Non-affected Relatives Research Articles

Definition, assessment and treatment of cognitive impairment associated with schizophrenia: expert opinion and practical recommendations.

A considerable proportion of patients with schizophrenia perform below population norms on standardized neuropsychological tests, and the performance of those performing within normal range is lower than predicted based on parental education. Cognitive impairment predates the onset of psychosis, is observed during symptom remission and in non-affected first-degree relatives of patients. At the present time, cognitive deficits are regarded as key features of schizophrenia, important determinants of poor psychosocial outcome and targets for both pharmacological and non-pharmacological treatment strategies. A group of eight key opinion leaders reviewed and discussed latest advances in scientific research and current good clinical practices on assessment, management, and treatment of CIAS. In the present paper they summarize the current evidence, identify main gaps between current knowledge and mental health services clinical practice, and provide practical recommendations to reduce the gap.

Germline Predisposition in Myeloid Neoplasms Aged ≥50: A Novel Approach for Allogeneic Stem Cell -Transplantation Decision-Making

Introduction Patients aged 50 or older (≥50) with myeloid neoplasms (MNs), non-affected relatives, and no previous platelet or organ disorder are routinely not tested for germline predisposition. However, approximately 70% of myelodysplastic neoplasms (MDS) patients undergoing an allogeneic hematopoietic stem cell transplantation (alloHSCT) from familial donors, in 2021, were ≥50 years old (y.o.) (EBMT). Given the significant frequency of pathogenic/likely pathogenic (P/LP) germline variants in these patients (about 8%) along with the risk of transplanting cells with the same variant, it seems reasonable to perform universal germline testing in hematological neoplasms although challenging due to labor and cost constraints. Aims To address this, we developed a pragmatic approach incorporating a specific gene list to the diagnostic myeloid somatic panel to identify patients and exclude relatives with shared germline variants. To do that we: (1) Conducted a literature review to assess the gene-disease association's validity in this specific context. (2) Designed a germline-augmented virtual somatic panel (GASP) based on our findings. (3) Tested the virtual panel's performance in 133 MNs cases, aged ≥50, with matched germline-tumor exome sequencing, and no prior organ or platelet disorders. Methods We considered those genes included in the WHO Classification and NCCN Clinical Practice Guidelines as myeloid predisposition genes. For autosomal recessive disorders, heterozygous carriers were not considered. We analyzed the relation of these genes with MNs diagnosed ≥50 y.o. without prior organ or platelet dysfunction: To establish a valid association for a gene, we required the presence of P/LP variants in at least two peer-reviewed studies in the subset of interest. GASP combined genes with recurrent somatic mutations in myeloid disorders, as proposed by Duncavage et al. (Blood 2022), and those associated with the specific cohort of interest. WES was performed on paired tumoral-germline samples on a HiSeq 2000/Novaseq6000 instrument (Illumina Inc) with a target of 100x depth coverage. Results From 2018 to 2023, we collected samples from 133 patients (121 MDS and 12 CMML cases -FAB myelodysplastic variant) diagnosed with WHO-established MDS, aged ≥50, without prior organ or platelet disorders. Among the main characteristics at baseline, we highlight a median age at diagnosis of 57 years old (range, 50-88), and the presence of a first-degree relative with a myeloid neoplasm diagnosis in 7% of the cases. The literature search revealed 11 genes associated with germline predisposition within the cohort of interest. Seven were WHO/NCCN genes: DDX41, TERT, GATA2, CEBPA, SAMD9, ERCC6L2, and TP53. Additionally, four “recently associated genes” were incorporated based on recent descriptions in germline MNs ≥50 y.o. and reported at least in two peer-reviewed articles: CHEK2, DNAH9, ATM, and SH2B3 (Table 1). Next, we tested the accuracy of both the GASP and Duncavage's recommended somatic panel in our cohort of 133 myeloid neoplasms characterized by WES. Among these cases, we identified 15 (11%) P/LP germline variants in both WHO/NCCN and recently associated genes. Duncavage's somatic panel could only detect 8 out of 15 (53%) cases, while the expanded GASP detected 13 out of 15 (87%) variants (Figure 1). The GASP showed a C-index of 0.933, outperforming Duncavage's panel, which scored 0.767. Conclusions Eleven genes have been found to harbor P/LP germline variants in patients with MNs diagnosed ≥50 y.o. and no previous organ or platelet disorder. In our cohort, 11% of patients carried a P/LP germline variant in a MNs predisposition gene. Such a finding would have gone undetected as germline predisposition testing is not typically advised for these patients. Expanding the myeloid somatic panel (GASP) allows the identification of 87% of P/LP variants during the diagnosis process, enabling clinicians to exclude carrier relatives as potential allo-SCT donors.

