Non-affected Relatives Research Articles

Low Serum Sphingolipids in Attention Deficit Hyperactivity Disorder (ADHD)

BackgroundADHD is the most prevalent neurodevelopmental disorder in children and has been associated with a lag in neuronal maturation. Sphingolipids are essential for myelination, neuronal function and development. We hypothesized that serum sphingolipid profiles are different in ADHD.ObjectiveTo characterize the serum sphingolipid profile in ADHD patients and two independent control groups: non‐affected relatives and non‐affected subjects without family history of ADHD.MethodSphingolipid profiles were determined by mass spectrometry in 77 participants (28 ADHD, 28 related controls and 21 unrelated controls). Diagnosis was based on the criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM IV‐TR). Groups were compared by parametrical statistics.ResultsAll major sphingomyelins (C16:0, C18:0, C18:1 and C24:1), ceramide C24:0 and deoxyceramide C24:1 were significantly decreased in ADHD at relative reductions between 20‐30%. In our sample, decreased serum sphingomyelin levels distinguished ADHD patients with 79% sensitivity, 78% specificity and an estimated negative predictive value of 97%.ConclusionSerum sphingomyelin and select ceramides are decreased in ADHD patients. Longitudinal studies are required to evaluate if these findings reflect an ADHD specific pathomechanisms. Low serum sphingomyelins levels are a potential biomarker for ADHD.Grant support: None

Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.

Neural correlates of negative emotion processing in bipolar disorder.

Bipolar disorder type I (BD-I) is characterized by a severe impairment in emotional processing during both acute and euthymic phases of the illness. The aim of the present study was to investigate negative emotion processing in both euthymic patients and non-affected first-degree relatives, looking for state and trait markers of BD-I. 22 healthy relatives of BD-I patients (mean age 31.5±7.3 years; 15 females), 23 euthymic BD-I patients (mean age 35.2±7.9 years; 14 females), and 24 matched controls (mean age 32.5±6.2 years; 16 females) performed an IAPS-based emotional task during 1.5T fMRI. They were required to identify vegetable items (targets) inside neutral or negative pictures. Euthymic BD-I patients showed a significant reduced accuracy in target detection during both neutral and negative images presentation, whereas first-degree relatives performed similarly to normal comparisons. We found a reduced activation of Left precuneus during negative images condition in the patients only. By contrast, both patients and relatives hyperactivated the Left insula and hypoactivated the Right supramarginal gyrus with respect to controls. Moreover, relatives showed an increased activation of Right lingual gyrus and lower activation of pre-supplementary motor area and Right superior frontal gyrus. During a negative emotion task, euthymic BD-I patients and non-affected first-degree relatives shared an abnormal activation of a limbic area (Left insula) coupled with a reduced activation of a parietal region (Right supramarginal gyrus), thus suggesting a trait-like anomalous processing of affective contents. On the other hand, functional abnormalities found only in unaffected relatives and not in patients and controls may correspond to resilience factors.

Genetics of myocarditis in arrhythmogenic right ventricular dysplasia.

Myocarditis occasionally is related to arrhythmogenic right ventricular dysplasia (ARVD) and sometimes overlaps during the early stages, which may lead to misdiagnosis. Acute myocarditis may reflect an active phase of ARVD. The purpose of this study was to evaluate the genetic basis of myocarditis in ARVD and to investigate the association with a poorer prognosis and a higher risk of ventricular arrhythmias. Two groups were analyzed: group A, which consisted of 131 affected patients-84 with ARVD (62% male, age 45 years [range 33-55 years]) and 47 with left-sided forms (arrhythmogenic left ventricular dysplasia [ALVD]) (47% male, age 45 years [range 25-61 years]); and group B, which consisted of 64 nonaffected mutation-carrying relatives (36% male, age 42 years [range 22-56 years]; 23 from classic ARVD families and 41 from ALVD families). Seven patients (3.5%) presented with a clinical diagnosis of acute myocarditis over median follow-up of 34 months. Myocarditis was the first clinical presentation in 6 of 7 cases. In 2 patients, acute myocarditis preceded worsening of left ventricular systolic function. In 1 case, myocarditis was associated with an increased gadolinium pattern in cardiac magnetic resonance. Two patients presented with ECG changes weeks after myocarditis resolution. Myocarditis preceded the development of ventricular tachycardia in 2 other patients. Myocarditis clustered in families bearing DSP Q447* and LDB3 c.1051A>G. Acute myocarditis reflects an active phase of ARVD that leads to changes in phenotype and abrupt progression of the disease. An active phase should be suspected in a patient with myocarditis associated with a family history of ARVD. Certain mutations may increase the susceptibility to superimposed myocarditis in ARVD.

