Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy.

BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function. METHODS: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities. RESULTS: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains. CONCLUSION: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature. TAKE- HOME MESSAGE: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome.

Bone mineral density in very low birthweight adults-A sibling study.

BACKGROUND: Children and adults born very low birthweight (VLBW, <1500 g) at preterm gestations have lower bone mineral density (BMD) and/or bone mineral content (BMC) than those born at term, but causality remains unknown. OBJECTIVES: Our aim was to assess BMD and BMC in adults born at VLBW in a sibling comparison setting to account for shared genetic and environmental confounders. METHODS: We conducted a cohort study of 77 adults born VLBW and 70 same-sex term-born siblings at mean age of 29 years. The primary outcome variables were BMD Z-scores, and BMC, of the femoral neck, lumbar spine, and whole body, measured using dual-energy X-ray absorptiometry. We analysed data by linear mixed models. RESULTS: The VLBW adults had a 0.25 (95% CI 0.02, 0.47) Z-score unit lower femoral neck BMD, and 0.35 (95% CI 0.16, 0.54) grams lower femoral neck BMC than their term-born siblings, after adjustment for sex, age, and maternal smoking. Additional adjustment for adult body size attenuated the results. Lumbar spine, and whole body BMC were also lower in the VLBW group. CONCLUSIONS: Individuals born at VLBW had lower BMC values at all three measurement sites, as well as lower femoral neck BMD Z-scores, compared to term-born siblings, partly explained by their smaller adult body size, but the differences were smaller than those reported previously with unrelated controls. This suggests that genetic or environmental confounders explain partly, but not exclusively, the association between preterm VLBW birth and adult bone mineralisation.

Selective mutism and the risk of mental and neurodevelopmental disorders among siblings.

The siblings of children with mental disorders are more likely to experience mental health issues themselves, but there has been a lack of sibling studies on selective mutism (SM). The aim of this population-based study was to use national registers to examine associations between children with SM and diagnoses of various mental disorder in their siblings. All singleton children born in Finland from 1987 to 2009, and diagnosed with SM from 1998 to 2012, were identified from national health registers and matched with four controls by age and sex. Their biological siblings and parents were identified using national registries and the diagnostic information on the siblings of the subjects and controls was obtained. The final analyses comprised 658 children with SM and their 1661 siblings and 2092 controls with 4120 siblings. The analyses were conducted using generalized estimating equations. Mental disorders were more common among the siblings of the children with SM than among the siblings of the controls. The strongest associations were observed for childhood emotional disorders and autism spectrum disorders after the data were adjusted for covariates and comorbid diagnoses among SM subjects. The final model showed associations between SM and a wide range of disorders in siblings, with strongest associations with disorders that usually have their onset during childhood. Our finding showed that SM clustered with other mental disorders in siblings and this requires further research, especially the association between SM and autism spectrum disorders. Strong associations with childhood onset disorders may indicate shared etiologies.

Maternal Anxiety and Infants Birthweight and Length of Gestation. A sibling design.

BACKGROUND: The overall aim of this study is to examine the effect of prenatal maternal anxiety on birthweight and gestational age, controlling for shared family confounding using a sibling comparison design. METHODS: The data on 77,970 mothers and their 91,165 children from the population-based Mother, Father and Child Cohort Study and data on 12,480 pairs of siblings were used in this study. The mothers filled out questionnaires for each unique pregnancy, at 17th and 30th week in pregnancy. Gestational age and birth weight was extracted from the Medical Birth Registry of Norway (MBRN). Associations between prenatal maternal anxiety (measured across the 17th and 30th weeks) and birth outcomes (birthweight and gestational age) were examined using linear regression with adjustment for shared-family confounding in a sibling comparison design. RESULTS: In the population level analysis the maternal anxiety score during pregnancy was inversely associated with new-born's birthweight (Beta = -63.8 95% CI: -92.6, -35.0) and gestational age (Beta = -1.52, 95% CI: -2.15, -0.89) after adjustment for several covariates. The association of the maternal anxiety score with birthweight was no longer significant, but remained for maternal anxiety at 30th week with gestational age (Beta = -1.11, 95% CI: -1.82, -0.4) after further adjusting for the shared-family confounding in the sibling comparison design. CONCLUSION: No association was found for maternal prenatal anxiety with birth weight after multiple covariates and family environment were controlled. However, there was an association between prenatal maternal anxiety at 30th week only with gestational age, suggesting a timing effect for maternal anxiety in third trimester.

College Expectations Promote College Attendance: Evidence From a Quasiexperimental Sibling Study.