From one to many: Hypertonia in schizophrenia spectrum psychosis an integrative review and adversarial collaboration report

Different types of resistance to passive movement, i.e. hypertonia, were described in schizophrenia spectrum disorders (SSD) long before the introduction of antipsychotics. While these have been rediscovered in antipsychotic-naïve patients and their non-affected relatives, the existence of intrinsic hypertonia vs drug-induced parkinsonism (DIP) in treated SSD remains controversial. This integrative review seeks to develop a commonly accepted framework to specify the putative clinical phenomena, highlight conflicting issues and discuss ways to challenge each hypothesis and model through adversarial collaboration.The authors agreed on a common framework inspired from systems neuroscience. Specification of DIP, locomotor paratonia (LMP) and psychomotor paratonia (PMP) identified points of disagreement. Some viewed parkinsonian rigidity to be sufficient for diagnosing DIP, while others viewed DIP as a syndrome that should include bradykinesia. Sensitivity of DIP to anticholinergic drugs and the nature of LPM and PMP were the most debated issues.It was agreed that treated SSD should be investigated first. Clinical features of the phenomena at issue could be confirmed by torque, EMG and joint angle measures that could help in challenging the selectivity of DIP to anticholinergics. LMP was modeled as the release of the reticular formation from the control of the supplementary motor area (SMA), which could be challenged by the tonic vibration reflex or acoustic startle. PMP was modeled as the release of primary motor cortex from the control of the SMA and may be informed by subclinical echopraxia. If these challenges are not met, this would put new constraints on the models and have clinical and therapeutic implications.

Network-based quantitative trait linkage analysis of microbiome composition in inflammatory bowel disease families.

Introduction: Inflammatory bowel disease (IBD) is characterized by a dysbiosis of the gut microbiome that results from the interaction of the constituting taxa with one another, and with the host. At the same time, host genetic variation is associated with both IBD risk and microbiome composition. Methods: In the present study, we defined quantitative traits (QTs) from modules identified in microbial co-occurrence networks to measure the inter-individual consistency of microbial abundance and subjected these QTs to a genome-wide quantitative trait locus (QTL) linkage analysis. Results: Four microbial network modules were consistently identified in two cohorts of healthy individuals, but three of the corresponding QTs differed significantly between IBD patients and unaffected individuals. The QTL linkage analysis was performed in a sub-sample of the Kiel IBD family cohort (IBD-KC), an ongoing study of 256 German families comprising 455 IBD patients and 575 first- and second-degree, non-affected relatives. The analysis revealed five chromosomal regions linked to one of three microbial module QTs, namely on chromosomes 3 (spanning 10.79 cM) and 11 (6.69 cM) for the first module, chr9 (0.13 cM) and chr16 (1.20 cM) for the second module, and chr13 (19.98 cM) for the third module. None of these loci have been implicated in a microbial phenotype before. Discussion: Our study illustrates the benefit of combining network and family-based linkage analysis to identify novel genetic drivers of microbiome composition in a specific disease context.