Facial Characteristics and Olfactory Dysfunction: Two Endophenotypes Related to Nonsyndromic Cleft Lip and/or Palate.

Evidence exists for the presence of a specific facial phenotype in nonaffected first-degree relatives of persons with CL/P. An increased risk for olfactory dysfunction has also been reported in CL/P-relatives. These phenotypic features can probably be explained via the presence of CL/P-related susceptibility genes. We aimed at confirming the occurrence of these endophenotypic traits in first-degree CL/P-relatives, and we investigated the link between the facial phenotype and the smell capacity in this group. We studied the facial morphology of 88 nonaffected first-degree relatives of patients with CL/P and 33 control subjects without family history of facial clefting by 3D surface imaging and a spatially dense analysis of the images. Smell testing was performed in 30 relatives and compared with 23 control subjects. Nonaffected relatives showed midface retrusion, hypertelorism, and olfactory dysfunction, compared to controls. In addition, we show for the first time that olfactory dysfunction in relatives is correlated to a smaller upper nasal region. This might be explained by a smaller central olfactory system. The different facial morphology in the relatives with olfactory impairment as compared to the total group may be an illustration of the contribution of different genetic backgrounds to the occurrence of CL/P via different biological pathways.

Carriers of Loss-of-Function Mutations in EXT Display Impaired Pancreatic Beta-Cell Reserve Due to Smaller Pancreas Volume

Exotosin (EXT) proteins are involved in the chain elongation step of heparan sulfate (HS) biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF) in EXT1 and EXT2 result in hereditary exostoses (HME). Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT) followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS) in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI). OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46–1.16] vs. controls 1.53 [0.69–3.36] nmol·l−1·min−1, p<0.05). Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22–10.5] vs. controls 10.2 [7.91–12.70] nmol·l−1·min−1 p<0.05), indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04). In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors.

Neural correlates of emotion regulation in patients with schizophrenia and non-affected siblings.

BackgroundPatients with schizophrenia often experience problems regulating their emotions. Non-affected relatives show similar difficulties, although to a lesser extent, and the neural basis of such difficulties remains to be elucidated. In the current paper we investigated whether schizophrenia patients, non-affected siblings and healthy controls (HC) exhibit differences in brain activation during emotion regulation.MethodsAll subjects (n = 20 per group) performed an emotion regulation task while they were in an fMRI scanner. The task contained two experimental conditions for the down-regulation of emotions (reappraise and suppress), in which IAPS pictures were used to generate a negative affect. We also assessed whether the groups differed in emotion regulation strategies used in daily life by means of the emotion regulation questionnaire (ERQ).ResultsThough the overall negative affect was higher for patients as well as for siblings compared to HC for all conditions, all groups reported decreased negative affect after both regulation conditions. Nonetheless, neuroimaging results showed hypoactivation relative to HC in VLPFC, insula, middle temporal gyrus, caudate and thalamus for patients when reappraising negative pictures. In siblings, the same pattern was evident as in patients, but only in cortical areas.ConclusionsGiven that all groups performed similarly on the emotion regulation task, but differed in overall negative affect ratings and brain activation, our findings suggest reduced levels of emotion regulation processing in neural circuits in patients with schizophrenia. Notably, this also holds for siblings, albeit to a lesser extent, indicating that it may be part and parcel of a vulnerability for psychosis.

Subjective cognitive complaints and functional disability in patients with borderline personality disorder and their nonaffected first-degree relatives.

