Novel solute carrier family 26, member 3 mutation in a prenatal recurrent case with congenital chloride diarrhea.

Congenital chloride diarrhea (CCD) is an autosomal recessive hereditary disease manifested by persistent, watery, profuse diarrhea with high chloride concentration (>90 mmol/L). Postnatally, neonates suffer from hypochloremia, hyponatremia, hypokalemia, metabolic alkalosis, dehydration, developmental retardation, or even death. Prenatal diagnosis is of great importance for the prognosis of CCD. We report a prenatal recurrent case of CCD. Prenatal ultrasound revealed fetal diffuse intestinal dilation with the typical honeycomb sign and polyhydramnios with high amniotic fluid index. The whole exome capture and massively-parallel DNA sequencing showed an abnormal mutation of Solute Carrier Family 26, Member 3 (SLC26A3), c.1039G>A (p.Ala347Thr), and the mutation sites were verified by sanger sequencing. When prenatal ultrasound shows polyhydramnios and diffuse intestinal dilation, CCD should be suspected. Molecular genetic testing can be helpful for the diagnosis.

Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis.

Mitochondrial disorders are among the most common inborn errors of metabolism; at least 15% are caused by mitochondrial DNA (mtDNA) mutations, which occur de novo or are maternally inherited. For familial heteroplasmic mtDNA mutations, the mitochondrial bottleneck defines the mtDNA mutation load in offspring, with an often high or unpredictable recurrence risk. Oocyte donation is a safe option to prevent the transmission of mtDNA disease, but the offspring resulting from oocyte donation are genetically related only to the father. Prenatal diagnosis (PND) is technically possible but usually not applicable because of limitations in predicting the phenotype. For de novo mtDNA point mutations, recurrence risks are low and PND can be offered to provide reassurance regarding fetal health. PND is also the best option for female carriers with low-level mutations demonstrating skewing to 0% or 100%. A fairly new option for preventing the transmission of mtDNA diseases is preimplantation genetic diagnosis (PGD), in which embryos with a mutant load below a mutation-specific or general expression threshold of 18% can be transferred. PGD is currently the best reproductive option for familial heteroplasmic mtDNA point mutations. Nuclear genome transfer and genome editing techniques are currently being investigated and might offer additional reproductive options for specific mtDNA disease cases.

Antenatal differential diagnosis of congenital chloride diarrhea: a case report.

Congenital chloride diarrhea (CCD) is a rare disease characterized by profound, watery diarrhea. It is inherited as an autosomal recessive trait and is caused by a dysfunction of electrolyte transport in the brush border of the ileum. CCD is a medically treatable condition but is frequently misdiagnosed as a surgically treatable condition, such as bowel obstruction, because of similar antenatal ultrasonographic findings. Therefore, a correct diagnosis is of upmost importance before treatment initiation. Although some methods for antenatal differential diagnosis were reported, antenatal diagnosis of CCD remains difficult. Here, we report the case of a patient with CCD, which was presumed antenatally and confirmed postnatally. We also discuss the results of antenatal ultrasonography and amniocentesis and provide some tips regarding ultrasonographic findings for the antenatal differential diagnosis of CCD. Further, we present a brief literature review.

Magnetic resonance spectroscopy of the fetal brain.

Fetal magnetic resonance spectroscopy (MRS) is technically feasible in utero and demonstrates similar findings to those observed in neonatal populations. MRS can provide additional information to conventional T1- and T2-weighted imaging of the fetal brain. It is of particular use when subtle changes are present on conventional fetal MRI sequences, and when imaging fetuses at risk of brain injury and metabolic abnormalities.

[Urea cycle disorders in adult patients]. / Les déficits du cycle de l'urée chez les patients adultes.