When adolescents are asked how likely they think it is that they will go to college, does their answer influence what they will actually do? Typically, it is difficult to determine whether college expectations promote academic achievement or just reflect a reasonable forecast of what is likely to happen to them. We used a sample of siblings from the National Longitudinal Study of Adolescent to Adult Health (N = 1,766) to test whether associations between college expectations and educational attainment remained after accounting for unobserved family factors that may shape both educational expectations and attainment. Compared with their siblings, adolescents with higher college expectations were also 43% more likely to attend college, even when analyses controlled for grades and IQ. The effect of college expectations on college attendance was strongest among youths living in higher-socioeconomic-status families.

Genetics, the Rearing Environment, and the Intergenerational Transmission of Divorce: A Swedish National Adoption Study.

We used classical and extended adoption designs in Swedish registries to disentangle genetic and rearing-environment influences on the intergenerational transmission of divorce. In classical adoption analyses, adoptees ( n = 19,715) resembled their biological parents, rather than their adoptive parents, in their history of divorce. In extended adoption analyses, offspring ( n = 82,698) resembled their not-lived-with fathers and their lived-with mothers. There was stronger resemblance to lived-with mothers, providing indirect evidence of rearing-environment influences on the intergenerational transmission of divorce. The heritability of divorce assessed across generations was 0.13. We attempted to replicate our findings using within-generation data from adoptive and biological siblings ( ns = 8,523-53,097). Adoptees resembled their biological, not adoptive, siblings in their history of divorce. Thus, there was consistent evidence that genetic factors contributed to the intergenerational transmission of divorce but weaker evidence for a rearing-environment effect of divorce. Within-generation data from siblings supported these conclusions.

Antibiotic use during pregnancy and asthma in preschool children: the influence of confounding.

BACKGROUND: A recent study suggested that early-life intestinal microbiota may play an important role in the development of childhood asthma, indicating that antibiotics taken during early life or in late pregnancy may be associated with childhood asthma. OBJECTIVE: This study aims to assess the association between prenatal antibiotic use and asthma in preschool children using data from the prescription database IADB.nl. To assess the influence of potential confounding, we conducted both a case-sibling and a case-control study and compared the results. METHODS: We conducted a case-sibling study in which 1228 children with asthma were compared to 1228 siblings without asthma, using data from the prescription database IADB.nl. In addition, a case-control study was conducted. Asthma in preschool children was defined as ≥ 3 prescriptions for anti-asthma medication within a year before the fifth birthday. Conditional logistic regression was used to estimate crude and adjusted odds ratios (aORs). RESULTS: In both the case-sibling and case-control analysis, the use of antibiotics in the third trimester of pregnancy was associated with an increased risk of asthma in preschool children (aOR 1.37; 95% CI 1.02-1.83 and aOR 1.40; 95% CI 1.15-1.47). Time-trend analyses showed that results were not influenced by a time trend in antibiotic exposure. A significant association between exposure to antibiotics in any trimester of pregnancy and the development of asthma in preschool children was observed in the case-control analysis only (aOR 1.46; 95% CI 1.34-1.59). CONCLUSION: Antibiotic use in the third trimester of pregnancy was associated with a small increased risk of asthma in preschool children. This association was robust to time-invariant confounding or exposure time trends, further supporting the important role for early-life intestinal microbiota in the development of childhood asthma.

Neuroimaging of social motivation during winning and losing: Associations with social anhedonia across the psychosis spectrum.

BACKGROUND: Individuals with psychosis spectrum disorders (PSD) have difficulty developing social relationships. This difficulty may reflect reduced response to social feedback involving functional alterations in brain regions that support the social motivation system: ventral striatum, orbital frontal cortex, insula, dorsal anterior cingulate cortex, and amygdala. Whether these alterations span PSD is unknown. METHODS: 71 individuals with PSD, 27 unaffected siblings, and 37 control participants completed a team-based fMRI task. After each trial, participants received performance feedback paired with the expressive face of a teammate or opponent. A 2 × 2 (win versus loss outcome x teammate versus opponent) repeated measures ANOVA by group was performed on activation in the five key regions of interest during receipt of feedback. RESULTS: Across groups, three social motivation regions, ventral striatum, orbital frontal cortex, and amygdala, showed sensitivity to feedback (significant main effect of outcome), with greater activation during win versus loss trials, regardless of whether the feedback was from a teammate or opponent. In PSD, ventral striatum and orbital frontal cortex activation to win feedback was negatively correlated with social anhedonia scores. CONCLUSIONS: Patterns of neural activation during social feedback were similar in PSD, their unaffected siblings, and healthy controls. Across the psychosis spectrum, activity in key social motivation regions during social feedback was associated with individual differences in social anhedonia.

Indirect Genetic Effects of ADIPOQ Variants on Lipid Levels in a Sibling Study of a Rural Chinese Population.

