section 38.2
Water-Soluble Vitamins
deficiency anemia are reversed by large doses of folate.
However, folate does not reverse the neurological abnor-
malities associated with vitamin B
deficiency and may
even exacerbate them. Correction of megaloblastosis by
folate is not necessarily an indication of the absence of
vitamin B
deficiency; in fact, it could mask developing
vitamin B
deficiency until the advent of neurological
The common point in metabolism of folate and
is transmethylation of homocysteine to methionine
(Figure 38-17). In humans and some other species, this
is the only route for conversion of N5-methyl FH
to other folate derivatives. According to the
folate trap hypothesis,
inhibition of this reaction by
cobalamin deficiency leads to accumulation of folate as
N5-methyl FH4, deprives the cell of other folate cofactors,
and leads to blockage of several enzymatic reactions. Ad-
ministration of large amounts of folates may circumvent
this inhibition and directly supply the folate derivatives.
Cobalamin deficiency decreases the activity of the methyl-
transferase and brings about increased urinary excretion of
formate, aminoimidazolecarboxamide, and formiminog-
(Chapter 17). Megaloblastosis occurs because of impaired
DNA synthesis secondary to an inadequate supply of
thymidylate. Synthesis of dTMP from dUMP requires
N10-methylene FH4. However, evidence for accumu-
lation of N5-methyl FH
is more equivocal. In patients
with pernicious anemia, methionine decreases the excre-
tion of Figlu, further depresses synthesis of dTMP, and
increases the severity of the megaloblastosis. Methion-
ine is a precursor of S-adenosylmethionine, an allosteric
inhibitor of N
,N10-methylene FH
reductase. Several
patients have been described who have abnormal cobal-
amin metabolism and decreased methyltransferase activ-
ity but no megaloblastosis or anemia. These observations,
and the ineffectiveness of folates in relieving the neuro-
logical symptoms of vitamin Bj
deficiency, suggest ad-
ditional vitamin B ^-dependent functions in mammalian
an amino acid associated with coronary
heart disease as a risk factor is elevated in folate deficiency
(discussed earlier and also see Chapter 17). If the eleva-
tion of plasma homocysteine is due to folate deficency,
supplementation of folate corrects the plasma homocys-
teine level and may decrease the morbidity and mortality
from atherosclerotic disease which can lead to heart attack
and stroke. Vitamin Bg and Vitamin B
deficencies can
also cause elevated plasma homocysteine levels.
Folate supplementation of 400 /zg/d, in addition to a
healthy diet that includes foods rich in folate, has been
recommended for women before and in the early weeks
of pregnancy. Folate supplementation helps prevent the
majority of birth defects of the brain and spinal cord,
called neural tube defects (NTDs). Although the exact
mechanism of folate in the prevention of NTDs is not
understood, the role of folate in nucleic acid and amino
acid metabolism in the raidly developing fetus is probably
involved. Also, supplementation of dietary folate may cor-
rect metabolic defects in individuals who inherit defects in
folate metabolism. A recent study indicates that as many
as one in seven people carry a mutation affecting folate
A screening test for NTDs has been developed using
maternal serum to measure a-fetoprotein (AFP) levels at
15-20 weeks of gestation. AFP is synthesized in the fetal
liver and yolk sac during development and is the major
fetal serum protein (analgous to serum albumin in adults).
AFP appears in amniotic fluid from fetal urination. Its am-
niotic fluid concentration parallels fetal serum levels ex-
cept that the amniotic fluid level is about 150 times lower
in concentration. Through placental transfer, AFP also
appears in maternal serum. During the screening test pe-
riod of 15-20 weeks, maternal serum AFP concentration
increases by about 15% per gestational week. If NTDs are
present (e.g., anencephaly, open spina bifida), fetal serum
leaks into the fluid compartment raising the AFP amniotic
fluid levels, as well as maternal serum levels. Thus, ele-
vated levels of maternal serum AFP are used to identify
women who may be carrying a fetus with a NTD. How-
ever, because of the overlap in AFP values between un-
affected and affected pregnancies, the test is not diagnos-
tic and requires confirmatory diagnostic procedures (e.g.,
acetylcholinesterase and AFP levels in the amniotic fluid,
high-resolution ultrasonography).
Low levels of maternal serum AFP also may be in-
formative in assessing other fetal abnormalities such as
Down’s syndrome. Some of the salient features of Down’s
syndrome include trisomy
2 1
, malformations, dysmorphic
features, and mental retardation. The risk of Down’s syn-
drome increases with maternal age. At age 35, the risk
at birth is 1 in 385 and at age 40 it is 1 in 105. In esti-
mating the risk of Down’s syndrome, two other biochem-
ical serum parameters are measured: unconjugated estriol
(which is decreased) and human chorionic gonadotropin
(hCG, which is increased). The measurement of these three
maternal serum markers is used in conjunction with ma-
ternal age, twin gestation, maternal insulin-dependent di-
abetes mellitus, maternal weight, ethnic derivation, and
smoking to assess risk. Evaluating all of these parameters
in comparison to values obtained with healthy women of
comparable gestational age has increased the sensitivity
and reduced false-positive rates in the assessment of
Down’s syndrome in the fetus. A four-marker maternal
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