1117 FAMILY SCREENING IN DILATED CARDIOMYOPATHY: CLINICAL CHARACTERIZATION AND FOLLOW UP OF RELATIVES

Abstract Background Familial patterns of inheritance and genetic mutations have been identified as pathogenic in nearly 40-50% of previously defined “idiopathic” Dilated Cardiomyopathy (DCM). Genetic testing in the proband allows cascade genetic screening in relatives, in order to promote an early diagnosis even in a pre-clinical stage of the disease, as recommended by international guidelines. This study aims to describe the clinical characteristics of screened relatives of Dilated Cardiomyopathy (DCM) patients, at baseline and during follow-up. Methods Screened relatives of patients affected by DCM were enrolled retrospectively and followed from January 2000 to August 2021. At baseline, the family screening included a clinical evaluation, ECG and echocardiogram. If likely pathogenetic (LP) or pathogenetic (P) variant was identified in the proband Genetic testing was offered and performed on relatives according to available consensus documents from the age of 10-12 years. The onset of disease was defined as left ventricular (LV) dilation and/or LV systolic dysfunction. The following information was obtained during the follow-up: all-cause death, cardiovascular death, sudden cardiac death (SCD), hospitalization for heart failure (HF), heart transplantation, ventricular assist device (VAD) implantation, ICD or CRT-D implantation and major ventricular arrhythmias (MVA). Results We enrolled 203 relatives from 32 families with DCM. The median follow-up was 94 months. At baseline, symptomatic relatives for dyspnea (NYHA II-III class) were 29 (14%), versus 174 (86%) of asymptomatic (NYHA I). All these subjects showed initial signs of DCM and experienced more frequently adverse outcomes, such as hospitalization for HF (p<0,001) and MVA (p<0,001) during follow-up. Among asymptomatic relatives, patients with initial signs of disease were 46 (26%), 20 (43%) with LV dilation and dysfunction, 18 (39%) with LV dysfunction and 7 (15%) with LV dilatation. During follow-up, 5 of them (11%) died and 2 (4%) experienced SCD (one carrier of FLNC variant). Globally, affected relatives at baseline carried a LP/P variant in more than half of the cases (57%), the remaining part being relative of proband with no or negative genetic testing. Non-affected relatives were 128 (74%) at baseline. 15 relatives (12%) developed initial signs of DCM (5 with LV dilation, 5 with LV dysfunction, 5 with LV dilation and dysfunction) during follow-up. Of those, 13 patients (87%) carried a LP/P variant. The genes mostly involved were TTN (9 cases,69%), followed by DSP and FLNC. Conclusions Familial screening allows an early diagnosis of DCM-affected patients. Asymptomatic relatives at the baseline showed a better outcome compared with symptomatic ones. However, SCD events were only detected in the asymptomatic group. Moreover, subjects who develop the disease during follow-up were carriers of a LP/P variant. Seriate follow-up is mandatory in relatives independently by symptoms at the baseline: genetic testing supports a focused clinical screening of high-risk relatives.

A-216 Construct Validity of The National Institutes of Health Toolbox- Cognition Battery (NIHTB-CB) in Children and Adolescents with Cerebral Cavernous Malformation, Type 1 (CCM-1) and their Non-Affected Relatives

Abstract Objective: This study assessed the convergent validity of the NIHTB-CB in a sample of children and adolescents with CCM-1 and non-affected relatives. Method: Twenty-two participants with CCM-1 and 7 non-affected relatives completed the NIHTB-CB and traditional neuropsychological measures. The following domains were assessed: memory (NIHTB-CB Picture Sequencing Memory and Child and Adolescent Memory Profile- Screening Index), word reading (NIHTB-CB Oral Reading and Wide Range Achievement Test-4th Word Reading [WRAT-4 WR]), processing speed (NIHTB-CB Pattern Comparison and Symbol Digit Modalities Test), and attention/working memory (NIHTB-CB List Sorting and Digit Span). Results: The non-affected group scored higher than the CCM-1 group on WRAT-4 WR (t = 2.68, p = .02) and NIHTB-CB Oral Reading (t = 2.18, p = .05). The groups did not differ on the other measures (p > .05). Pearson’s correlations ranged from .45 for memory to .81 for word reading, demonstrating adequate construct validity for memory, processing speed, and attention/ working memory and good to very good for word reading. The NIHTB-CB was more likely to identify participants as impaired for memory (17.2% vs 6.9%) and processing speed (62.1% vs. 3.4%). The traditional attention/working memory measure was more likely to identify participants as impaired (27.6% vs 3.4%). Impairment rates were similar for the word reading measures. Conclusions: Of the domains considered, convergent validity was best established for word reading. Although correlations were adequate, rates of impairment differed for memory, processing speed, and attention/ working memory, suggesting that caution is warranted when comparing the NIHTB-CB to traditional measures in these areas.