To examine the contributions of subjective cognitive complaints to functional disability in patients with borderline personality disorder (BPD) and their nonaffected relatives. Patients with BPD (n = 26), their first-degree biological relatives (n = 17), and nonpsychiatric control subjects (n = 31) completed a self-report measure of cognitive difficulties and rated the severity of their functional disability on the World Health Organization Disability Assessment Schedule 2.0. After accounting for group differences in age and severity of depressive symptoms, patients and relatives endorsed more inattention and memory problems than control subjects. Whereas probands reported greater disability than relatives and control subjects across all functional domains, relatives described more difficulties than control subjects in managing multiple life activities, including domestic activities and occupational and academic functioning, and participating in society. For both probands and relatives, inattention and memory problems were linked primarily to difficulties with life activities, independent of depression and other comorbid psychiatric disorders. Problems with inattention and forgetfulness may lead to difficulties carrying out activities of daily living and occupational or academic problems in patients with BPD, as well as their nonaffected first-degree relatives.

Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives.

Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and (18)F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as µmol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P < 0.001), anterior vermis (40%, P < 0.001) and fusiform gyrus (20%, P < 0.001) compared with controls or siblings, and lower metabolism in hippocampus (12%, P = 0.05) compared with controls, and showed significant intersubject variability (decreases in vermis ranged from 18% to 60%). Participants with ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic rates including hyperactivity in globus pallidus indicative of basal ganglia involvement. Changes in basal ganglia metabolism offer potential insight into targeting strategies for therapeutic deep brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives suggests that heterozygocity influences the function of these brain regions.

Ocular and craniofacial phenotypes in a large Brazilian family with congenital aniridia

Congenital aniridia is a rare genetic disorder characterized by varying degrees of iris hypoplasia that are associated with additional ocular abnormalities. More than 90% of the causal mutations identified are found in the PAX6 gene, a transcription factor of critical importance in the process of neurogenesis and ocular development. Here, we investigate clinical, molecular, and craniofacial features of a large Brazilian family with congenital aniridia. Among the 56 eyes evaluated, phenotype variation encompassed bilateral total aniridia to mild iris defects with extensive variation between eyes of the same individual. PAX6 molecular screening indicated a heterozygous splice mutation (c.141 + 1G>A). Thus, we hypothesize that this splicing event may cause variation in the expression of the wild-type transcript, which may lead to the observed variation in phenotype. Affected individuals were more brachycephalic, even though their face height and cephalic circumference were not significantly different when compared to those of non-affected relatives. From this, we infer that the head shape of affected subjects may also be a result of the PAX6 splice-site mutation. Our data summarize the clinical variability associated with the ocular phenotype in a large family with aniridia, and help shed light on the role of PAX6 in neurocranial development.

Handedness in schizophrenia and schizoaffective disorder in an afrikaner founder population

Objective: An association between the Leucine-rich repeat trans membrane neuronal 1 gene (LRRTM1), schizophrenia/ schizoaffective disorder and handedness was recently claimed to be established. This study aimed to test the hypothesis that Afrikaner patients with schizophrenia/schizoaffective disorder are more non-right handed than their non-affected firstdegree relatives and that of two separate control groups. The association between handedness, gender and age at onset of illness in the patients group was also determined. Method: Two cross-sectional studies were carried out, which compared the handedness of a group of 100 (30 females and 70 males) Afrikaner patients with schizophrenia/schizoaffective disorder, their non-affected first-degree relatives, and two separate control groups. Handedness was determined by the Edinburg Handedness Inventory (EHI). Results: Patients were found to be more right-handed than expected with only 17 out of 100 being non-right-handed compared to 11 out of 100 non-affected relatives; 36 out of 100 students and 75 out of 500 nonaffected Afrikaner participants. The students were significantly more non-right handed than the patient and family groups but no difference in handedness was found when comparing the patients, family members and 500 participant control group. There was no significant difference between age at onset of illness and handedness. A significant association between female gender and non-right handedness in the patient group was found but no gender difference in the family and student groups. A highly significant association was found between the male gender of the patients and student control group regarding handedness. A significant difference was found between the median EHI raw scores of the patients and the family members. The median EHI raw scores of the patients were significantly lower than their paired family members. Conclusion: The study failed to prove a leftward shift of handedness in the patients with Schizophrenia and Schizoaffective disorder in the Afrikaner Founder population. Whether or not LRRTM1 is indeed the genetic basis of handedness, remains unclear.

