Search Results (6)

Microvillus inclusion disease (MVID) is a rare, inherited, congenital, diarrheal disorder that is invariably fatal if left untreated. Within days after birth, MVID presents as a life-threatening emergency characterized by severe dehydration, metabolic acidosis, and weight loss. Diagnosis is cumbersome and can take a long time. Whether MVID could be diagnosed before birth is not known. Anecdotal reports of MVID-associated fetal bowel abnormalities suspected by ultrasonography (that is, dilated bowel loops and polyhydramnios) have been published. These are believed to be rare, but their prevalence in MVID has not been investigated. Here, we have performed a comprehensive retrospective study of 117 published MVID cases spanning three decades. We find that fetal bowel abnormalities in MVID occurred in up to 60% of cases of MVID for which prenatal ultrasonography or pregnancy details were reported. Suspected fetal bowel abnormalities appeared in the third trimester of pregnancy and correlated with postnatal, early-onset diarrhea and case-fatality risk during infancy. Fetal bowel dilation correlated with MYO5B loss-of-function variants. In conclusion, MVID has already started during fetal life in a significant number of cases. Genetic testing for MVID-causing gene variants in cases where fetal bowel abnormalities are suspected by ultrasonography may allow for the prenatal diagnosis of MVID in a significant percentage of cases, enabling optimal preparation for neonatal intensive care. Full article

Border Disease (BD) is a major sheep disease characterized by immunosuppression, congenital disorders, abortion, and birth of lambs persistently infected (PI) by Border Disease Virus (BDV). Control measures are based on the elimination of PI lambs, biosecurity, and frequent vaccination which aims to prevent fetal infection and birth of PI. As there are no vaccines against BDV, farmers use vaccines directed against the related Bovine Viral Diarrhea Virus (BVDV). To date, there is no published evidence of cross-effectiveness of BVDV vaccination against BDV infection in sheep. We tested three commonly used BVDV vaccines, at half the dose used in cattle, for their efficacy of protection against a BDV challenge of ewes at 52 days of gestation. Vaccination limits the duration of virus-induced leukopenia after challenge, suggesting partial protection in transient infection. Despite the presence of BDV neutralizing antibodies in vaccinated ewes on the day of the challenge, fetuses of vaccinated and unvaccinated sheep were, two months after, highly positive for BDV RNA loads and seronegative for antibodies. Therefore, BVDV vaccination at half dose was not sufficient to prevent ovine fetal infection by BDV in a severe challenge model and can only be reconsidered as a complementary mean in BD control. Full article

Congenital diarrheal disorders (CDDs) are early-onset enteropathies generally inherited as autosomal recessive traits. Most patients with CDDs require rapid diagnosis as they need immediate and specific therapy to avoid a poor prognosis, but their clinical picture is often overlapping with a myriad of nongenetic diarrheal diseases. We developed a next-generation sequencing (NGS) panel for the analysis of 92 CDD-related genes, by which we analyzed patients suspect for CDD, among which were (i) three patients with sucrose-isomaltase deficiency; (ii) four patients with microvillous inclusion disease; (iii) five patients with congenital tufting enteropathy; (iv) eight patients with glucose-galactose malabsorption; (v) five patients with congenital chloride diarrhea. In all cases, we identified the mutations in the disease-gene, among which were several novel mutations for which we defined pathogenicity using a combination of bioinformatic tools. Although CDDs are rare, all together, they have an incidence of about 1%. Considering that the clinical picture of these disorders is often confusing, a CDD-related multigene NGS panel contributes to unequivocal and rapid diagnosis, which also reduces the need for invasive procedures. Full article

Zn²⁺ deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn²⁺-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn²⁺ deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn²⁺ status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn²⁺ uptake in the gut using different nutritional supplementation of Zn²⁺ could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn²⁺ diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn²⁺ in hemostasis. Storage protein metallothionein maintains or releases Zn²⁺ in the cytoplasm, and the dynamic change of this cytoplasmic Zn²⁺ pool is regulated by the redox status of the cell. An increase of labile Zn²⁺ pool can be toxic for the cells, and therefore cytoplasmic Zn²⁺ levels are tightly regulated by several Zn²⁺ transporters located on the cell surface and also on the intracellular membrane of Zn²⁺ storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn²⁺ is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn²⁺ transport and the physiological role of Zn²⁺ store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn²⁺ to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn²⁺ homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases. Full article

Congenital lactase deficiency (CLD) is a severe autosomal recessive genetic disorder that affects the functional capacity of the intestinal protein lactase-phlorizin hydrolase (LPH). This disorder is diagnosed already during the first few days of the newborn’s life due to the inability to digest lactose, the main carbohydrate in mammalian milk. The symptoms are similar to those in other carbohydrate malabsorption disorders, such as congenital sucrase-isomaltase deficiency, and include severe osmotic watery diarrhea. CLD is associated with mutations in the translated region of the LPH gene that elicit loss-of-function of LPH. The mutations occur in a homozygote or compound heterozygote pattern of inheritance and comprise missense mutations as well as mutations that lead to complete or partial truncations of crucial domains in LPH, such as those linked to the folding and transport-competence of LPH and to the catalytic domains. Nevertheless, the identification of the mutations in CLD is not paralleled by detailed genotype/protein phenotype analyses that would help unravel potential pathomechanisms underlying this severe disease. Here, we review the current knowledge of CLD mutations and discuss their potential impact on the structural and biosynthetic features of LPH. We also address the question of whether heterozygote carriers can be symptomatic for CLD and whether genetic testing is needed in view of the severity of the disease. Full article

Congenital diarrheal disorders (CDDs) are a group of inherited enteropathies with a typical onset early in the life. Infants with these disorders have frequently chronic diarrhea of sufficient severity to require parenteral nutrition. For most CDDs the disease-gene is known and molecular analysis may contribute to an unequivocal diagnosis. We review CDDs on the basis of the genetic defect, focusing on the significant contribution of molecular analysis in the complex, multistep diagnostic work-up. Full article