We have calculated the incidence of Menkes disease for Denmark, France, The Netherlands, the United Kingdom and West Germany, based on known Menkes patients born during the time period 1976-87. Considering live-born Menkes patients, the combined incidence for these five countries is 1 Menkes patient per 298,000 live-born babies. If the number of affected aborted fetuses are taken into account, the incidence is 1 Menkes per 254,000 live-born babies. This incidence, which is 2-4 times lower than earlier published incidence figures, places Menkes disease as an extremely rare disease. The mutation rate for Menkes disease is estimated to be 1.96 x 10(-6), based on the number of isolated Menkes cases born during the time period 1976-87 and the total number of newborn males during this time.

Intestinal disaccharidases in amniotic fluid were studied in 41 pregnancies with a recurrence risk for cystic fibrosis (CF). In 11 out of 13 pregnancies with CF fetuses the maltase and sucrase activities were either below the control range (8 cases) or below the 10th percentile of control values (3 cases). Trehalase and lactase were slightly less informative indicators of CF. Of the other 28 pregnancies 3 had low amniotic fluid activities of several intestinal enzymes and were terminated, 12 resulted in the birth of a healthy child and 13 are continuing. The findings in fetal CF suggest an impairment of the defaecation of intestinal contents into the amniotic fluid. Reduced or low amniotic fluid disaccharidase activities were also found in other fetal disorders with demonstrated or presumed intestinal anomalies: e.g. anal atresia (2 cases), anencephaly (3 our of the 7 cases), trisomy 13 (5 cases), trisomy 18 (3 of the 5 cases) and trisomy 21 (19 of the 22 cases). Reduced amniotic fluid disaccharidase activities, although not specific for CF, are highly informative in pregnancies at high risk for CF. Using the 10th percentile of the normal range for amniotic fluid disaccharidase activities as an action line, the sensitivity of CF detection is estimated at 80 to 90 per cent, which could in high risk pregnancies reduce the risk of having another affected child from 1 in 4 to 1 in 20.

We describe the results and follow-up of chorionic villus studies in 1,034 pregnancies at risk for chromosome or metabolic disorders. Direct chromosome studies were successful in 99.7% and yielded results within a few days. Fifty pregnancies at risk for an unbalanced translocation, inherited from parents with many small reciprocal translocations, were a good test for the quality of the direct method. The 101 metabolic studies involving 28 disorders were correct in 99 pregnancies in the first trimester. In two cases a correct diagnosis was obtained by the confirmatory amniocentesis. DNA studies were carried out in pregnancies of male fetuses at risk for Duchenne muscular dystrophy and a few metabolic disorders. The abortion rate after chorionic villus sampling was 5.1% but more than half of the pregnant women were greater than or equal to 36 years old and have a spontaneous abortion rate of 10% between the 10th and 14th week according to Gustavii [Lancet 1:562, 1984]. Follow-up studies confirmed results of all chromosome studies after termination when there was fetal cell growth; the outcome of 504 consecutive continuing pregnancies showed no discrepancies of the phenotype after birth. It was concluded that first-trimester chorionic villi studies gave reliable results and were increasingly preferred by the patients, while the sampling can be considered a safe procedure based on the currently available data.

Deficiency of lysosomal protective protein/cathepsin A in humans is the primary cause of galactosialidosis, a lysosomal storage disease characterized by combined deficiency of beta-galactosidase and neuraminidase. We have investigated 20 galactosialidosis patients and nine of their obligate heterozygous parents. A group of 12 patients with the early infantile type of the disease exhibited practically complete absence of cathepsin A activity, whereas eight patients with either the late infantile or the juvenile/adult type had 2-5% residual activity. Highest levels (5%) were present in two patients with milder clinical manifestations and later onset of the disease. In most fibroblast strains, beta-galactosidase activity was 10-15% of normal levels, whereas neuraminidase was reduced to less than 4%. Interestingly, a substantial residual activity (10%) of the latter enzyme was detected in the patient with the mildest phenotype and the highest cathepsin A activity. Heterozygous values for cathepsin A were reduced on average to half of normal levels. However, in two cell strains, the activity was far below control range, and in these cases, neuraminidase activity was severely depressed. Finally, we showed that cathepsin A had considerable activity in chorionic villi and amniocytes, but was deficient in amniocytes from a pregnancy with an affected fetus, indicating the relevance of cathepsin A assay for prenatal diagnosis of galactosialidosis.