Visual contrast sensitivity in adults with schizophrenia and relatives not affected

The aim of this study was to measure visual contrast sensitivity (CS) for vertical sine-wave gratings with spatial frequencies of 0,6; 5 and 10 in adults with medicated schizophrenic and no-affected relatives in the range of 20-30 years old. We measured the visual CS for ten volunteers without schizophrenia, nine schizophrenia patients and five no-affected relatives, all volunteers were free from identifiable ocular disease and had normal acuity, except the condition schizophrenia. We use a temporal two-alternative forced-choice psychophysical method with mean luminance of 40.1 cd/m². The results showed maximum contrast sensitivity occurred in the range of 5.0 cpd for both groups and that the visual CS for participants with schizophrenia was lower than those of adults without schizophrenia and the non-affected relatives. These results showed changes in the visual mechanisms that process vertical sine-wave gratings related the schizophrenia.

Schizophrénie et/ou trouble bipolaire : les endophénotypes neurocognitifs

Although Kraepelinian dichotomous conceptualization of psychosis was historically beneficial, modern studies do not support the existence of a sub-typing of psychotic illnesses into schizophrenic and affective psychoses. Years of intensive investigation on the genetic bases of schizophrenia and bipolar disorder suggest that these disorders, rather than being wholly distinct disorders, share common genetic risks. However, one of the most serious difficulties for genetic research in these illnesses is their enormous phenotypic heterogeneity. A response to this problem is the use of neurocognitive functions as endophenotypes or intermediate phenotypes. A review of the literature suggests that in both schizophrenia and bipolar disorder, neurocognitive functions are influenced by genetic factors and that there exists neuropsychological deficits in the nonaffected relatives of probands. However, it is unclear whether or not patterns of performance on neurocognitive tasks across probands as well as unaffected family members offer potential for identifying shared and illness-specific neurocognitive phenotypes for schizophrenia and bipolar disorder. Overlapping and unique neurocognitive endophenotypic signatures of the two psychoses are comprehensively described.

APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family

BackgroundSevere hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family.MethodsWe carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives.ResultsA large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls.ConclusionThe Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

Impaired sustained attention in euthymic bipolar disorder patients and non‐affected relatives: an fMRI study

Behavioral deficits in sustained attention have been reported during both acute and euthymic phases of type I bipolar disorder (BD-I) and also in non-affected relatives of bipolar disorder (BD) patients. In particular, selective failure in target recognition was proposed as a potential trait marker for BD, but there are few studies exploring the neural correlates. The aim of the present study was to analyze the behavioral and functional magnetic resonance imaging (fMRI) response of euthymic BD-I patients and non-affected relatives during a sustained attention task. Twenty-four euthymic BD-I patients, 22 non-affected first-degree relatives of BD-I subjects, and 24 matched controls underwent a continuous performance test (CPT) with two levels of difficulty during event-related fMRI scanning. Both patients and relatives showed a lower accuracy in target detection when compared to controls. The fMRI data analysis revealed between-group differences in several brain regions involved in sustained attention. During error in target recognition, both patients and relatives showed a larger activation in the bilateral insula and the posterior part of the middle cingulate cortex. By contrast, during correct target response, only patients failed to activate the right insula, whereas relatives showed an increased activation of the left insula and bilateral inferior parietal lobule - limited to the higher attention load - and an augmented deactivation of the posterior cingulate/retrosplenial cortex. A selective impairment in target recognition during a CPT was behaviorally and functionally detectable in both euthymic BD-I patients and non-affected first-degree relatives, suggesting that specific sustained attention deficits may be a potential trait marker for BD-I.

A NOVEL MUTATION IN YWTD DOMAIN OF LRP6 IMPAIRS ENDOTHELIAL CELL FUNCTION AND LEAD TO FAMILIAL CORONARY ARTERY DISEASE

ObjectivesPURPOSE: Our purpose is to identify the causal gene and it's mechanism for familial coronary artery disease in Chinese Han Population.MethodsWe recruited a large Chinese Han family with coronary artery...

Brain-Region Size May Be Long-Sought Biomarker

Brain-Region Size May Be Long-Sought Biomarker

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

BackgroundMaturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY-X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY-X family to identify a new susceptibility gene for MODY.MethodologyWES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out.Principal FindingsBy focusing on variants of interest (i.e. gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in KCNJ11) co-segregated with diabetes in the family (with a LOD-score of 3.68). No KCNJ11 mutation was found in 25 other MODY-X unrelated subjects.Conclusions/SignificanceBeyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene (‘MODY13’), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e. KCNJ11, ABCC8 and INS). Therefore, the molecular diagnosis of MODY should include KCNJ11 as affected carriers can be ideally treated with oral sulfonylureas.

