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)