Variations in lipid levels are the result of combinations of genetic and environmental factors. We aim to investigate the indirect effect between siblings of the three polymorphisms of ADIPOQ on serum lipid levels in rural Chinese populations. A total of 2571 sibling pairs were enrolled as study participants. A generalized estimating equation was used to accommodate a family-based design. We used stratified analysis to detect sex combination differences in the indirect genetic effect. We found a significant association between the number of altered risk alleles of rs182052 and ego lipid levels of TG (ß = 0.177, P = 0.003), TC (ß = 0.140, P = 0.004) and LDL-C (ß = 0.098, P = 0.014). Ego and altered genotypes of rs182052 demonstrated a joint effect on ego lipid levels of TC (ß = 0.212, P = 0.019), HDL-C (ß = 0.099, P = 0.002) and LDL-C (ß = 0.177, P = 0.013) in recessive inheritance mode. In opposite-sex siblings, the altered GG genotype of rs182052 increased the ego lipid levels. Thus, our findings demonstrate that ADIPOQ has an indirect genetic effect on lipid levels in sibling pairs, and there are sex-combination differences in the indirect genetic effect in siblings.

Infant Effortful Control Mediates Relations Between Nondirective Parenting and Internalising-Related Child Behaviours in an Autism-Enriched Infant Cohort.

Internalising problems are common within Autism Spectrum Disorder (ASD); early intervention to support those with emerging signs may be warranted. One promising signal lies in how individual differences in temperament are shaped by parenting. Our longitudinal study of infants with and without an older sibling with ASD investigated how parenting associates with infant behavioural inhibition (8-14 months) and later effortful control (24 months) in relation to 3-year internalising symptoms. Mediation analyses suggest nondirective parenting (8 months) was related to fewer internalising problems through an increase in effortful control. Parenting did not moderate the stable predictive relation of behavioural inhibition on later internalising. We discuss the potential for parenting to strengthen protective factors against internalising in infants from an ASD-enriched cohort.

Timing is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair.

Hunter syndrome, or mucopolysaccharidosis (MPS) II, is a rare lysosomal disorder characterized by progressive, multi-system disease. As most symptoms cannot be reversed once established, early detection and treatment prior to the onset of clinical symptoms are critical. However, it is difficult to identify affected individuals early in disease, and therefore the long-term outcomes of initiating treatment during this optimal time period are incompletely described. We report long-term clinical outcomes of treatment when initiated prior to obvious clinical signs by comparing the courses of two siblings with neuronopathic Hunter syndrome (c.1504 T > G[p.W502G]), one who was diagnosed due to clinical disease (Sibling-O, age 3.7 years) and the other who was diagnosed before disease was evident (Sibling-Y, age 12 months), due to his older sibling's findings. The brothers began enzyme replacement therapy within a month of diagnosis. Around the age of 5 years, Sibling-O had a cognitive measurement score in the impaired range of <55 (average range 85-115), whereas Sibling-Y at this age received a score of 91. Sibling-O has never achieved toilet training and needs direct assistance with toileting, dressing, and washing, while Sibling-Y is fully toilet-trained and requires less assistance with daily activities. Both siblings have demonstrated sensory-seeking behaviors, hyperactivity, impulsivity, and sleep difficulties; however, Sibling-O demonstrates physical behaviors that his brother does not, namely biting, pushing, and frequent elopement. Since the time of diagnosis, Sibling-O has had significant joint contractures and a steady deterioration in mobility leading to the need for an adaptive stroller at age 11, while Sibling-Y at age 10.5 could hike more than 6 miles without assistance. After nearly a decade of therapy, there were more severe and life-limiting disease manifestations for Sibling-O; data from caregiver interview indicated substantial differences in Quality of Life for the child and the family, dependent on timing of ERT. The findings from this sibling pair provide evidence of superior somatic and neurocognitive outcomes associated with presymptomatic treatment of Hunter syndrome, aligned with current considerations for newborn screening.

MicroRNA Expression Profiles in Autism Spectrum Disorder: Role for miR-181 in Immunomodulation.