Plasma Pro-B-Type Natriuretic Peptide Testing as a Screening Method for Hypertrophic Cardiomyopathy

BackgroundClinical multistage risk assessment associated with electrocardiogram (ECG) and NT-proBNP may be a feasible strategy to screen hypertrophic cardiomyopathy (HCM). We investigated the effectiveness of a screening based on ECG and NT-proBNP in first-degree relatives of patients with HCM. Methods and ResultsA total of 106 first-degree relatives were included. All individuals were evaluated by echocardiography, ECG, NT-proBNP, and molecular screening (available for 65 individuals). From the 106 individuals, 36 (34%) had diagnosis confirmed by echocardiography. Using echocardiography as the gold standard, ECG criteria had a sensitivity of 0.71, 0.42, and 0.52 for the Romhilt-Estes, Sokolow-Lyon, and Cornell criteria, respectively. Mean values of NT-ProBNP were higher in affected as compared with nonaffected relatives (26.1 vs. 1290.5, P < .001). The AUC of NT-proBNP was 0.98. Using a cutoff value of 70 pg/mL, we observed a sensitivity of 0.92 and specificity of 0.96. Using molecular genetics as the gold standard, ECG criteria had a sensitivity of 0.67, 0.37, and 0.42 for the Romhilt-Estes, Sokolow-Lyon, and Cornell criteria, respectively. Using a cutoff value of 70 pg/mL, we observed a sensitivity of 0.83 and specificity of 0.98. ConclusionValues of NT-proBNP above 70 pg/mL can be used to effectively select high-risk first-degree relatives for HCM screening.

Su1913 Anti-Glycan Antibodies in Relatives of Patients With Crohn's Disease

Background: Serum anti-glycan antibodies are a promising tool for differential diagnosis, disease stratification and prediction of Crohn's disease (CD). We assessed the presence of serum anti-glycan antibodies in affected and non-affected relatives of patients with CD and ulcerative colitis (UC). Methods: 393 non-inflammatory bowel disease (IBD)-affected relatives (330 CD and 63 UC relatives) of 169 IBD patients (140 CD and 29 UC patients) as well as 46 healthy controls were tested for the presence of anti-laminarin IgA (Anti-L), anti-chitin IgA (Anti-C), anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA) and anti-Saccaromyces cervisiae IgG (gASCA) carbohydrate antibodies by ELISA in a blinded fashion. Detailed clinical data of the IBD patients were available. Results:Non-affected relatives of CD patients had lower antibody levels for gASCA, ALCA, Anti-L and Anti-C and a lower quartile sum score (QSS), compared to the affected CD subjects (p<0.01). There was no difference in the levels of the antibodies when comparing first and second degree CD relatives. No similarity could be found for the pattern of positive markers in the affected CD patients compared to the non-affected relatives. In addition the ASCA status or a high versus low QSS of the affected CD patient did not influence the extent of the marker expression in the non-affected CD relative. While the QSS was similar, levels of and positivity for ACCA and AMCA were higher in the non-affected CD relatives compared to healthy controls (p<0.05). A higher proportion of healthy controls were negative for all anti-glycan antibodies compared to the non-affected IBD relatives (p<0.01). In the affected CD patients a positive family history for IBD was linked to higher levels of ACCA (p<0.03) and ALCA (p<0.04) with all other markers being unchanged. Non-affected UC relatives had lower levels of ALCA and Anti-L as well as a lower QSS compared to the affected UC patient. Conclusions: Non-affected relatives of CD patients may show a stronger immune response to glycan epitopes compared to healthy controls. The type of response appears to be distinct from the immune response of the affected CD patient. No difference between first compared to second degree relatives could be found. The presence of the antiglycan-antibodies in non-affected relatives of CD patients may represent the manifestation of a genetic susceptibility to CD. Therefore they might serve as an immunologic risk marker for CD and indicate a family member with an increased risk for developing CD in the future.