Necrotizing Enterocolitis and Respiratory Distress Syndrome as First Clinical Presentation of Mitochondrial Trifunctional Protein Deficiency

Abstract

Background: Newborn screening (NBS) for long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency does not discriminate between isolated LCHAD deficiency, isolated long-chain keto acyl-CoA (LCKAT) deficiency and general mitochondrial trifunctional protein (MTP) deficiency. Therefore, screening for LCHAD deficiency inevitably comprises screening for MTP deficiency, which is much less amenable to treatment. Furthermore, absence of a clear classification system for these disorders is still lacking. Materials and Methods:Two newborns screened positive for LCHAD deficiency died at the age of 10 and 31 days, respectively. One due to severe necrotizing enterocolitis (NEC), cardiomyopathy and multiorgan failure and the other due to severe infant respiratory distress syndrome (IRDS) and hypertrophic cardiomyopathy. (Keto)-acylcarnitine concentration and enzymatic analysis of LCHAD and LCKAT suggested MTP deficiency in both patients. Mutation analysis revealed a homozygous HADHB c.357+5delG mutation in one patient and a homozygous splice-site HADHB mutation c.212+1G>C in the other patient.Data on enzymatic and mutation analysis of 40 patients with presumed LCHAD, LCKAT or MTP deficiency were used to design a classification to distinguish between these disorders.Discussion: NEC as presenting symptom in MTP deficiency has not been reported previously. High expression of long-chain fatty acid oxidation enzymes reported in lungs and gut of human foetuses suggests that the severe NEC and IRDS observed in our patients are related to the enzymatic deficiency in these organs during crucial stages of development.Furthermore, as illustrated by the cases we propose a classification system to discriminate LCHAD, LCKAT and MTP deficiency based on enzymatic analysis.

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

“…Even though peripheral neuropathy and pigmentary retinopathy are reported in both LCHAD and MTP deficiency, retinopathy seems to be more prevalent in isolated LCHAD deficiency and peripheral neuropathy is more often seen in MTP deficiency [ 127 – 130 ]. There is a broad clinical spectrum, but the proportion of patients with a severe clinical presentation and who are refractory to treatment - despite early detection by NBS - is larger than seen in VLCAD deficiency [ 62 , 131 ]. Some cases of hypoparathyroidism are reported for both isolated LCHAD as well as generalized MTP deficiency [ 132 – 134 ].…”

Fulminant Necrotizing Enterocolitis and Multiple Organ Dysfunction in a Toddler with Mitochondrial DNA Depletion Syndrome-13

“…The first occurred at 10 days of age in a patient born at 35 weeks' gestation with trifunctional protein deficiency, a disease of mitochondrial fatty acid oxidation. 19 In addition to mitochondrial DNA depletion, at least three interrelated factors may have contributed to the development of NEC in this patient: intestinal dysmotility, hypocarbia, and hyperoxia. Intestinal villi are particularly susceptible to circulatory insufficiency and hypoxia.…”

Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands

“…Creatine kinase (CK) levels were elevated up to 5876 U/L. Patients #3 and #4 were previously described by Diekman et al 17 …”

“…Creatine kinase (CK) levels were elevated up to 5876 U/L. Patients #3 and #4 were previously described by Diekman et al 17 MTPD patient #5 is now an 11-year-old girl. NBS showed normal levels of hydroxy-C16-carnitine.…”