium pump disorders, and AHC is the most common phenotype. The treatment strategies and prognosis depend on the phenotype categories caused by different variation sites and types. The correlation between the genotype and phenotype requires further exploration. •Pathogenic heterozygous ATP1A3 variants cause a spectrum of neurological phenotypes, and ATP1A3-disorders are viewed as a phenotypic continuum presenting with atypical and overlapping features. • The genotype-phenotype correlation of ATP1A3-disorders remains unclear. •In this study, the genotypes and phenotypes of ATP1A3-related disorders from Southwest of China were described. The splice-site variation c.2542+1G>T was detected for the first time in ATP1A3-related disorders. • The prognosis of twins with AHC p. Gly947Arg was more serious than AHC cases with other variants, which was inconsistent with previous reports. The phenomenon indicated the diversity of the correlation between the genotype and phenotype.

The Prevalence and Clinical Phenotype of Dual Positive Neuromyelitis Optica Spectrum Disorders (NMOSD) at a National Reference Centre

Objective To assess the prevalence of dual positive NMOSD and outline its clinical phenotype. Background Neuromyelitis Optica Spectrum Disorders (NMOSD) is an autoimmune syndrome that is frequently positive for Aquaporin 4 (AQP4) IgG or Myelin Oligodendrocyte Glycoproteins (MOG) IgG. However, dual positivity to both is rare. Design/Methods This is a retrospective cross-sectional study conducted at a tertiary healthcare center in South Asia between August 2018 and November 2021. The serum and/or CSF samples of suspected cases of NMOSD were tested for both AQP4-IgG and MOG-IgG using an Indirect immunofluorescence test on transfected cells. Results During the study period, 1935 cases of NMOSD were tested for both antibodies- 65 patients (3.36%; 57 females and 8 males) tested positive for AQP4-IgG, 217 patients (11.23%; 122 females and 95 males) tested positive for MOG-IgG and 3 patients (0.15%; 2 females and 1 male) showed dual positivity. There was a strong female preponderance in all three groups (87.69%, 56.22% and 66.66% respectively). This study identified 3 patients with dual positivity. The first patient (42 years, Male) presented with area postrema syndrome initially and subsequently relapsed by developing right-sided numbness of the temporal area and limbs during which he tested dual positive. The second patient (27 years, Female) presented with bilateral optic neuritis (left &gt;right) initially and subsequently relapsed following an episode of a seizure with left-sided hemiplegia and right-sided facial deviation. The third patient (25 years, Female) initially presented with acute bilateral optic neuritis and later developed left-sided hemiplegia post-recovery at which point she tested dual positive. Management using methylprednisolone was ineffective for all three patients, however, plasmapheresis and/or periodic rituximab injections produced an excellent response. Conclusions Our study reports that the prevalence of dual positive NMOSD is 0.15% and its clinical phenotype is more similar to NMO rather than MOG- associated disease.

Associations of serum zinc, copper, and selenium with sleep disorders in the American adults: Data from NHANES 2011–2016

BackgroundEven though various studies have been conducted to investigate the relationship between trace metals and sleep, few epidemiological studies have evaluated the relationship between trace metals and sleep disorders in American adults. ObjectiveThis study intended to evaluate the associations of serum zinc (Zn), copper (Cu), selenium (Se), Zn/Cu, Zn/Se, and Cu/Se ratios with sleep disorders in American adults. MethodsWe conducted a cross-sectional analysis of 3660 adults aged ≥18 years old who participated in the National Health and Nutrition Examination Survey (NHANES) 2011–2016. Binary logistic regression was employed to calculate the odds ratio (OR) and 95 % confidence interval (CI) of either serum trace metals or serum trace metals ratios with risks among sleep disorder phenotypes. The restricted cubic spline (RCS) model was additionally utilized to check the dose-response relationships between serum trace metals, serum trace metals ratios, and sleep disorders. ResultsLogistic regression demonstrated that higher serum Zn (OR: 0.70, 95 % CI: 0.51–0.97, p = 0.035), Zn/Cu (OR: 0.62, 95 % CI: 0.45–0.87, p = 0.007), and Zn/Se (OR: 0.68, 95 % CI: 0.49–0.95, p = 0.025) were related to a decreased likelihood of self-reported sleep disorders, and dose-response relationships were detected by the RCS models, after adjustment for sociodemographic, behavioral, and health characteristics. No associations between serum Cu, Se, Cu/Se, and sleep disorders were observed. The findings in the sensitivity analyses were consistent with these results. ConclusionOur study revealed that serum Zn, Zn/Cu, and Zn/Se were inversely associated with the risk of self-reported sleep disorders in US adults.

