Analysis of acylcarnitines in maternal urine for prenatal diagnosis of glutaric aciduria type 2

The urinary acylcarnitine profiles of two mothers whose first children were diagnosed to have glutaric aciduria type 2 (multiple acyl-CoA dehydrogenation deficiency, electron transfer flavoprotein (ETF) deficiency) were analysed in the second pregnancy. Large volumes of tigrylcarnitine and isovalerylcarnitine and a little glutarylcarnitine were detected. Each fetus was also diagnosed to be abnormal by enzyme activity and immunoassay of ETF protein. The acylcarnitines in the mothers' urine disappeared in 1 week after labour or artificial abortion. Acylcarnitines were never detected in the urine of controls.     

Eleventh week amniocentesis for prenatal diagnosis of some metabolic diseases

We report the results of 23 prenatal diagnoses performed at the 11th or 12th week of gestation by the simultaneous analysis of chorionic villi (for direct or indirect enzymatic analysis) and cell-free amniotic fluid (for search of accumulated catabolites). For six cases of citrullinaemia, four cases of argininosuccinic aciduria, seven cases of propionic acidaemia, and six cases of methylrnalonic acidaemia, three discrepancies were observed between the two methods used. The amniotic fluid analysis for accumulated catabolites seems to be a safe method and should always be used in conjunction with the enzymatic assays performed for the prenatal diagnosis of these diseases.     

Novel mutation and prenatal sonographic findings of glutaric aciduria (type I) in two Taiwanese families

Glutaric aciduria type I (GA I) is an autosomal recessively inherited inborn error with a defect of the enzyme glutaryl-CoA dehydrogenase (GCDH), which has never been diagnosed prenatally in Taiwanese patients. We present the prenatal sonographic findings and mutational analysis data of three children in two Taiwanese families. One patient from each family was diagnosed postnatally due to macrocephaly and neurological deterioration at 4 months and 10 months, respectively. The third child, sister of the first patient, was diagnosed prenatally at 11 weeks' gestation through chorionic villus sampling (CVS). Molecular analysis revealed that the fetus and child in Family 1 were homozygous for a common mutation, IVS10 -2A>C, which has not been reported in the Caucasian population. The patient in Family 2 was a compound heterozygote for IVS10 -2A>C and a novel mutation 749T>C (L238P). After genetic counseling, the couple decided to continue the second pregnancy. However, dilatation of quadrigeminal cistern (QC) and suspicious macrocephaly were noted at 30 weeks. Progressive dilatation of the QC associated with macrocephaly, fronto-temporal atrophy and wide space of perisylvian fissure were found in the follow-up scans. The affected girl was delivered at 37 weeks' gestation by cesarean section. Postnatal magnetic resonance imaging (MRI) studies confirmed the prenatal sonographic findings. With prenatal sonographic findings and mutational analysis presented in the present cases, the feasibility of prenatal diagnosis of GA I in high-risk pregnancy can not be overlooked. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis of multiple acyl-CoA dehydrogenase deficiency: association with elevated α-fetoprotein and cystic renal changes

We report the occurrence of multiple acyl-CoA dehydrogenase deficiency (MADD) in two consecutive pregnancies in a young, Caucasian, non-consanguineous couple. In the first pregnancy, the maternal serum α-fetoprotein was elevated. A sonogram showed growth delay, cystic renal disease, and oligohydramnios; the parents decided to terminate the pregnancy. Postmortem examination confirmed the cystic renal disease and showed hepatic steatosis, raising the suspicion of a metabolic disorder. The diagnosis of MADD was made by immunoblot studies on cultured fibroblasts. In the subsequent pregnancy, a sonogram at 15 weeks' gestation showed an early growth delay but normal kidneys. The maternal serum and amniotic fluid concentrations of α-fetoprotein were elevated, and the amniotic fluid acylcarnitine profile was consistent with MADD. In vitro metabolic studies on cultured amniocytes confirmed the diagnosis. A follow-up sonogram showed cystic renal changes. These cases provide additional information regarding the evolution of renal changes in affected fetuses and show a relationship with elevated α-fetoprotein, which may be useful in counseling the couple at risk. MADD should be considered in the differential diagnosis of elevated α-fetoprotein and cystic renal disease. Early growth delay may be an additional feature. Copyright © 2001 John Wiley & Sons, Ltd.     

First trimester diagnosis of methylmalonic aciduria

We have studied methylmalonyl CoA mutase activity in control chorionic villi to establish the potential use of assays performed directly on this tissue for prenatal diagnosis of methylmalonic aciduria. We report the detection of a fetus affected with the apo-mutase deficient form of this condition at 9 weeks' gestation. Methylmalonyl CoA mutase was markedly deficient in chorionic villi, approximately 2–5 per cent of the mean control value. However, incorporation of label from [¹⁴C]-propionate into protein was 10 and 40 per cent of the mean control value, respectively, in two portions of the same biopsy, highlighting potential problems in the use of this indirect assay. Normal results were obtained in chorionic villus samples from four other pregnancies ‘at risk’ for methylmalonic aciduria which were subsequently shown to be unaffected with this condition. The diagnosis in the affected pregnancy was confirmed by demonstration of a marked deficiency of methylmalonyl CoA mutase activity in villi obtained at termination and in cultured fetal fibroblasts. Reduced incorporation of [¹⁴C]-propionate label into protein was also found in these tissues.