Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia.
BACKGROUND
In the course of 25 years, we have experienced a high rate of affected fetuses in the prenatal diagnosis of citrullinemia.


RESULTS
Ninety-one pregnancies at 1 in 4 risk were tested; 36 were diagnosed as affected (39.5%; P = 0.0015). The high rate of positive diagnoses was found both after chorionic villus sampling (24/68 = 35.3%) and amniocentesis (12/23 = 52.2%) despite the completely different and independent techniques used. Using exactly the same (indirect) enzyme assay for argininosuccinic aciduria on chorionic villi and a similar method on amniotic fluid, the expected rate of affected fetuses was found: 13/53 = 24.5%. Technical and genetic causes for the unexpected results were excluded by confirmatory studies performed on independent fetal material, which was available for 27 of the 36 fetuses affected with citrullinemia. Biochemical confirmation was obtained in the 27 cases, whereas in 18 fetuses homozygosity or compound heterozygosity for disease-causing mutations were retrospectively demonstrated in the stored fetal cells.


CONCLUSIONS
The results suggest the occurrence of preferential transmission of the mutant allele. An explanation for this phenomenon may be found in a protective role of argininosuccinic acid synthetase deficiency in mutant sperm cells against the possibly detrimental or apoptotic effect of nitric oxide produced normally from arginine by nitric oxide synthase.
Kleijer
Wim J
WJ
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. w.kleijer@erasmusmc.nl
Garritsen
Victor H
VH
van der Sterre
Marianne L T
ML
Berning
Christoph
C
Häberle
Johannes
J
Huijmans
Jan G M
JG
D000649:Amniocentesis; D001123:Argininosuccinate Lyase / Q000032:analysis; D001125:Argininosuccinic Acid / Q000652:urine*; D015193:Chorionic Villi Sampling; D020159:Citrullinemia / Q000175:diagnosis*; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis*; D006801:Humans; D009154:Mutation; D011247:Pregnancy; D012680:Sensitivity and Specificity
D001125:Argininosuccinic Acid; D001123:Argininosuccinate Lyase