Bibliometric Analysis of Acupuncture in the Treatment of Anxiety Disorders

Acupuncture therapy has great application value in the clinical treatment of anxiety disorders. In the future, we should focus on the exploration of the phenotype of anxiety disorders, the immediate and sustained effects of acupuncture and its mechanism of action to better guide the clinic

Variants of the single nucleotide polymorphisms of thymic stromal lymphopoietin and orsomucoid-1-like protein 3 as predictors of the mono- and polyorganic clinical phenotypes of atopic disorders in children

Background. Atopic disorders (AtD), in particular atopic dermatitis (AD), have a complex genetic basis. There is reliable evidence for associations of thymic stromal lymphopoietin (rs_11466749 TSLP) and orsomucoid-1-like protein 3 (rs_7216389 ORMDL3) gene polymorphisms with the risk of developing mono- and polyorganic phenotypes of AtD in children. The aim of study: to determine associations between SNPs rs_11466749 TSLP and rs_7216389 ORMDL3 and the mono-organic phenotype of AD, to determine the risks of its occurrence with different variants of SNP data related to polyorganic phenotypes of AtD. Materials and methods. Two hundred and ninety-three children of the main group and 105 controls aged 3 to 18 years were recruited in the study. Patients of the main group had established diagnoses of AD, allergic rhinitis/conjunctivitis (AR/AC) and bronchial asthma (BA) in both mono- and multiorganic phenotypes, and the control group did not have AtD and suffered from the gastrointestinal diseases. All patients underwent buccal swab for genotyping the variants A/A, A/G and G/G rs_11466749 TSLP, C/T, C/C and T/T rs_7216389 ORMDL3 using standardized kits by the means of real-time polymerase chain reaction with restriction fragment length polymorphism (qPCR). Pearson’s χ2 test, Fisher’s exact test, Bravais-Pearson correlation coefficient (rb) and odds ratio with 95% confidence interval (CI) were used to achieve the stated study aim. The level of statistical significance was taken at p &lt; 0.05, the trend was determined at p &lt; 0.1. Results. The most frequent genotypes among those investigated within the mono-organic phenotype of AD are A/A and A/G rs_11466749 TSLP and C/T rs_7216389 ORMDL3. Genotype T/T rs_7216389 ORMDL3 has a significantly negative low association, and genotype A/G rs_11466749 TSLP — significantly direct medium association with mono-organic AD phenotype relative to polyorganic AD + AR/AC and AD + AR/AC + BA, respectively. There is a significantly reduced risk of developing mono-organic phenotype of AD compared to polyorganic phenotype of AD + AR/AC with the T/T rs_7216389 ORMDL3 genotype — 0.36 (95% CI 0.15–0.88). Related to the full polyorganic phenotype of AD + AR/AC + BA with the A/G rs_11466749 TSLP genotype, the risk of developing the AD phenotype is significantly increased to 5.81 times (95%CI 1.57–21.5). Conclusions. Carriers of A/A rs_11466749 TSLP, C/T and T/T rs_7216389 ORMDL3 genotypes have a higher risk of developing mono-organic AD phenotype than digestive disorders. Carriership of the A/G rs_11466749 TSLP genotype significantly increases the risk of the developing the mono-organic AD phenotype compared to the full polyorganic phenotype AD + AR/АC + BA, and of the T/T rs_7216389 ORMDL3 variant has a protective effect for the development of AD compared to the polyorganic phenotype AD + AR/AC.

Delineation of the clinical profile of CNOT2 haploinsufficiency and overview of the IDNADFS phenotype.

