Mitochondrial Neurogastrointestinal Encephalopathy: Clinical, Biochemical and Molecular Study in Three Egyptian Patients.

Background: Mitochondrial Neurogastrointestinal Encephalopathy syndrome is a rare autosomal recessive disorder. The disease is caused by mutations in the thymidine phosphorylase gene. This article reports the clinical, biochemical and molecular findings in three Egyptian patients with Mitochondrial Neurogastrointestinal Encephalopathy sundrome from two different pedigrees. Subjects and Methods: The three patients were subjected to thorough neurologic examination. Brain Magtnetic Resonance Imaging. Histochemical and biochemical assay of the mitochondrial respiratory chain complexes in muscle homogenate was performed (1/3). Thymidine Phosphorylase enzyme activity was performed in 2/3 patients and Thymidine Phosphorylase gene sequencing was done (2/3) to confirm the diagnosis. Results: All patients presented with symptoms of severe gastrointestinal dysmotility with progressive cachexia, neuropathy, sensory neural hearing loss, asymptomatic leukoencephalopathy. Histochemical analysis of themuscle biopsy revealed deficient cytochrome C oxidase and mitochrondrial respiratory chain enzyme assay revealed isolated complex 1 deficiency (1/3). Thymidine Phosphorylase enzyme activity revealed complete absence of enzyme activity in 2/3 patients. Direct sequencing of Thymidine Phosphorylase gene revealed c.3371 A>C homozygous mutation. Molecular screening of both families revealed heterozygous mutation in both parents and 4 siblings. Conclusions: Mitochondrial Neurogastrointestinal Encephalopathy syndrome is a rare mitochondrial disorder with an important diagnostic delay. In case of pathogenic mutations in Thymidine Phosphorylase gene in the family, carrier testing and prenatal diagmosis of at risk members is recommended for early detection. The possibility of new therapeutic options makes it necessary to diagnose the disease in an early state.

Biochemical Monitoring and Management During Pregnancy in Patients with Isovaleric Acidaemia is Helpful to Prevent Metabolic Decompensation.

The facilities for neonatal screening, early diagnosis, and effective treatment of isovaleric acidaemia (IVA) have improved greatly over the past decades. Accordingly, IVA patients reach adolescence and may consider having children. The maintenance of a stable metabolic condition is a challenge to both the patients and their multidisciplinary team of care providers. This report presents three women with IVA during their five single or twin pregnancies, whose clinical condition were monitored with contrasting approaches. Metabolic profiles were determined and compared in these pregnancies. In one case, two pregnancies were strictly managed and monitored by measuring plasma acylcarnitine and amino acid profiles, together with adjustment of the diet and/or supplementation of L-carnitine and/or glycine. In addition, complications were prevented by intravenous glucose and L-carnitine during labor and postpartum. In two other cases, the metabolic condition of patients was less frequently monitored and additional treatment with intravenous L-carnitine and intravenous glucose/dextrose was only prescribed during periods of hyperemesis gravidarum. With respect to the differences in management and monitoring of maternal IVA all pregnancies were without complications for mother and child. Despite the favorable outcome in uncontrolled pregnancies in IVA, careful monitoring and management during pregnancy is helpful to prevent life-threatening conditions like metabolic decompensation.

Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification.

AIMS/HYPOTHESIS: Changes in cardiac substrate utilisation leading to altered energy metabolism may underlie the development of diabetic cardiomyopathy. We studied cardiomyocyte substrate uptake and utilisation and the role of the fatty acid translocase CD36 in relation to in vivo cardiac function in rats fed a high-fat diet (HFD). METHODS: Rats were exposed to an HFD or a low-fat diet (LFD). In vivo cardiac function was monitored by echocardiography. Substrate uptake and utilisation were determined in isolated cardiomyocytes. RESULTS: Feeding an HFD for 8 weeks induced left ventricular dilation in the systolic phase and decreased fractional shortening and the ejection fraction. Insulin-stimulated glucose uptake and proline-rich Akt substrate 40 phosphorylation were 41% (p < 0.001) and 45% (p < 0.05) lower, respectively, in cardiomyocytes from rats on the HFD. However, long-chain fatty acid (LCFA) uptake was 1.4-fold increased (p < 0.001) and LCFA esterification into triacylglycerols and phospholipids was increased 1.4- and 1.5-fold, respectively (both p < 0.05), in cardiomyocytes from HFD compared with LFD hearts. In the presence of the CD36 inhibitor sulfo-N-succinimidyloleate, LCFA uptake and esterification were similar in LFD and HFD cardiomyocytes. In HFD hearts CD36 was relocated to the sarcolemma, and basal phosphorylation of a mediator of CD36-trafficking, i.e. protein kinase B (PKB/Akt), was increased. CONCLUSIONS/INTERPRETATION: Feeding rats an HFD induced cardiac contractile dysfunction, which was accompanied by the relocation of CD36 to the sarcolemma, and elevated basal levels of phosphorylated PKB/Akt. The permanent presence of CD36 at the sarcolemma resulted in enhanced rates of LCFA uptake and myocardial triacylglycerol accumulation, and may contribute to the development of insulin resistance and diabetic cardiomyopathy.