Mitochondrial Trifunctional Protein Deficiency: Severe Cardiomyopathy and Cardiac Transplantation

We describe mitochondrial trifunctional protein deficiency (MTPD) in two male siblings who presented with severe cardiomyopathy in infancy. The first sibling presented in severe cardiac failure at 6\ua0months of age and succumbed soon after. The second sibling came to attention after newborn screening identified a possible fatty acid oxidation defect. Dietary therapy and carnitine supplementation commenced in the neonatal period. Despite this the second child required cardiac transplantation at 3\ua0years of age after a sudden and rapid decline in cardiac function. The outcome has been excellent, with no apparent extra-cardiac manifestations of a fatty acid oxidation disorder at the age of 7. Pathogenic HADHA mutations were subsequently identified via genome wide exome sequencing. This is the first reported case of MTPD to undergo cardiac transplantation. We suggest that cardiac transplantation could be considered in the treatment of cardiomyopathy in MTPD

Necrotizing enterocolitis and respiratory distress syndrome as first clinical presentation of mitochondrial trifunctional protein deficiency

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 analysi

Management of an LCHADD Patient During Pregnancy and High Intensity Exercise

In this report we describe a female Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) patient who suffered from severe exercise intolerance. At age 34, the patient became pregnant for the first time. After an uneventful first 32 weeks of pregnancy she developed sinus tachycardia (resting heart rate 120–134 bpm) and lactate and creatinine kinase levels increased (3.3 mmol/L and 264 U/L, respectively). Increasing MCT supplementation (dose and frequency of administration) lowered heart rate and improved biochemical parameters. At 34 weeks the heart rate rose again and it was decided to deliver the child by caesarean section. Postpartum both mother and child did well. Prior to pregnancy, she performed exercise tests with different doses of medium chain triglycerides (MCTs) to establish a safe and effective exercise program (baseline test, second test with 10 g MCTs and third test with 20 g of MCTs). In the MCT supplemented tests the maximal power output was 23% (second test) and 26% (third test) higher, while cardiac output at maximal power output was the same in all three tests (~15.8 L/min). In conclusion, this is the first report of pregnancy in an LCHADD patient, with favourable outcome for both mother and child. Moreover, in the same patient, MCT supplementation improved cardiac performance and metabolic parameters during high intensity exercise. Using impedance cardiography, we got a clear indication that this benefit was due to improved muscle energy generation at high intensity exercise, since at the same cardiac output a higher power output could be generated