CNOT2 haploinsufficiency underlies a rare neurodevelopmental disorder named Intellectual Developmental disorder with NAsal speech, Dysmorphic Facies, and variable Skeletal anomalies (IDNADFS, OMIM 618608). The condition clinically overlaps with chromosome 12q15 deletion syndrome, suggesting a major contribution of CNOT2 haploinsufficiency to the latter. CNOT2 is a member of the CCR4-NOT complex, which is a master regulator of multiple cellular processes, including gene expression, RNA deadenylation, and protein ubiquitination. To date, less than 20 pathogenic 12q15 microdeletions encompassing CNOT2, together with a single truncating variant of the gene, and two large intragenic deletions have been reported. Due to the small number of affected subjects described so far, the clinical profile of IDNADFS has not been fully delineated. Here we report five unrelated individuals, three of which carrying de novo intragenic CNOT2 variants, one presenting with a multiexon intragenic deletion, and an additional case of 12q15 microdeletion syndrome. Finally, we assess the features of IDNADFS by reviewing published and present affected individuals and reevaluate the clinical phenotype of this neurodevelopmental disorder.

Orthorexia and autism spectrum in University workers: relationship with gender, body mass index and dietary habits.

To date, few studies have investigated the relationship between autistic traits and emerging phenotypes of restrictive disorders, such as Orthorexia nervosa (ON). The aim of the present work was to investigate the relationship between ON symptoms and autistic traits in a population of University employees, focusing on the impact of gender, weight and type of diet. All academic and technical/administrative workers of University of Pisa were invited by mail to fulfil through an anonymous online form the Adult Autism Sub-threshold Spectrum (AdAS Spectrum) and the ORTO-R. A total of 285 subjects filled out the questionnaires. Participants with significant autistic traits were included into the Broad autism phenotype (BAP) group, while others into the No BAP group. Subjects in the BAP group reported significantly higher ORTO-R scores than others, while no difference was reported for gender, work position, type of diet, age and BMI. Females showed significantly higher ORTO-R scores and lower BMI than males. Older subjects showed a higher BMI. No significant differences in ORTO-R scores were reported depending on type of diet and work position. A decision tree model, with ORTO-R score as dependent variable, revealed in the first step significantly higher ORTO-R scores in the BAP group than in the No BAP group, and in the second step significantly higher ORTO-R scores among females only in the No BAP group. Our results further confirm the association between ON and autism spectrum, which seems to overcome the impact of gender in this population. Level V, descriptive study.

Blended Phenotype of Prader-Willi Syndrome and HSP-SPG11 Caused by Maternal Uniparental Isodisomy.

Uniparental isodisomy can lead to blended phenotypes of imprinting disorders and autosomal recessive diseases. To determine whether a presentation of Prader-Willi syndrome (PWS) and progressive neurologic symptoms was caused by uniparental isodisomy, a detailed clinical and molecular characterization was performed. A combination of clinical, molecular, and imaging data was included in this study. We present the case of a 12-year-old boy with a blended phenotype of PWS and hereditary spastic paraplegia type 11 (HSP-SPG11) caused by maternal uniparental isodisomy of chromosome 15 (UPiD(15)mat) covering a loss-of-function variant in SPG11 (NM_025137.4: c.733_734del; p.Met245ValfsTer2). Although symptoms in early childhood including hypotonia, global developmental delay, hyperphagia, obesity, and seizures were consistent with PWS, additional features of progressive spastic paraparesis, parkinsonism, and cognitive decline in later childhood were atypical. Brain MR imaging showed thinning of the corpus callosum and signal abnormalities of the forceps minor, consistent with a "ears of the lynx" sign. Exome sequencing confirmed a frameshift variant in SPG11 located in the PWS imprinting region on chromosome 15. This case highlights that atypical clinical features in patients with well-described imprinting disorders should lead to investigations for recessive conditions caused by variants in genes that localize to the region of homozygosity, including autosomal recessive forms of HSP.

Whole Exome Sequencing Identifies a Heterozygous Variant in the Cav1.3 Gene CACNA1D Associated with Familial Sinus Node Dysfunction and Focal Idiopathic Epilepsy.

Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in CACNA1D encoding the Cav1.3 α1-subunit are described in congenital sinus node dysfunction and deafness. In addition, germline mutations in CACNA1D have been linked to neurodevelopmental syndromes including epileptic seizures, autism, intellectual disability and primary hyperaldosteronism. Here, a three-generation family with a syndromal phenotype of sinus node dysfunction, idiopathic epilepsy and attention deficit hyperactivity disorder (ADHD) is investigated. Whole genome sequencing and functional heterologous expression studies were used to identify the disease-causing mechanisms in this novel syndromal disorder. We identified a heterozygous non-synonymous variant (p.Arg930His) in the CACNA1D gene that cosegregated with the combined clinical phenotype in an autosomal dominant manner. Functional heterologous expression studies showed that the CACNA1D variant induces isoform-specific alterations of Cav1.3 channel gating: a gain of ion channel function was observed in the brain-specific short CACNA1D isoform (Cav1.3S), whereas a loss of ion channel function was seen in the long (Cav1.3L) isoform. The combined gain-of-function (GOF) and loss-of-function (LOF) induced by the R930H variant are likely to be associated with the rare combined clinical and syndromal phenotypes in the family. The GOF in the Cav1.3S variant with high neuronal expression is likely to result in epilepsy, whereas the LOF in the long Cav1.3L variant results in sinus node dysfunction.

Expansion of the mutation spectrum and phenotype of USP7-related neurodevelopmental disorder.

Hao-fountain syndrome (HAFOUS) is a neurodevelopmental syndrome characterized by global developmental and severe language delays, behavioral abnormalities (including autism), and mild dysmorphic impairment of intellectual development. It is a dominant genetic disease caused by USP7 gene (*602519) mutations on chromosome 16p13.2. So far, only 15 cases with 14 deleterious variants in the USP7 gene have been reported. This study describes three unrelated patients with USP7 variants. Besides, we identified novel de novo heterozygous USP7 variants using trio-whole exome sequencing and verified by Sanger sequencing. Furthermore, clinical characteristics were evaluated by reviewing the medical records. The three identified variants, i.e., one frameshift variant (c.247_250del, p.Glu83Argfs × 18) and two missense variants (c.992A > G, p.Tyr331Cys; c.835T > G, p.Leu279Val) are unreported. The predominant clinical manifestations of the three patients included: DD/ID; language impairment; abnormal behavior; abnormal brain magnetic resonance (dilation of lateral ventricles, dilation of Virchow-Robin spaces, dilated the third ventricle, abnormal cerebral white matter morphology in bilateral occipital lobes, hypodysplasia of the corpus callosum, arachnoid cyst, delayed myelination, and widened subarachnoid space); some also had facial abnormalities. In summary, DD/ID is the most prevalent clinical phenotype of HAFOUS, although some patients also exhibit language and behavioral abnormalities. For the first time in China, we identified three variants of the USP7 gene using whole-genome sequence data. This work expands the USP7 gene mutation spectrum and provides additional clinical data on the clinical phenotype of HAFOUS.

Complement Factor I (CFI) Deficiency Is Linked to Alterations in Humoral Immunity and Accelerated Development of JAK2V617F-Dependent Phenotype

