Hindbrain malformation and myoclonic seizures associated with a deleterious mutation in the INPP4A gene.

Hindbrain malformations with predominant cerebellar involvement have many causes including chromosomal disorders, specific genetic syndromes, and prenatal disruptions. The combination of a hindbrain malformation and myoclonic epilepsy is rare. Using exome sequencing in a consanguineous family, we identified a homozygous genomic deletion of 1770 bp within the INPP4A gene in a patient with myoclonic epilepsy, microcephaly, and atrophy of the inferior vermis and cerebellum. INPP4A participates in the excitatory glutamate signaling pathway and is essential for the degradation of phosphatidylinositol (3,4)-bisphosphate. Glutamatergic signaling is important for hindbrain development and is implicated in the pathogenesis of epilepsy, as well as excitotoxic cell death. Indeed, excessive glutamatergic stimulation was previously reported in INPP4A knockout mice. Our data adds a new etiology to the spectrum of hindbrain malformations in human, and when presented with myoclonic epilepsy may lead to the clinical suspicion of INPP4A defect. The present report further underscores the importance of phosphoinositides for the development of the inferior cerebellum and vermis.

International trade and the neoliberal diet in Central America and the Dominican Republic: Bringing social inequality to the center of analysis.

Scholarship on international trade and health analyzes the effects of trade and investment policies on population exposure to non-nutritious foods. These policies are linked to the nutrition transition, or the dietary shift towards meat and processed foods associated with rising overweight and obesity rates in low- and middle-income countries. We argue for expanding the trade and health literature's focus on population exposure through the concept of the neoliberal diet, which centers subnational social inequality as both an outcome of neoliberal agri-food trade policies and a determinant of dietary change. We develop this perspective through a regional analysis of non-nutritious food availability following the implementation of the Dominican Republic-Central America Free Trade Agreement (CAFTA-DR), together with an extended case study, from the late 1990s to the present, of household expenditure and food price changes in the Dominican Republic, the region's largest food importer. Our analysis demonstrates that low-income consumers face increasing household food expenditures in a context of overall food price inflation, in addition to relatively higher price increases for healthy versus ultraprocessed foods. Neoliberal policies not only contribute to restructuring the availability and pricing of healthy food for low-income consumers, but they also exacerbate social inequality in the food system through corporate-controlled supply chains and farmer displacement. Our findings support policy proposals for socially distributive forms of healthy food production to stem the negative effects of the nutrition transition.

A human laterality disorder associated with a homozygous WDR16 deletion.

The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.

Cytokine secretion and NK cell activity in human ADAM17 deficiency.

Genetic deficiencies provide insights into gene function in humans. Here we describe a patient with a very rare genetic deficiency of ADAM17. We show that the patient's PBMCs had impaired cytokine secretion in response to LPS stimulation, correlating with the clinical picture of severe bacteremia from which the patient suffered. ADAM17 was shown to cleave CD16, a major NK killer receptor. Functional analysis of patient's NK cells demonstrated that his NK cells express normal levels of activating receptors and maintain high surface levels of CD16 following mAb stimulation. Activation of individual NK cell receptors showed that the patient's NK cells are more potent when activated directly by CD16, albeit no difference was observed in Antibody Depedent Cytotoxicity (ADCC) assays. Our data suggest that ADAM17 inhibitors currently considered for clinical use to boost CD16 activity should be cautiously applied, as they might have severe side effects resulting from impaired cytokine secretion.

The 8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome: report on two patients and review of the literature.

Nablus mask-like facial syndrome (NMFLS) is a rare microdeletion syndrome with a mask-like facial appearance as the most characteristic feature. In 2000, Teebi, was the first to report on a 4 years old boy affected with NMFLS. Since then two additional patients have been reported. Three years later, with the development of the array CGH technology, Shieh et al., elucidated the etiology of NMFLS by showing that the two patients studied share a approximately 4 Mb microdeletion in the long arm of chromosome 8 (q21.3-q22.1). Here we report on two NMFLS patients among which the first patient described by Teebi in 2000, and present newly described clinical findings including the common happy behaviour of the children. Array CGH analysis of these two patients permitted to reveal a deletion in the same region, 8q21.3-q22.1. Combining the available literature and our data, we were able to narrow the common deleted region to 2.78 Mb (93.56-96.34 Mb) in 8q22.1. Direct relations between the clinical findings with (one of) the genes in the critical region have to await further studies on NFMLS patients with overlapping or smaller deletions.

Monozygotic multiple gestation after intracytoplasmic sperm injection and preimplantation genetic diagnosis.

OBJECTIVE: To report a possible association between intracytoplasmic sperm injection (ICSI)-preimplantation genetic diagnosis (PGD) and monozygotic multiple gestation. DESIGN: Small case series. SETTING: In vitro fertilization unit in an academic medical center. PATIENT(S): Three patients were treated with ICSI-PGD for sexing as well as selection against a known translocation. INTERVENTION(S): Transfer of day 4 embryos to the uterus. MAIN OUTCOME MEASURE(S): Clinical pregnancy. RESULT(S): Two pairs of monozygotic twins and a triplet pregnancy. CONCLUSION(S): Repeated manipulation of the zona pellucida as well as extended embryo culture during ICSI-PGD treatments may result in monozygotic twin and triplet pregnancies.

A patient with Prader-Willi syndrome and a supernumerary marker chromosome r(15)(q11.1-13p11.1)pat and maternal heterodisomy.

We report on a Prader-Willi patient with a de novo supernumerary marker chromosome (SMC) in 16% of the cells. The SMC was a ring chromosome and it included the PWS/AS critical region as was demonstrated by FISH. Segregation analysis indicated that the SMC originated from a paternal chromosome 15 and the two normal chromosomes 15 of the patients were of the maternal homologues. Namely, the patient had maternal heterodisomy in 85% of the cells and triplication of the PWS/AS region in 15% of the cells. The Prader-Willi features were the result of the low mosaicism of the SMC. The evolution of the maternal heterodisomy and the SMC were two unrelated events, the occurrence of both events in the same embryo rescued it from lethality.