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Our laboratory at Vanderbilt continues to examine
many aspects of fatty acid oxidation proteins and genes, both in
patients with fatty acid oxidation disorders and in mice in whom
several FAO enzymes have been deleted. Three projects are summarized
below.
First, in conjunction with state laboratories
responsible for newborn screening using tandem mass spectrometry,
we have searched for mutations in medium chain acyl-CoA dehydrogenase
(MCAD), trifunctional protein subunits (TFP and LCHAD deficiency),
and very long chain-acyl-CoA dehydrogenase (VLCAD). The results
from the Massachusetts/New England initial two-year experience (Zytkovicz
et al., Clinical Chemistry 47: 945-55, 2001) and previous data from
Pennsylvania and North Carolina (Andresen et al., American Journal
of Human Genetics 68:1408, 2001) clearly show that the screening
methodology is effective and efficient in finding newborns with
MCAD deficiency. However, some heterozygotes may also be detected
by screening. The incidence of MCAD deficiency is about 1:15,000
newborns. The mutation studies show that mutations other than A985G,
the common MCAD mutation discovered 10 years ago, occur more frequently
than previously suspected (about 30% of alleles). In short term
follow-up, treatment with frequent feedings and vigilance is effective
in preventing metabolic crises and death. The numbers of TFP, LCHAD,
and VLCAD patients picked up by screening seems to be insufficient
to conclude much about the effectiveness of screening for these
disorders yet.
Second, we have generated mice with deletions of
the TFP and VLCAD genes. Because these animals have no expression
of TFP or VLCAD protein, the mice are similar genetically to only
the most severe of human mutations. VLCAD deficient mice appear
normal after birth and survive well. However, when stressed by fasting
and/or exposure to the cold, the deficient mice rapidly develop
low glucose and/or low body temperature and die. Later in life,
VLCAD deficient animals become fatter than normal mice and develop
heart rhythm problems. Because we can study these animals in detail
to determine how they have adapted to loss of VLCAD and as to how
they respond to various stresses, drugs (such as carnitine), and
differences in diet, we believe that we may find some important
data that may prove relevant to children with VLCAD deficiency.
The TFP deficient mice have a more severe problem, and most die
spontaneously and suddenly shortly after birth because of breathing
difficulties and low blood sugar (Ibdah et al, Journal of Clinical
Investigation 107:1403-1409, 2001). This is similar to severe and
complete TFP deficiency that occurs very rarely in babies. These
animals are NOT similar to LCHAD deficiency. Again, we hope to study
these animals in detail to better understand how fatty acid oxidation
defects cause illness in children.
Third, we have now found 15 families worldwide
with complete TFP deficiency. Three types of presentation occur,
(1) infants with severe heart problems and metabolic crisis who
have all died; (2) toddlers with hypoglycemia and metabolic crises
who may recover and do well; and (3) older children or adolescents
who have episodes of muscle pain and weakness with stress but who
are mostly healthy. These results emphasize that some TFP mutations
are fairly mild and that children, even with complete TFP deficiency,
can survive well. That is, there is great variability in clinical
status of TFP deficiency, as in other FAO.
Thus, we continue to learn novel and exciting things
about FAO disorders, both in people and in mice.
Arnold W. Strauss, M.D.
James C. Overall Professor and Chair
Room AA-0216 Medical Center North
Vanderbilt University
Nashville, TN 37232
Telephone: 615-322-3377 (Office) 615-322-2678 (Lab)
arnold.strauss@vanderbilt.edu
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