INTRODUCTION: Urea cycle disorders (UCD) usually present after 24 h to 48 h of life with failure to thrive, lethargy and coma leading to death, but milder forms may occur from infancy to adulthood. STATE OF THE ART: Survival of children with UCD has significantly improved and the need for transitional care to adulthood has emerged. Adult onset UCD present with chronic or acute neurological, psychiatric and digestive symptoms associated with protein avoidance. Ornithine transcarbamylase (OTC) deficiency, which is inherited as an X-linked disorder, is the most well-described UCD in adults. Acute decompensations associate the triad of encephalopathy, respiratory alkalosis and hyperammonemia. Acute encephalopathy is characterized by brain edema, which is life-threatening without treatment. Specific urea cycle enzyme deficiency can be suspected in the presence of abnormal plasma amino acids concentrations and urinary excretion of orotic acid. A measurement enzyme activity in appropriate tissue, or DNA analysis if available, is required for diagnosis. Treatment requires restriction of dietary protein intake and the use of alternative pathways of waste nitrogen excretion with sodium benzoate and sodium phenylbutyrate. Patients with acute forms may need hemodialysis or hemodiafiltration. Therapeutic goals for OTC deficiency are to maintain plasma ammonia<80 micromol/L, plasma glutamine<1,000 micromol/L, argininemia 80-150 micromol/L and branched chain amino acids within the normal range, in order to prevent episodes of potentially lethal acute hyperammonemia. CONCLUSION: Potentially fatal acute hyperammonemia may occur in male or female patients at any age. Ammonia should be measured promptly in case of acute neurological and psychiatric symptoms or coma.

Celocentesis for in utero stem cell therapy: where we now stand and future directions.

As the number of inborn errors of metabolism that can be diagnosed prenatally by direct DNA analysis increases, so will the number of patients interested in having prenatal diagnosis for these conditions. The phenotypic expression of these inherited inborn errors of metabolism in theory could be prevented by the in utero transplantation of donor stem cells. It is the authors' opinion that ultrasound-guided celocentesis performed in the timed-pregnant baboon animal model could have an important role for determining if stem cell transplantation in the nonfunctional immunocompetent embryo has any clinical potential.

First-trimester fetal nuchal translucency and inherited metabolic disorders.

OBJECTIVES: To assess the association between inherited metabolic disorders and nuchal translucency (NT) measurements. METHODS: The NT measurements obtained from 66 fetuses at high risk for metabolic diseases prior to chorionic villus sampling (CVS) were retrospectively analysed. RESULTS: NT was found to be within the normal range in all of the 13 affected fetuses, which included three with Gaucher disease, two with glycogenosis type II, two with mucopolysaccharidosis type I and six others with Krabbe disease, metachromatic leukodystrophy, mucopolysaccharidosis type II, Niemann-Pick A disease, Pelizaeus-Merzbacher disease and sialidosis, respectively. An increased nuchal thickness was found only in one fetus affected with trisomy 21 but not affected with mucopolysaccharidosis type II. CONCLUSION: NT appears to have a limited role in identifying affected fetuses in pregnancies at high risk for inherited metabolic disorders. NT may be normal in early pregnancy even for fetuses affected with conditions known to be associated with non-immune hydrops fetalis.

Whatever happened to "neonatal hepatitis"?

'Idiopathic neonatal hepatitis' is a term that has traditionally been used to denote a clinical syndrome manifest by prolonged jaundice in the neonate. This description is now used much less frequently because recent studies unite well-defined clinical, biochemical and molecular features of intrahepatic cholestasis into specific syndromes. Advances in the understanding of the molecular basis of cholestatic syndromes now enable the classification of syndromes based on biology and offer an opportunity to develop new diagnostic approaches and treatment strategies that take into account the genetic make-up of the child with cholestasis.

[Pregnancy and inborn errors of metabolism]. / Wrodzone bledy metaboliczne a ciaza.