A-6 Pediatric Cerebral Cavernous Malformation, Type 1 (CCM1): Cognitive and Psychosocial Functioning, The Role of Neuropsychology, and Emerging Clinical Care Guidelines

Abstract Objective: CCM1 is a rare condition that confers risk for negative neurological sequelae, including hemorrhage, seizures, and chronic headache. This study examines cognitive and psychosocial functioning in pediatric patients with CCM1 and describes emerging clinical care guidelines. Method: Twenty-two children and adolescents with CCM-1 and 7 non-affected relatives participated in this cross-sectional pilot study. Cognitive testing and behavior and emotion questionnaires were completed. A subset of participants with CCM1 (n = 11) had repeat brain MRI (average 4.89 years between scans). Results: Patients with CCM1 and their non-affected relatives did not differ on the NIH Toolbox Fluid and Crystallized composites (p > 0.05). Processing speed also did not significantly differ, although both group means were below average normatively (NIH Toolbox Pattern Comparison T-score; CCM1 = 31.50 [12.02], non-affected relatives = 37.57 [14.58]). In the subgroup with repeat imaging, slower processing speed was associated with an increase in large lesions (p = 0.03) and with younger age at CCM1 diagnosis (p = 0.04). Self- and parent-reported internalizing problems and parent-reported externalizing problems did not differ between groups (p > 05). In the CCM1 group, patient-reported disengaged coping was associated with more internalizing problems (p = 0.03). Conclusions: Neuropsychological evaluation is an important component of long-term, multi-disciplinary care for pediatric patients with CCM1, particularly if lesions are progressive. The pilot sample was overall well-adjusted behaviorally and emotionally. The use of disengaged coping strategies was associated with more internalizing symptoms and coping may be a key modifiable risk factor in this population. Psychosocial monitoring may therefore be warranted.

Coeliac disease re-screening among once seronegative at-risk relatives: A long-term follow-up study.

BackgroundSerological screening of the relatives of coeliac disease patients is widely endorsed. However, the need for and the optimal timing of possible re‐testing of once seronegative at‐risk individuals for coeliac disease remain unclear.ObjectiveWe investigated this issue by inviting a large cohort of previously screening‐negative relatives of patients with coeliac disease to participate in a follow‐up study.MethodsAltogether 599 relatives of coeliac disease index patients not diagnosed with coeliac disease in a screening study carried out in 2006–2010 were asked about possible later diagnosis or re‐tested with coeliac disease autoantibodies in 2017–2021. Besides incidence, the possible impact of various patient‐related clinical factors and HLA haplotype on the later diagnosis or screening positivity was examined.ResultsFifteen (2.5%) relatives were either diagnosed with a coeliac disease (n = 8) during the follow‐up period or were found to be screening‐positive in the re‐testing (n = 7), giving a combined annual incidence of 221/100,000 person‐years in all relatives and 336/100,000 among those carrying coeliac disease‐associated HLA DQ2/DQ8. The new cases more often carried the high‐risk (DQ2.5/2.5 or DQ2.5/2.2; 35.7% vs. 7.4%, respectively, p < 0.001) HLA and were younger at initial screening (23.3 vs. 40.5 years, p = 0.028) and – in spite of a negative screening outcome – had higher median transglutaminase antibody level in the first study than those not affected. There were no significant differences between the affected and non‐affected relatives in other demographic data, degree of kinship with the index, current symptoms or frequency of chronic co‐morbidities.ConclusionThe incidence rate for later coeliac disease diagnosis or new seropositivity in relatives who had been tested once was 221/100,000 person‐years in all and 336/100,000 among those carrying at‐risk HLA genetics after ∼10 years of follow‐up. HLA‐typing could help to target a subgroup of relatives who would benefit most from re‐testing.