BACKGROUND: MicroRNAs (miRNAs) are important regulators of molecular pathways in psychiatric disease. Here, we examine differential miRNAs expression in lymphoblastoid cell lines (LCLs) derived from 10 individuals with autism spectrum disorder (ASD) and compare them to seven typically developing unrelated age- and gender-matched controls and 10 typically developing siblings. Small RNAseq analysis identified miRNAs, and selected miRNAs were validated using quantitative real-time polymerase reaction (qRT-PCR). KEGG analysis identified target pathways, and selected predicted mRNAs were validated using qRT-PCR. RESULTS: Small RNAseq analysis identified that multiple miRNAs differentiated ASD from unrelated controls and ASD from typically developing siblings, with only one, hsa-miR-451a_R-1, being in common. Verification with qRT-PCR showed that miR-320a differentiated ASD from both sibling and unrelated controls and that several members of the miR-181 family differentiated ASD from unrelated controls. Differential expression of AKT2, AKT3, TNF α and CamKinase II predicted by KEGG analysis was verified by qRT-PCR. Expression of CamKinase II ßwas found to be correlated with the severity of stereotyped behavior of the ASD participants. CONCLUSIONS: This study provides insight into the mechanisms regulating molecular pathways in individuals with ASD and identifies differentiated regulated genes involved in both the central nervous system and the immune system.

Adolescent nonsuicidal self-injury and cortisol response to the retrieval of adversity: A sibling study.

BACKGROUND: There is evidence for alterations in hypothalamus-pituitary-adrenal (HPA) axis response to the retrieval of traumatic events among individuals with Posttraumatic Stress Disorder. However, no study has so far investigated HPA response to trauma retrieval among individuals engaging in non-suicidal self-injury (NSSI). In the present study, we compared reports of childhood adversity (CA) between adolescents engaging in NSSI and their siblings and tested for differences in the cortisol response to the retrieval of CA. METHODS: The sample consisted of 32 adolescents engaging in NSSI (Mage = 15.8 years) and their siblings (Mage = 15.6 years). Standardized interviews were used for the assessment of CA, NSSI, and axis I diagnoses. Salivary cortisol was measured before and after the trauma interview. Basal HPA axis activity was measured in hair. RESULTS: Reports of CA were moderately interrelated between siblings. Adolescents engaging in NSSI reported more severe CA. A significant decrease of salivary cortisol during the trauma interview was found only in the NSSI group. The NSSI group had significantly higher hair cortisol levels. CONCLUSIONS: Moderate relations in siblings' reports of CA point to non-shared experiences that may play a role in the development of NSSI. In the NSSI group, the decrease of salivary cortisol during the interview may be explained by a downregulation of the HPA axis subsequent to the retrieval of former experience of CA.

Nasal DNA methylation is associated with childhood asthma.

AIM: We aim to study DNA methylation (DNAm) variations associated with childhood asthma. METHODS: Nasal DNAm was compared between sibling pairs discordant for asthma, 29 sib pairs for genome-wide association studies and 54 sib pairs for verification by pyrosequencing. Associations of methylation with asthma symptoms, allergy and environmental exposures were evaluated. In vitro experiments and functional genomic analyses were performed to explore biologic relevance. RESULTS: Three CpGs were associated with asthma. cg14830002 was associated with allergies in nonasthmatics. cg23602092 was associated with asthma symptoms. cg14830002 and cg23602092 were associated with traffic-related air pollution exposure. Nearby genes were transcriptionally regulated by diesel exhaust, house dust mite and 5-aza-2'-deoxycytidine. Active chromatin marks and transcription factor binding were found around these sites. CONCLUSION: We identified novel DNAm variations associated with childhood asthma and suggested new disease-contributing epigenetic mechanisms.

Modifiable Arousal in Attention-Deficit/Hyperactivity Disorder and Its Etiological Association With Fluctuating Reaction Times.

BACKGROUND: Cognitive theories of attention-deficit/hyperactivity disorder (ADHD) propose that high within-subject fluctuations of cognitive performance in ADHD, particularly reaction time (RT) variability (RTV), may reflect arousal dysregulation. However, direct evidence of arousal dysregulation and how it may account for fluctuating RTs in ADHD is limited. We used skin conductance (SC) as a measure of peripheral arousal and aimed to investigate its phenotypic and familial association with RTV in a large sample of ADHD and control sibling pairs. METHODS: Adolescents and young adults (N = 292), consisting of 73 participants with ADHD and their 75 siblings, and 72 controls and their 72 siblings, completed the baseline (slow, unrewarded) and fast-incentive conditions of a RT task, while SC was simultaneously recorded. RESULTS: A significant group-by-condition interaction emerged for SC level (SCL). Participants with ADHD had decreased SCL, compared with controls, in the baseline condition but not the fast-incentive condition. Baseline SCL was negatively associated with RTV, and multivariate model fitting demonstrated that the covariance of SCL with RTV, and of SCL with ADHD, was mostly explained by shared familial effects. CONCLUSIONS: ADHD is associated with decreased, but modifiable, tonic peripheral arousal. A shared familial cause underlies the relationship between arousal and RTV and between arousal and ADHD. Given the malleability of SCL, if our findings are replicated, it warrants further exploration as a potential treatment target for ADHD.