👤 Matthew A Deardorff

Dichlorodiphenyltrichloroethane (DDT), a persistent organochlorine pesticide, continues to be used for malaria control under the Stockholm Convention. We investigated associations between exposure to DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) and midlife cognitive function and brain structure among primarily Mexican-born Latina women in an agricultural community in California, USA. In the CHAMACOS Maternal Cognition Study, a prospective cohort study, we assessed global and domain-specific cognitive performance in 472 women. A subset of 95 women underwent T1-weighted brain MRI to measure cortical thickness. We evaluated associations between serum p,p'-DDT and p,p'-DDE concentrations-measured 12 years earlier-and cognitive Z scores and cortical thickness using linear regression. Bayesian hierarchical models accounted for co-exposure to other organochlorine pesticides. Apolipoprotein E (APOE) genotype was assessed as a potential modifier. Higher p,p'-DDT and p,p'-DDE concentrations were significantly associated with lower executive function scores (p,p'-DDT β=-0·10 [95% CI -0·18 to -0·02]; p,p'-DDE β=-0·09 [-0·19 to 0·00]; SDs per ten-fold increase in serum concentration). No associations were observed with other cognitive domains. Results were robust to adjustment for APOE genotype and organochlorine co-exposures. No effect modification by APOE ε4 status was found. Both exposures were associated with greater frontal lobe cortical thickness, particularly in the medial orbitofrontal and pars orbitalis regions. p,p'-DDT and p,p'-DDE exposure was associated with reduced executive function more than a decade later, and with altered frontal brain structure. These findings suggest potential long-term neurodevelopmental effects of legacy organochlorine exposure and warrant further investigation. US National Institutes of Health and US Environmental Protection Agency. Show less

Congenital disorders of Glycosylation (CDG) are increasingly emerging as a major underlying etiology for patients with complex neurogenetic malformations and dysmorphic features. We describe a newborn female with arthrogryposis multiplex due to fetal akinesia secondary to CDG-DPAGT1. Pregnancy was complicated by reduced fetal movements. At birth, the patient was evaluated for intrauterine growth restriction, bilateral cataracts, and multiple joint contractures. She had markedly reduced spontaneous movements, hypotonia, weak cry, and poor suck. She had ventilator-dependent central respiratory depression. Brain MRI showed delayed myelination and an incomplete cerebellar vermis. Transferrin isoelectric focusing was suggestive of a type I congenital disorder of glycosylation. Sequencing revealed a homozygous missense mutation in dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1), exon 3, p.Leu118Val, consistent with DPAGT1-CDG. There have been seventeen previously reported cases of DPAGT1-CDG, including two similar cases with multiple contractures. This case highlights the importance of considering congenital disorders of glycosylation in the differential diagnosis for arthrogryposis. Show less

The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified. We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported. The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations. In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour. Show less

Axin is a recently identified protein encoded by the fused locus in mice that is required for normal vertebrate axis formation. We have defined a 25-amino-acid sequence in axin that comprises the glycogen synthase kinase 3beta (GSK-3beta) interaction domain (GID). In contrast to full-length axin, which has been shown to antagonize Wnt signaling, the GID inhibits GSK-3beta in vivo and activates Wnt signaling. Similarly, mutants of axin lacking key regulatory domains such as the RGS domain, which is required for interaction with the adenomatous polyposis coli protein, bind and inhibit GSK-3beta in vivo, suggesting that these domains are critical for proper regulation of GSK-3beta activity. We have identified a novel self-interaction domain in axin and have shown that formation of an axin regulatory complex in vivo is critical for axis formation and GSK-3beta activity. Based on these data, we propose that the axin complex may directly regulate GSK-3beta enzymatic activity in vivo. These observations also demonstrate that alternative inhibitors of GSK-3beta can mimic the effect of lithium in developing Xenopus embryos. Show less

Axin is encoded by the fused locus in mice and is required for normal vertebrate axis formation. It has recently been shown that axin associates with APC, beta-catenin and glycogen synthase kinase-3 (GSK-3) in a complex that appears to regulate the level of cytoplasmic beta-catenin. We have identified the Xenopus homologue of axin through its interaction with GSK-3b. Xenopus axin (Xaxin) is expressed maternally and throughout early development with a low level of ubiquitous expression. Xaxin also shows remarkably high expression in the anterior mesencephalon adjacent to the forebrain-midbrain boundary. Show less