Background: Inflammation is an important phenomenon in hematologic malignancies, though its drivers are not well defined. Within the hematopoietic system, the complement cascade plays a complex role in regulating hematopoietic stem and progenitor cell (hSPC) homing and exit to systemic circulation (Lenkiewicz et al, Frontiers in Immunology 2019). The role the complement system plays in both normal and malignant hSPC egress from the bone marrow has been recognized, though its role in pathogenesis of hematologic malignancies is not well established. Complement cascade contributions to inflammation-mediated pathologies expanded the traditional view of the cascade from an acute process at the site of injury or pathogen invasion, to a mediator of chronic inflammation (Markiewskiet al, American Journal of Pathology 2007). We previously uncovered a rare single nucleotide polymorphism in an inhibitor of the complement cascade Complement Factor I - CFI (CFIG119R). This loss-of-function mutation was detected using whole genome sequencing in 20% of patients with primary myelofibrosis (PMF). In a separate PMF patient cohort, we observed an increase in global complement activity through elevated CH50 levels and decrease in C3 levels (Sadler et al, Blood 2021). There remains a gap in the understanding of how the complement cascade in general and CFI specifically contribute to development and progression of hematologic malignancies. Therefore, we established a murine model of CFI deficiency to determine mechanistic details of complement cascade contribution to both systemic and local inflammation and development of JAK2V617F-dependent pathologies. Methods: To determine the effect of CFI deficiency on homeostasis of hematopoietic system a CFI KO mouse model was generated by floxing exon 2 of the Cfi gene and removing it using CRISPR/Cas9-driven cre recombination. Inactivation of Cfi was confirmed by genotyping. Frequencies of granulocytes, B cells, plasmacytes, T cells, macrophages/monocytes, platelets, erythroid cells were assessed by FACS within the fraction of bone marrow mononuclear cells in 4-week-old CFIWT, HET (n=8) and KO (n=8) mice using established profiling protocols (Chorzalska et al, Blood 2018). Complete blood counts (CBCs) were performed on peripheral blood of 4-week-old Cfi WT (n=20), HET (n=26) and KO (n=10) mice. To determine the effect of CFI deficiency on JAK2V617F-driven phenotypes we performed colony forming assay using CFI WT (n=4, 2F, 2M)) or HET (n=4, 2F, 2M) bone marrows that were transduced with JAK2 V617F encoding retrovirus. Results: CFI KO and HET animals were viable and fertile. CBC analyses of CFI KO, HET vs. WT 4-week-old mice indicated no significant changes with an exception of a significant increase in red blood cell width distribution (RDW) in KO vs. WT and KO vs. HET peripheral blood samples suggestive of a mild anemia. Trends towards granulocytosis and monocytosis as well as leukopenia, erythropenia and decrease in hemoglobin levels were noted. Changes within the red blood cell compartment were confirmed by FSCS. In addition, flow cytometry data showed a significant decrease in CD19+ B-cells in CFI HET vs. WT animals, suggestive of dysregulation of B-cell maturation. Finally, colony forming unit assays showed 59% increase in number of colonies formed by CFI HET/JAK2 V617F+ vs. CFI WT/JAK2 V617F+ bone marrow cells indicative that loss of one copy of Cfi is sufficient to exacerbate JAK2V617F-dependent cellular phenotype. Conclusions: Early characterization of our newly generated CFI KO mouse model shows a phenotype indicative of CFI-loss induced changes within the homeostasis of hematopoietic system affecting red blood cell and B-cell compartments. Our data also indicate that loss of one copy of Cfi may accelerate cell growth and proliferation characteristics of JAK2 V617F-dependent myeloproliferative neoplasms. Detailed analysis of the CFI KO model may uncover novel therapeutically targetable mechanisms that link the pro-inflammatory and myeloproliferative phenotypes of some stem cell disorders, including JAK2 V617F-dependent MPNs.

Clinical-immunological phenotypes of the autistic spectrum disorders

Autistic spectrum disorders (ASD) affect about one in every 59 children. It is noteworthy that patients with ASD are more likely to have other comorbidities than the general population. Undoubtedly, they may aggravate clinical course of the underlying disease or affect the diagnostics. The aim of this work was to identify clinical and immunological phenotypes of the ASD clinical course. Patients and methods. The study included children classified in 2 groups: pediatric patients with ASD (n = 100), and clinically healthy children (n = 30). Based on the presence of comorbidities, the children were divided into 3 types of clinical patterns: convulsive, infectious, dermato-respiratory and gastrointestinal phenotypes. Cytokine concentrations in blood serum were determined by ELISA using Bender Medsystems (Austria) for IL-17А and Vector-Best (Russia) for IL-4, IL-6, IL-10, IFNγ. The concentration of spIgG to 111 nutritional antigens (IgG) was determined by a modified ELISA method using the Immunohealth™ technique. Assessment of cognitive and psychophysiological indices in children was carried out using the ATEC questionnaire. As a result of the study, clinical and immunological phenotypes were identified among the ASD patients, being associated with certain types of food tolerance, cytokine profile, clinical severity of psycho-physiological disorders and concomitant comorbid diseases. In all four phenotypes, were have revealed an increased synthesis of specific antibodies associated with humoral immunity for the studied food antigens, increased concentration of total spIgG to food antigens, concentration of spIgG to legumes and casein, and C-reactive protein levels.Moreover, in convulsive phenotype (concomitant epilepsy and convulsions), the maximal concentrations of spIgG are shown for Solanaceae products, the concentration of IL-10 is increased, IL-4 amounts are reduced, and the content of serum iron and ferritin is also lowered. In the infectious phenotype (frequently ill children) the spIg’s to grain and fermented products are detected, IL-10 and IFNγ concentrations are increased and IL-4 contents is reduced, along with increased absolute and relative number of lymphocytes and fibrinogen. In the dermato-respiratory phenotype (skin rashes) – to dairy products, the concentrations of IL-4 and IL-17A are increased. In the gastrointestinal phenotype, the highest number of elevated IgG responses to the largest range of food antigens was found in presence of changing cytokine profile , i.e., an increase in IFNγ in IFNγ/IL-4 and IFNγ/IL-10 ratios. Thus, the identified phenotypes of the ASD course are associated with the influence of food antigens and reflect a special variant of the immunological inflammatory pathogenesis, which makes it possible to personalize elimination diets, propose measures for correction and individual prevention, and, probably, to predict clinical course of the disease.