Cortico-cognition coupling in treatment resistant schizophrenia

BackgroundBrain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC). MethodForty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted. ResultsUnivariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients. ConclusionsMB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature.

Executive functioning in adults with borderline personality disorder and first-degree biological relatives

Objectives Behavioural dysregulation is a heritable core symptom domain in borderline personality disorder (BPD) that is likely influenced by the integrity of executive functions (EFs). However, the extent to which familial risk for BPD confers decrement to EFs has yet to be comprehensively studied. Methods In this family study, probands with BPD (n = 73), first-degree biological relatives (n = 65), and healthy controls without psychiatric diagnoses (n = 77) were assessed in abstraction, attentional vigilance, working memory, cognitive flexibility, interference resolution, planning, problem solving, and response inhibition. Results In univariate analyses, probands demonstrated lower response inhibition than relatives. Comparatively, discriminant function analyses revealed that lower interference resolution and response inhibition jointly discriminated probands from relatives and controls, whereas a combination of less efficient problem solving and difficulty manipulating mental information discriminated probands and relatives from controls. Moreover, the subset of psychiatrically non-affected relatives demonstrated a pattern of resilience to psychiatric morbidity substantiated by stronger response inhibition and abstraction abilities despite less efficient problem solving. Conclusions Familial risk for BPD is represented predominantly by a pattern of problem-solving and working memory deficits. Resilience to a psychiatric disorder in non-affected relatives reflects both EF weaknesses and strengths, highlighting potential protective factors that should be considered in future neurocognitive research on BPD families.

087 International Rare and Severe Psoriasis Expert Network (IRASPEN) – A prospective multi-centre pustular psoriasis registry with genotype-phenotype correlation

Pustular psoriasis (PP) encompasses a range of well-defined, severe inflammatory conditions characterized by production of sterile pustules. Our understanding of this rare disease’s pathophysiology, clinical course and optimal treatment is as yet limited. The goal of this prospective international registry is to describe the natural course of disease in different subtypes of PP and create phenotype-genotype correlations as well as elucidate therapeutic molecular pathways. The IRASPEN registry plans to include at least 180 patients at approximately 15 sites world-wide, aiming for minimum numbers of 140 Palmoplantar Psoriasis (PPP), 20 Generalized Pustular Psoriasis (GPP) and 20 Acrodermatitis Continua of Hallopeau (ACH) patients and up to 360 non-affected first degree relatives.

Presence of high‐risk HLA genotype is the most important individual risk factor for coeliac disease among at‐risk relatives

Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure. To investigate the individual risk of coeliac disease among patients' relatives. Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression. There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18years at diagnosis (odds ratio 1.60, 95% CI 1.04-2.45) in index, and age 41-60years (1.73, 1.10-2.73), being a sibling (1.65, 1.06-2.59) and having the high-risk genotype (3.22, 2.01-5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80-4.78) in multivariable analysis. Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. ClinicalTrials.gov identifier NCT03136731.

