We report a homozygote guanine-to-adenine substitution at nucleotide 543 in exon 5 of the AFP gene (c.543G>A) in an Algerian family, whereas serum and amniotic AFP were undetectable during the second trimester maternal serum screening for Down syndrome. This nonsense mutation was most likely to be responsible for a reduction of AFP mRNA stability, thus resulting in a premature RNA degradation, but this hypothesis could not be verified. The implication of this mutation in the phenotype of null production of AFP was not determined by in vitro expression studies, but convincing arguments support this relation. First, no AFP was detected in both maternal serum and amniotic fluid using immunological detection methods even though high AFP levels are usually observed. Secondly, the c.543G>A mutation was the only non-synonymous sequence abnormality observed in the 14 sequenced exons of the AFP gene. Unfortunately, the presence of the mutation at the heterozygote state in the parents could not be confirmed (blood sample refused).
Low or undetectable level of AFP during gestation is a rare condition. Its frequency was estimated to be 1/105
In such situations, the difficulty is to distinguish real low AFP values in patients at high risk of maternal or fetal abnormalities7
from congenital absence of AFP.3
Indeed, molecular defect in the AFP
gene expression could conceal 1 of the 18 clinical manifestations observed in case of low levels of serum AFP.7
In our case, these clinical manifestations have been excluded thanks to cytogenetic and biochemical investigations and to ultrasound examinations.
Congenital AFP deficiency is always considered as a benign trait, but this specific point may need to be modulated. Indeed, congenital AFP deficiency is generally diagnosed on second trimester maternal serum screening for Down syndrome, in other words, lately in the fetal development. To illustrate this interrogation, analbuminemia is a very rare metabolic abnormality considered as remarkably benign in infancy, but it could be responsible for severe disorders during intrauterine development (intrauterine growth retardation and intrauterine death).8
In this way and knowing its potential role in fetal immune function and in maintenance of osmotic pressure, AFP deficiency should be responsible for precocious fetal loss in some cases in which the diagnosis is not established. Molecular analyses of the AFP
gene in precocious pregnancy loss are necessary to elucidate this specific point.
The mechanisms of the switch between AFP and albumin at the end of the embryonic period are not completely elucidated. In mouse, AFP and albumin mRNAs accumulate in parallel during the prenatal period, not only in hepatic cells but also in other tissues, suggesting a systematic concomitant expression of both genes.9
According to this hypothesis, albumin can replace AFP since the first developmental stages. Albumin rate and total protein fraction repartition differences between our case and controls suggest the implication of other proteins than albumin in the compensating mechanisms of AFP deficiency. However, this observation has to be interpreted with precaution because we studied only one case and total proteins and albumin measured in the control amniotic fluids were different from one another, probably due to variation in renal functions. Several studies on AFP deficiency are necessary for a better understanding of the mechanisms of compensation of the absence of AFP.
Although AFP deficiency is considered as benign, molecular analysis in case of total absence of AFP on second trimester maternal serum screening for Down syndrome should be systematic to inform the patient and his family for an accurate interpretation of AFP monitoring should hepatocellular carcinoma or testis tumors occur.