Developmental disorders in children born to women with sickle cell disease: A report from the Boston Birth Cohort.

Children exposed to maternal sickle cell disease (SCD) have many theoretical risks for developmental disorders, but little is known about long-term outcomes for these children. We used the Boston Birth Cohort to compare developmental outcomes between children exposed to maternal SCD and matched, unexposed controls. Children with exposure to maternal SCD had increased risk of attention deficit hyperactivity disorder (OR 5.12, 95% CI 1.36-19.19, p = 0.02) and obesity (OR 2.74, 95% CI 1.10-6.87, p = 0.03). In utero and/or environmental exposures may help explain these findings. Further studies of outcomes of children born to women with SCD are needed.

The association between maternal lipid profile after birth and offspring risk of autism spectrum disorder.

PURPOSE: Maternal obesity has been consistently associated with offspring risk for ASD, as well as lipid metabolism derangements. However, few ASD studies have examined maternal lipids in conjunction with maternal prepregnancy body mass index (BMI). METHODS: This nested case-control study was based on the Boston Birth Cohort, a prospective cohort study of mother-child dyads recruited at the Boston Medical Center. Maternal blood samples were collected shortly after delivery and analyzed for total plasma cholesterol, HDL, and triglyceride (TG) concentrations. Low-density lipoprotein (LDL) was subsequently calculated by the Friedewald equation. Cases were identified using ASD diagnoses in children's medical records. The odds of ASD were estimated with continuous lipid levels for a linear relationship, and we further explored the nonlinear relationship using the tertile of each lipid analyte with the highest tertile as the reference group. Logistic regression was used to estimate the risk of ASD adjusting for potential confounders. The analyses were performed separately for mothers with normal weight and overweight/obese based on maternal prepregnancy BMI. RESULTS: One standard deviation decrease in postpartum maternal LDL was associated with increased odds of ASD aOR 1.35 [1.04-1.75]. There was no association between postpartum maternal HDL and TG levels and ASD risk. Decreasing levels of LDL were not associated with ASD risk in normal-weight mothers (aOR 1.2 [0.83-1.75]), but the ASD risk was more pronounced in overweight and obese mothers (aOR 1.54 [1.03-2.27]). Follow-up analysis of nonlinear association models showed that, when compared to the highest tertile, lower maternal LDL concentrations were associated with approximately two times increased risk of ASD (first tertile: aOR 2.49 [1.27-4.87] and second tertile: aOR 2.79 [1.42-5.48]). A similar pattern was observed with overweight/obese mothers but not in normal-weight mothers. CONCLUSIONS: Lower maternal postpartum plasma LDL concentration was associated with increased odds of ASD in offspring among children born to overweight and obese mothers. Our findings suggest that both maternal BMI and lipids should be considered in assessing their role in offspring ASD risk, and additional longitudinal studies are needed to better understand maternal lipid dynamics during pregnancy among normal-weight and overweight/obese mothers.

Interaction between Maternal Immune Activation and Antibiotic Use during Pregnancy and Child Risk of Autism Spectrum Disorder.

Prenatal exposure to maternal immune activation (MIA) has been implicated as a risk factor for the development of autism spectrum disorder (ASD), though the conditions under which this elevated risk occurs are unclear. Animal literature demonstrates that antibiotic use, which affects the composition of the maternal gut microbiota, modifies the effect of MIA on neurodevelopmental outcomes in the offspring. The aim of this study was to assess whether antibiotic use during pregnancy modifies the association between MIA and subsequent risk of ASD, in a prospective birth cohort with 116 ASD cases and 860 typically developing (TD) child controls. There was no evidence of interaction between fever or genitourinary infection and antibiotic use on the odds of ASD in unadjusted or adjusted analyzes. However, we found evidence of an interaction between flu, specifically in second trimester, and antibiotic use at any point during pregnancy on the odds of ASD in the child. Among women who received an antibiotic during pregnancy, flu in trimester two was not associated with ASD (adjusted odds ratio [aOR] = 0.99 [0.43-2.28]). Among women who were not exposed to an antibiotic at any point during pregnancy, flu in second trimester was significantly associated with increased odds of ASD (aOR = 4.05 [1.14-14.38], P = .03), after adjustment for child sex, child birth year, maternal age, gestational age, C-section delivery, and low birthweight. These findings should be treated as hypothesis-generating and suggest that antibiotic use may modify the influence that MIA has on autism risk in the child. LAY SUMMARY: We looked at whether the association between activation of the immune system during pregnancy and risk of the child developing autism spectrum disorder (ASD) differed among women who did or did not take an antibiotic at any point during pregnancy. We examined 116 children with ASD and 860 without ASD and found that flu in second trimester was associated with increased ASD, but only among women who did not take an antibiotic during pregnancy. No other immune activation exposures seemed to interact with antibiotic use.

Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring.

BACKGROUND: To examine the prospective association between multivitamin supplementation during pregnancy and biomarker measures of maternal plasma folate and vitamin B12 levels at birth and child's Autism Spectrum Disorder (ASD) risk. METHODS: This report included 1257 mother-child pairs, who were recruited at birth and prospectively followed through childhood at the Boston Medical Center. ASD was defined from diagnostic codes in electronic medical records. Maternal multivitamin supplementation was assessed via questionnaire interview; maternal plasma folate and B12 were measured from samples taken 2-3 days after birth. RESULTS: Moderate (3-5 times/week) self-reported supplementation during pregnancy was associated with decreased risk of ASD, consistent with previous findings. Using this as the reference group, low (≤2 times/week) and high (>5 times/week) supplementation was associated with increased risk of ASD. Very high levels of maternal plasma folate at birth (≥60.3 nmol/L) had 2.5 times increased risk of ASD [95% confidence interval (CI) 1.3, 4.6] compared to folate levels in the middle 80th percentile, after adjusting for covariates including MTHFR genotype. Similarly, very high B12 (≥536.8 pmol/L) showed 2.5 times increased risk (95% CI 1.4, 4.5). CONCLUSION: There was a 'U shaped' relationship between maternal multivitamin supplementation frequency and ASD risk. Extremely high maternal plasma folate and B12 levels at birth were associated with ASD risk. This hypothesis-generating study does not question the importance of consuming adequate folic acid and vitamin B12 during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B12 exposure in-utero on early brain development.

Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.

Prenatal exposure to fever is associated with autism spectrum disorder in the boston birth cohort.

Autism spectrum disorder (ASD) is phenotypically and etiologically heterogeneous, with evidence for genetic and environmental contributions to disease risk. Research has focused on the prenatal period as a time where environmental exposures are likely to influence risk for ASD. Epidemiological studies have shown significant associations between prenatal exposure to maternal immune activation (MIA), caused by infections and fever, and ASD. However, due to differences in study design and exposure measurements no consistent patterns have emerged revealing specific times or type of MIA exposure that are most important to ASD risk. No prior studies have examined prenatal MIA exposure and ASD risk in an under-represented minority population of African ancestry. To overcome these limitations, we estimated the association between prenatal exposure to fever and maternal infections and ASD in a prospective birth cohort of an understudied minority population in a city in the United States. No association was found between prenatal exposure to genitourinary infections or flu and the risk of ASD in a nested sample of 116 ASD cases and 988 typically developing controls in crude or adjusted analyses. Prenatal exposure to fever was associated with increased ASD risk (aOR 2.02 [1.04-3.92]) after adjustment for educational attainment, marital status, race, child sex, maternal age, birth year, gestational age, and maternal smoking. This effect may be specific to fever during the third trimester (aOR 2.70 [1.00-7.29]). Our findings provide a focus for future research efforts and ASD prevention strategies across diverse populations. Autism Res 2017, 10: 1878-1890. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We looked at whether activation of the immune system during pregnancy increases the chance a child will develop ASD. We examined 116 children with ASD and 988 children without ASD that came from a predominantly low income, urban, minority population. We found that having the flu or genitourinary tract infections during pregnancy is not related to the child being diagnosed with ASD. However, we did find children were at increased risk for ASD when their mothers had a fever during pregnancy.

A regulatory loop involving PAX6, MITF, and WNT signaling controls retinal pigment epithelium development.

The separation of the optic neuroepithelium into future retina and retinal pigment epithelium (RPE) is a critical event in early eye development in vertebrates. Here we show in mice that the transcription factor PAX6, well-known for its retina-promoting activity, also plays a crucial role in early pigment epithelium development. This role is seen, however, only in a background genetically sensitized by mutations in the pigment cell transcription factor MITF. In fact, a reduction in Pax6 gene dose exacerbates the RPE-to-retina transdifferentiation seen in embryos homozygous for an Mitf null allele, and it induces such a transdifferentiation in embryos that are either heterozygous for the Mitf null allele or homozygous for an RPE-specific hypomorphic Mitf allele generated by targeted mutation. Conversely, an increase in Pax6 gene dose interferes with transdifferentiation even in homozygous Mitf null embryos. Gene expression analyses show that, together with MITF or its paralog TFEC, PAX6 suppresses the expression of Fgf15 and Dkk3. Explant culture experiments indicate that a combination of FGF and DKK3 promote retina formation by inhibiting canonical WNT signaling and stimulating the expression of retinogenic genes, including Six6 and Vsx2. Our results demonstrate that in conjunction with Mitf/Tfec Pax6 acts as an anti-retinogenic factor, whereas in conjunction with retinogenic genes it acts as a pro-retinogenic factor. The results suggest that careful manipulation of the Pax6 regulatory circuit may facilitate the generation of retinal and pigment epithelium cells from embryonic or induced pluripotent stem cells.

Membrane attachment is key to protecting transducin GTPase-activating complex from intracellular proteolysis in photoreceptors.

The members of the R7 regulator of G-protein signaling (RGS) protein subfamily are versatile regulators of G-protein signaling throughout the nervous system. Recent studies indicate that they are often found in complexes with membrane anchor proteins that serve as versatile modulators of their activity, intracellular targeting, and stability. One striking example is the interplay between the membrane anchor R9AP and the RGS9-1 · Gß5 GTPase-activating complex responsible for the rapid inactivation of the G-protein transducin in vertebrate photoreceptor cells during their recovery from light excitation. The amount of this complex in photoreceptors sets their temporal resolution and is precisely regulated by the expression level of R9AP, which serves to protect the RGS9-1 and Gß5 subunits from intracellular proteolysis. In this study, we investigated the mechanism by which R9AP performs its protective function in mouse rods and found that it is entirely confined to recruiting RGS9-1 · Gß5 to cellular membranes. Furthermore, membrane attachment of RGS9-1 · Gß5 is sufficient for its stable expression in rods even in the absence of R9AP. Our second finding is that RGS9-1 · Gß5 possesses targeting information that specifies its exclusion from the outer segment and that this information is neutralized by association with R9AP to allow outer segment targeting. Finally, we demonstrate that the ability of R9AP · RGS9-1 · Gß5 to accelerate GTP hydrolysis on transducin is independent of its means of membrane attachment, since replacing the transmembrane domain of R9AP with a site for lipid modification did not impair the catalytic activity of this complex.