Targeted α7 Nicotinic Acetylcholine Receptor Treatment for the Modulation of Speech MMN in Schizophrenia: An Optimized CDP-Choline and Galantamine Combination Approach Personalized to Baseline-Deviance Detection Levels

α7 nicotinic acetylcholine receptors (nAChR) pathophysiology is associated with sensory and cognitive dysfunction in schizophrenia (SCZ), a multigenic neurodevelopmental disorder. The mismatch negativity event-related potential (MMN-ERP) is sensitive to early deviance detection and sensory memory processing, which are impaired in SCZ and their non-affected relatives. Improvement in MMN amplitudes is associated with clinical and functional outcomes, making this ERP an ideal endophenotype to assess novel pharmacological treatments. As genetics, smoking status, personality, and functioning level were emphasized as trait factors underlying response variability to pharmacological therapies and specific α7 nAChR agonists, the MMN use for participant baseline electrophysiological response stratification is an increasingly applied strategy demonstrating converging evidence of deviance detection improvements in SCZ. Evidence for sensory processing improvements mediated by α7 nAChR-agonists and considering this receptor’s fast desensitization rate, a novel optimized approach combining CDP-choline (a selective α7 agonist) with galantamine (a nAChR positive allosteric modulator) was shown to increase deviance detection in healthy low-baseline groups.

Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under \u03b2-adrenergic stimulation

The variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to β-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under β-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under β-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to β-blocker therapy.

Gender roles and behavioral problems in children with 21-hydroxylase deficiency in Southern China

PurposeTo assess the gender roles and behavioral outcomes in children with 21-hydroxylase deficiency (21-OHD) in Southern China. MethodsA total of 50 individuals with 21-OHD participated in our study, (30 boys and 20 girls), as well as another 19 age-matched non-affected relatives of patients (12 boys and 7 girls). Psychological adjustment was assessed with a preschool activity survey and a Conner parent symptom questionnaire was modified for retrospective reporting. ResultsThe response rate of the questionnaire in the control group was only 36.5%. All the patients were diagnosed with salt-wasting of 21-OHD. Our study revealed that the masculine score was higher in male patients with 21-OHD than male controls and female patients. Compared with that in the female 21-OHD patient group, the masculine score in the female control group was lower, while comparative masculinization was found in the male controls. Regarding behavioral problems, there was a higher incidence of parent-reported problems among children with 21-OHD than controls, including conduct problems, impulsive hyperactivity, anxiety, and hyperactivity index. ConclusionParents of 21-OHD patients in Southern China were unwilling to disclose the condition of their children to the society. Masculinization and behavioral problems were prevalent among patients with 21-OHD, which highlighted the importance of psychological and social support for 21-OHD patients and their families.

Neurophysiological biomarkers of response inhibition and the familial risk for borderline personality disorder

Understanding of the biological factors that run in families affected with borderline personality disorder (BPD) is limited. The authors investigated the familial aggregation of neurophysiological biomarkers of response inhibition in the first-degree biological relatives of probands with BPD and associations with psychiatric diagnosis and impulsive traits. In the present study, psychiatric diagnoses and impulsive traits were measured in BPD probands (n = 86), psychiatrically affected and non-affected relatives (n = 60) and controls (n = 83). While undergoing neuroimaging using functional near-infrared spectroscopy, prefrontal cortex (PFC) activation was measured during a go/no-go response inhibition task and compared between probands, relatives and controls. Additionally, non-psychiatrically affected relatives and controls were contrasted to examine the potential impact of familial risk for BPD on response inhibition-related PFC activation in the absence of confounding psychiatric morbidity. Probands showed bilateral decreases in PFC activation during response inhibition compared to relatives and controls. Conversely, both affected and non-affected relatives displayed higher activation than controls and probands in left lateral/medial and right medial PFC, although non-affected relatives showed a lesser extent of activation than affected relatives. Probands and controls reporting greater impulsive traits displayed deactivation across the PFC during response inhibition, whereas relatives showed increased activation. In this first family study of neuroimaging biomarkers in BPD, we show that the familial risk for BPD is reflected in activation of the PFC during response inhibition, with lifetime psychiatric diagnosis and higher impulsive traits in relatives associated with larger increases in PFC activity. Higher PFC activity during response inhibition including among non-affected relatives could reflect a neurophysiological compensatory mechanism.

LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa.

In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals.

A-235 Construct validity of the National Institutes of Health Toolbox- Cognition Battery (NIHTB-CB) in children and adolescents with cerebral cavernous malformation, type 1 (CCM-1) and their non-affected relatives

Abstract Objective This study assessed the convergent validity of the NIHTB-CB in a sample of children and adolescents with CCM-1 and non-affected relatives. Method Twenty-two participants with CCM-1 and 7 non-affected relatives completed the NIHTB-CB and traditional neuropsychological measures. The following domains were assessed: memory (NIHTB-CB Picture Sequencing Memory and Child and Adolescent Memory Profile- Screening Index), word reading (NIHTB-CB Oral Reading and Wide Range Achievement Test-4th Word Reading [WRAT-4 WR]),processing speed (NIHTB-CB Pattern Comparison and Symbol Digit Modalities Test), and attention/working memory (NIHTB-CB List Sorting and Digit Span). Results The non-affected group scored higher than the CCM-1 group on WRAT-4 WR (t = 2.68, p = .02) and NIHTB-CB Oral Reading (t = 2.18, p = .05). The groups did not differ on the other measures (p &amp;gt; .05). Pearson’s correlations ranged from .45 for memory to .81 for word reading, demonstrating adequate construct validity for memory, processing speed, and attention/working memory and good to very good for word reading. The NIHTB-CB was more likely to identify participants as impaired for memory (17.2% vs 6.9%) and processing speed (62.1% vs. 3.4%). The traditional attention/working memory measure was more likely to identify participants as impaired (27.6% vs 3.4%). Impairment rates were similar for the word reading measures. Conclusions Of the domains considered, convergent validity was best established for word reading. Although correlations were adequate, rates of impairment differed for memory, processing speed, and attention/working memory, suggesting that caution is warranted when comparing the NIHTB-CB to traditional measures in these areas.

T158. NO ALTERATION OF PITUTARY VOLUME IN PATIENTS WITH FIRST-EPISODE SCHIZPHRENIA BUT A TREND OF ENLARGEMENT IN NON-PSYCHOTIC FIRST-DEGREE RELATIVES

BackgroundThere is growing evidence suggesting that the abnormal pituitary volume (PV) may be an essential deficit in schizophrenia spectrum disorders, and PV may change depending on the stage of the illness. However, previous studies assessing PV in schizophrenia spectrum disorders, especially in ultra-high risk individuals, were confounding. The present study aimed to assess whether there would be alteration of the PV in patients with first-episode schizophrenia and their non-affected first-degree relatives.MethodsThis study recruited 147 subjects, including subjects with 62 first-episode schizophrenia (31 man, 31 female), 25 non-psychotic first-degree relatives (11 male, 14 female), and 60 healthy controls (30 male, 30 female). All of them underwent a T1 weighted image magnetic resonance imaging using 3T MRI Scanner (Siemens, Germany). All volumes were examined with the 3D-Slicer 4.10.1 (Surgical Planning Laboratory, Brigham and Women’s Hospital, USA; http://www. slicer.org/). The PV was traced in all coronal slices with well-defied boundaries (such as diaphragma sellae (superiorly), the sphenoid sinus (inferiorly), the cavernous sinuses(bilaterally)). The infundibular stalk was excluded while the bright posterior pituitary was included. All images were tranced manually by a trained rater who was blind to the participants’ group assignment. In a random subset of 24 cases, both the inter-rater reliability (intraclass correlation coefficient r=0.916, p<0.001) and the intra-rater reliability (intraclass correlation coefficient r=0.924 p<0.001) were high. We conducted MANCOVA with gender, and whole brain volumes (WBV) as covariates to compare the PV among the groups.ResultsWe found no significant differences in gender ratio, age, and WBV (p>0.05) among the three groups, but patients with first-episode schizophrenia showed shorter length of education than healthy controls (p<0.001). As expected, we found that male participants in general (Mean ± SD: 486.85 ± 100.24) exhibited a prominently smaller PV than female participants (Mean ± SD: 562.13 ± 102.90) after controlling for WBV (t=25.087, p<0.001). Findings from MANCOVA analysis showed that although first-episode schizophrenia patients (Mean ± SD: 523.81 ± 116.41) and healthy controls (Mean ± SD: 513.17 ± 103.57) showed no significant difference in PV (F=0.581, p=0.447), there was a trend of statistical significance in their non-psychotic first-degree relatives (Mean ± SD: 557.85 ± 93.58) compared with healthy controls (F=3.334, p=0.072). We also found a negative correlation between the duration of treatment and PV in female schizophrenia patients (r=-0.398, p=0.029), whose mean duration of treatment was 4.71 months (SD=2.18 months). No significant correlation was observed in in male patients.DiscussionOur findings found no alteration of PV in first-episode schizophrenia patients but a trend of enlargement was observed in their non-psychotic first-degree relatives. Moreover, female schizophrenia patients with longer duration of treatment exhibited smaller PV. These findings suggested that the enlarged PV might be an early detection signal for individuals with potentially high risk of developing into schizophrenia, and such an enlargement of PV might be responsive to antipsychotic medications.