Increasing number of patients with inborn errors of metabolism (IEM) are now reaching adulthood and are in position to reproduce. Because of the rarity of individual disorders our knowledge of risks factors associated with pregnancy is limited. Obstetrics problems in IEM can be divided into two categories: pregnancy effects on maternal metabolic disorders and relation between mother and fetus related to who of them is affected. Detrimental effects upon the fetus may be directly caused by maternal disease, as it occurs in PKU, or indirectly by maternal supplementation with harmful substrate, as occurs in galactosemia. Less commonly, fetal inborn error of metabolism may affect the mother's health. Pregnancies in which the fetus had long-chain hydroxyacyl-CoA dehydrogenase deficiency have been complicated by life-threatening HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) or AFL (acute fatty liver of pregnancy) during third trimester. The management of labor and the postpartum period (for women and newborns) has to be carefully planned to avoid significant metabolic decompensation.

Reproductive effects of maternal metabolic disorders: implications for pediatrics and obstetrics.

The reproductive effects of metabolic disorders in women can be divided into four categories. The first of these is infertility. Galactosemia with its complication of ovarian failure is the disorder in this category. This complication may be prenatal in origin but whether this is so and its cause are unknown. The second category includes pregnancy effects of maternal metabolic disorders. The urea cycle disorder ornithine transcarbamylase (OTC) deficiency, maternal maple syrup urine disease and maternal homocystinuria are in this category. In the first two disorders, postpartum life-threatening illness due to metabolic crisis has occurred. Maternal homocystinuria is associated with a high risk for postpartum thromboembolic complications. The third category is the pregnancy effect of a fetal metabolic disorder. Pregnancies in which the fetus had long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) have been complicated by the life-threatening (HELLP) syndrome during the third trimester. Rapid recovery of the mothers followed delivery, on occasion by emergency cesarean section. The fourth category is the fetal effects (teratogenicity) from a maternal metabolic disorder. The best-known example of this is maternal phenylketonuria (PKU), which produces microcephaly, mental retardation, congenital heart disease and intrauterine growth retardation. Treatment with a low phenylalanine diet begun before conception or no later than the earliest weeks of the first trimester markedly reduces the risk to the fetus and can result in normal offspring. Other examples of teratogenicity may include maternal homocystinuria and maternal hypothyroidism.

Prenatal diagnosis of succinyl-coenzyme A:3-ketoacid coenzyme A transferase deficiency.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare disorder of ketone body catabolism. In the present study, we prenatally diagnosed SCOT deficiency in a fetus in a family of which the proband was the first patient with SCOT deficiency identified in Japan, by analysis of enzyme activity levels in samples of chorionic villi and cultured amniocytes. In the fetus of the family, SCOT activity was not detected in either chorionic villi or cultured amniocytes. Since the levels of SCOT activity in control chorionic villi were close to our minimal detectable level and were much lower than those in control cultured amniocytes, enzyme assay in cultured amniocytes was more feasible than that in chorionic villi for prenatal diagnosis of SCOT deficiency. No elevated accumulation of 3-hydroxybutyrate or acetoacetate was detected in the amniotic fluid of the fetus. To our knowledge, this report is the first of prenatal diagnosis of SCOT deficiency.

In utero transplantation of fetal liver stem cells into human fetuses.

Based on our experience in the field of fetal liver transplantation (FLT) that we have developed since 1976, we initiated, in 1988, in utero FLT into human fetuses, taking advantage of the immunologic tolerance in young fetuses. The transplants have involved fetuses suffering from various diseases at 12-28 weeks postfertilization, with 2 of the 6 cases eventually resulting in abortion. With the 4 other fetuses, a favorable outcome was observed. Three children are more than 4 years old, and they are alive and well, with evidence of engraftment, reconstitution of immunity, and partial correction of beta-thalassemia. In the fourth case, the fetus is alive and well and birth is expected soon. In utero transplantation of stem cells is a therapy with remarkable advantages: (a) tolerance induction due to immune immaturity of the host, (b) lack of graft-versus-host disease (GVHD) due to immaturity of the donor, (c) ideal isolation of the fetus in the maternal uterus, and (d) optimal environment for donor fetal cell development in the vicinity of host fetal cells and growth factors.

