One of the genes that regulates the production of the fat (also called triglyceride) is called DGAT1 which is an abbreviation for acyl-CoA:diacylglycerol acyltransferase. Each person has two copies of the DGAT1 gene on chromosome 8, one from each parent. If both genes are altered the synthesis of triglycerides is affected and the child develops diarrhea shortly after birth. This diarrhea is characterized by a loss of protein in the stool. Children with DGAT1 mutations often need to be hospitalized as infants due to dehydration and poor growth. Different mutations in DGAT1 have been described, some cause complete loss of DGAT1 function, while others result in only a partial loss of function, such that the severity of the diarrhea can vary. Importantly, collaboration between the medical team and scientists has led to the understanding that intake of fat causes the diarrhea illness. Since these discoveries, other mutations in DGAT1 have been reported, but not all have been characterized as to the degree of function.
Patients who have DGAT1 deficiency respond to treatment with a low-fat diet. This results in improvement in diarrhea and growth. This usually results in improvement in diarrhea and growth, but the severity of symptoms may vary with the mutation. Children do not need to take any specific medications, but do need to continue a diet with limited fat and might need vitamin supplements. The medical team is able to follow a marker of bowel integrity to see improvement (stool alpha-1-antitrypsin). As demonstrated in the figure below, when dietary fat is decreased, the loss of protein in the stool decreases and then increases when dietary fat is increased. Children with complete loss of DGAT1 function tolerate between 4-7% of calories from fat; whereas, children with some DGAT1 function might tolerate up to 10% of calories from fat. It is best to give fat in small amounts at multiple feedings, but the amount of fat a child can tolerate will vary from individual to individual. Infants do need fat for growth and development, particularly essential fatty acids. Infants who are treated with a fat-free formula can be supplemented with appropriate amounts of canola oil or a mixture of sunflower and flaxseed oils. Monitoring of essential fatty acids is an important aspect of care. Most children grow normally and even catch up when on a fat restricted diet.
Pathophysiology and mechanism of DGAT1
The reason why children with DGAT1 deficiency develop diarrhea is not known. Mice that are deficient in DGAT1 have decreased obesity, increased energy, are resistant to diet related obesity and fatty liver, are more sensitive to insulin, and live longer. Because of these observations, attempts were made to find medications that would inhibit DGAT1 in people, hoping that these favorable results would benefit people. However, DGAT1 inhibition in humans caused many of the subjects who participated in the clinical trials to develop diarrhea.