OR01-06 Resistance to Thyroid Hormone Beta Is Associated with an Increase in Hepatic Fat Measured by Transient Elastography (Fibroscan®) with Controlled Attenuation Parameter (CAP)

Hepatic regulation of lipid metabolism is dependent on thyroid hormone receptors (TRs) with TRβ as the predominantly expressed TR isoform in the liver. Patients with resistance to thyroid hormone (RTH) harboring mutations in the THRB gene have loss-of-function of TRβ. Thus, we investigated whether these patients can present with alterations in the lipid homeostasis.We evaluated hepatic fat content and metabolic parameters in patients bearing the R243Q mutation of THRB gene (n=21) and in their non-affected (WT) first degree relatives (n=22). All participants belonged to the same family, lived in the same small island, therefore exposed to similar environmental conditions. Family members with disorders known to affect lipid metabolism as well as a history of drinking habits of more 30 g alcohol/day were excluded. Whenever possible, medications were suspended one month before the tests. Hepatic fat content was estimated by transient elastography (FibroScan®, TE) with controlled attenuation parameter (CAP) as a noninvasive marker of hepatic steatosis. Measurements of CAP and metabolic parameters were carried after an overnight fast. The observers were blinded to the status of the patients.There were no significant difference between the two groups, RTHβ and WT respectively, in age (mean±SD) 36±11 years (range 18-55) and 34±9 years (19-59) and body mass index, BMI, 21.9 Kg/m2 (14.2-31.7) and 23.8 Kg/m2 (18.9-37.7). CAP values were significantly higher in RTHβ patients when compared to those measured in their WT relatives, 263±21 dB/m and 218.7±43 dB/m, respectively (P<0.001). Measurements of CAP correlated positively with age and BMI in the WT group (r=0.56; P<0.05 and r=0.59; P<0.05 respectively) but not in the group of RTHβ (r=0.19; P>0.05 and r=0.21;P>0.05. The lipid profile was not significant difference between the two group regarding total cholesterol (165±27 and 175±30 mg/dl), LDL cholesterol (103±16 and 113±29 mg/dl) and tryglicerides (115±45 and 108±43mg/dl). However, the HDL cholesterol was significantly lower in RTHβ patients (40±8 and 52±10 mg/dl; P<0.006). Glycemia, insulin levels and HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) were within the normal range and showed no significant differences between the two groups.In conclusion, RTHβ was associated with hepatic steatosis indicating that the TRβ dependent signaling of thyroid hormone plays an important role in lipid homeostasis. This finding further emphasizes the rational for the development of thyroid hormone analogues selective for TRβ which may offer alternatives for treatment of lipid-associated hepatic disorders without generating cardiac toxicity or accelerated bone loss.