Stable-isotope dilution analysis of D- and L-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of D- and L-2-hydroxyglutaric acidemias.

A stable-isotope dilution assay has been developed for quantitation of D- and L-2-hydroxyglutaric acids in physiologic fluids. D- and L-2-hydroxyglutaric acids are separated as the O-acetyl-di-(D)-2-butyl esters. The method uses D,L-[3,3,4,4-2H4]-2-hydroxyglutaric acid as internal standard with ammonia chemical ionization, selected ion monitoring gas chromatography-mass spectrometry. For 13 patients with L-2-hydroxyglutaric aciduria, the concentrations of L-2-hydroxyglutaric acid were urine, 1283 +/- 676 mmol/mol creatinine (range, 332-2742; n = 12 patients); plasma, 47 +/- 13 mumol/L (range, 27-62; n = 8); cerebrospinal fluid, 62 +/- 30 mumol/L (range, 34-100; n = 6). In a child with D-2-hydroxyglutaric aciduria, the levels of D-2-hydroxyglutaric acid were urine, 1565 +/- 847 mmol/mol creatinine (range, 729-2668; n = 4); plasma, 61 +/- 14 mumol/L (range, 46-73; n = 3); cerebrospinal fluid, 15 and 25 mumol/L (n = 2). Control concentrations of D- and L-2-hydroxyglutaric acids were (D:L): urine (n = 18), 6.0 +/- 3.6 mmol/mol creatinine (range, 2.8-17): 6.0 +/- 5.4 (range, 1.3-19); plasma (n = 10), 0.7 +/- 0.2 mumol/L (range, 0.3-0.9): 0.6 +/- 0.2 (range, 0.5-1.0); cerebrospinal fluid (n = 10), 0.1 +/- 0.1 mumol/L (range, 0.07-0.3): 0.7 +/- 0.6 (range, 0.3-2.3). Investigation of control amniotic fluid (n = 10) revealed the following values (D:L): 1.2 +/- 0.4 mumol/L (range, 0.6-1.8): 4.0 +/- 0.7 (range, 3.1-5.2), suggesting the feasibility of prenatal diagnosis in families at risk.

Growth analysis in clinical genetics.

The number of genetic and environmental determinants of human growth is very large and their interplay is responsible for the enormously complex phenomenon of prenatal and postnatal growth and simultaneous differentiation in function. Genetic factors participate substantially in determining size at birth, but become more and increasingly important in the realization of inherent potential after the age of two years. Thus, prenatal growth is determined by a greater number of environmental factors than postnatal growth, including parity, pregnancy spacing, maternal age, size, blood pressure, race, health, smoking, alcohol intake, twinning, intrauterine constraint, etc. Galilei's scale effect sets the upper limit of human size, and our surface area determines our metabolic rate and to some extent our life span. Age and rate of pubertal maturation varies with sex, race, and health of the individual, and may be dramatically influenced by numerous environmental and genetic disturbances. One of the most consistent and dramatic effects of autosomal aneuploidy on development is permanent reduction of growth rate, beginning very early in embryonic development. This effect on growth can be interpreted as an abnormality of developmental homeostasis or canalization. Reduced buffering or canalization of growth has been demonstrated in the DS and constitutes most elegant confirmation of the Waddington-Shapiro hypothesis; it ought to be demonstrable also in most if not all of the gonosomal aneuploidies. Thus, an ultrasonographic analysis of embryonic and fetal growth ought to be normal practice in all, not just high--risk pregnancies, and serve as valuable indicator of fetal developmental abnormality if IUGR is found. Because of difference in prognosis and possible difference in obstetric management, ultrasonographers ought to make a distinction in practice between (proportionate) IUGR and (disproportionate) CSOS. Depending on age of onset and severity, reduced prenatal movement can lead to the fetal akinesia sequence including growth retardation of all or part of the fetus. Neurohypotrophy shows that normal innervation is required for normal growth and function of limbs.