Moving towards a taxonomy of cognitive impairments in epilepsy: application of latent profile analysis to 1178 patients with temporal lobe epilepsy.

In efforts to understand the cognitive heterogeneity within and across epilepsy syndromes, cognitive phenotyping has been proposed as a new taxonomy aimed at developing a harmonized approach to cognitive classification in epilepsy. Data- and clinically driven approaches have been previously used with variability in the phenotypes derived across studies. In our study, we utilize latent profile analysis to test several models of phenotypes in a large multicentre sample of patients with temporal lobe epilepsy and evaluate their demographic and clinical profiles. For the first time, we examine the added value of replacing missing data and examine factors that may be contributing to missingness. A sample of 1178 participants met the inclusion criteria for the study, which included a diagnosis of temporal lobe epilepsy and the availability of comprehensive neuropsychological data. Models with two to five classes were examined using latent profile analysis and the optimal model was selected based on fit indices, posterior probabilities and proportion of sample sizes. The models were also examined with imputed data to investigate the impact of missing data on model selection. Based on the fit indices, posterior probability and distinctiveness of the latent classes, a three-class solution was the optimal solution. This three-class solution comprised a group of patients with multidomain impairments, a group with impairments predominantly in language and a group with no impairments. Overall, the multidomain group demonstrated a worse clinical profile and comprised a greater proportion of patients with mesial temporal sclerosis, a longer disease duration and a higher number of anti-seizure medications. The four-class and five-class solutions demonstrated the lowest probabilities of a group membership. Analyses with imputed data demonstrated that the four-class solution was the optimal solution; however, there was a weak agreement between the missing and imputed data sets for the four-Class solutions (κ = 0.288, P < 0.001). This study represents the first to use latent profile analysis to test and compare multiple models of cognitive phenotypes in temporal lobe epilepsy and to determine the impact of missing data on model fit. We found that the three-phenotype model was the most meaningful based on several fit indices and produced phenotypes with unique demographic and clinical profiles. Our findings demonstrate that latent profile analysis is a rigorous method to identify phenotypes in large, heterogeneous epilepsy samples. Furthermore, this study highlights the importance of examining the impact of missing data in phenotyping methods. Our latent profile analysis-derived phenotypes can inform future studies aimed at identifying cognitive phenotypes in other neurological disorders.

Propranolol hydrochloride induces neurodevelopmental toxicity and locomotor disorders in zebrafish larvae

Propranolol hydrochloride is the first-line drug for the clinical treatment of hypertension, arrhythmia, and other diseases. However, with the increasing use of this drug, its safety and environmental health have received more and more attention. In this study, aquatic vertebrate zebrafish were used as a model to study the toxic effects and mechanisms of propranolol hydrochloride. It was revealed that zebrafish larvae exposed to propranolol hydrochloride showed aberrant head nerve development and locomotor disorders. Additionally, exposure to propranolol hydrochloride could induce oxidative stress, alter the activities of AChE and ATPase, and disrupt the expression of genes involved in neurodevelopment and neurotransmitter pathways. More interestingly, the expression of Parkinson's disease-related genes was altered in zebrafish treated with propranolol hydrochloride. We detected the expression of genes related to the Wnt signaling pathway and found that their expression appeared to be down-regulated. The phenotype of nerve developmental defects and locomotor disorders can be effectively rescued by astaxanthin and Wnt activators. Collectively, the results suggest that propranolol hydrochloride may induce neurotoxicity and abnormal movement behavior with PD-like symptoms in zebrafish larvae.