Balkan Journal of Medical Genetics

NOVEL DGAT1 MUTATIONS IDENTIFIED IN CONGENITAL DIARRHEAL DISORDER 7: A CASE REPORT WITH THERAPEUTIC EXPERIENCE
Shi C, Liu XL, Li XN, Zhao YJ
*Corresponding Author: Yunjing Zhao, PhD, Department of Pediatrics, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang 110004, China; Email: zhaoyunjing@sj-hospital.org
page: 69

DISCUSSION

CDDs are a group of uncommon, clinically varying enteropathies that are often missed or misdiagnosed, and usually present with persistent diarrhea in the first few months of life [6]. If unrecognized, patients can suffer from malnutrition, failure to thrive, and even death [7]. CDD7 is a rare autosomal recessive condition caused by loss of function mutations in the DGAT1 gene. Since the first case with DGAT1 mutation was described in 2012 [3], only 32 patients with 24 DGAT1 mutations have been identified, with varied severity in the disease phenotype [7]. More data about the clinical features are needed to enhance our awareness of the disease. All of the patients with DGAT1 mutations suffer from diarrhea or vomiting within the first week of life, as well as hypoalbuminemia, and failure to thrive. The severity of the disease is correlated with the amount of residual DGAT1 activity [8]. Our patient had an early disease onset at 2 days and aroused the attention of the parents as late as 3 months. Moreover, a wrong treat- ment of high energy formula was provided to deteriorate the diarrhea. The necessity of early genetic diagnosis is critical for the correct breeding strategy of these patients. To date, 26 variants (including ours) in the DGAT1 gene have been identified (Table 1), including various types of nonsense, missense, splicing, frameshift, and insertion-deletion. We added two novel mutations to the DGAT1 mutation spectrum, both of which were supposed to be loss-of-function by creating frame-shift and prema- ture termination codon. The symptoms of our patient were also more severe than in the previously reported cases. It is interesting to see that the construction of DGAT1 deficient mice were lean and resistant to obesity but did not recapitulate the diarrhea observed in human patients [9-10]. The etiology of diarrhea due to DGAT1 deficiency is still unknown [3]. One of the hypotheses is that increased levels of DGAT1 lipid substrates from the diet in the in- testine mucosa or lumen could result in cellular dysfunc- tion due to lipotoxic stress in enterocytes [3]. In addition, toxicity to enterocytes could also lead to protein-losing enteropathy which occurs in all patients. Furthermore, a deficiency of DGAT1 could affect bile acid metabolism, and bile acid malabsorption can cause diarrhea [3]. Mild hypertriglyceridemia occurred in some affected patients. Some reasons may be from overcompensation of hepatic DGAT2 or the interruption of bile acid absorption in the distal small intestine [3]. However, not all patients with DGAT1 mutations present with hypertriglyceridemia. In addition, hypertriglyceridemia also did not appear to be associated with homozygous or heterozygous mutations in DGAT1. Therefore, more clinical cases and experiments are needed to clarify this question. Our patient was promptly switched to a fat-restricted diet as soon as the genetic diagnosis was obtained. We carefully explored the amount of dietary fat, which was on one hand tolerable to the patient, and on the other hand satisfactory for growth. A limited fat to 2%-10% of total calories intake was found effective. This constitution was similar to previous experience suggested by Eldredge et al. [5]. Moreover, the patient was suggested to be fed with small amounts of fat multiple times, which was supposed to increase the tolerance of dietary fat in these patients [8]. Patients with a fat-restricted diet must be monitored for the levels of essential fatty acids, fat-soluble vitamins, serum lipid, and total protein levels. As described in previous lit- erature, most patients develop catch-up growth and normal development after diet modification [11]. Our experience provides an alternative method using calculated adult low- fat milk powder for children who are unable to obtain low- fat infant formula. Our follow-up data showed a satisfac- tory rate of weight gain and normal metabolic parameters. However, the increase in length was less satisfactory. We speculated that it may be related to the short treatment and follow-up period or the fact that the two novel mutations in the DGAT1 gene in the child might cause short stature. Therefore, more cases and longer follow-up times will need to be studied in the future.

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