To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.

The lipolysis stimulated receptor (LSR) recognizes apolipoprotein B/E-containing lipoproteins in the presence of free fatty acids, and is thought to be involved in the clearance of triglyceride-rich lipoproteins (TRL). The distribution of LSR in mice was studied by Northern blots, quantitative PCR and immunofluorescence. In the adult, LSR mRNA was detectable in all tissues tested except muscle and heart, and was abundant in liver, lung, intestine, kidney, ovaries and testes. During embryogenesis, LSR mRNA was detectable at 7.5 days post-coitum (E7) and increased up to E17 in parallel to prothrombin, a liver marker. In adult liver, immunofluorescence experiments showed a staining at the periphery of hepatocytes as well as in fetal liver at E12 and E15. These results are in agreement with the assumption that LSR is a plasma membrane receptor involved in the clearance of lipoproteins by liver, and suggest a possible role in steroidogenic organs, lung, intestine and kidney). To explore the role of LSR in vivo, the LSR gene was inactivated in 129/ Ola ES cells by removing a gene segment containing exons 2-5, and 129/Ola-C57BL/6 mice bearing the deletion were produced. Although heterozygotes appeared normal, LSR homozygotes were not viable, with the exception of three males, while the total progeny of genotyped wild-type and heterozygote pups was 345. Mortality of the homozygote embryos was observed between days 12.5 and 15.5 of gestation, a time at which their liver was much smaller than that of their littermates, indicating that the expression of LSR is critical for liver and embryonic development.Keywords: lipoprotein receptors; Northern-blot; quantitative PCR; immunofluorescence; gene-targetting.Lipids, absorbed exogenously by the intestine and synthesized endogenously by the liver, are secreted into the circulation as lipoproteins for their transport to tissues, where they are used mainly for membrane synthesis, steroidogenesis and fat storage. Dietary cholesterol, phospholipids, triglycerides (TG) and fat-soluble vitamins absorbed by the intestine after a meal are transported by chylomicrons into lymph, then into blood. Lipoprotein lipase (LPL), anchored to the surface of capillary endothelium, hydrolyzes TG of chylomicrons into free fatty acids (FFA) that are taken up by the underlying muscle and adipose tissues. Chylomicron remnants are then taken up by the liver [1]. Transport of lipids to tissues is achieved by very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Excess cholesterol is removed from the peripheral cells by high density lipoproteins (HDL) that are able to return it to the liver for excretion via the LDL receptor (LDLR) or the scavenger receptor class BI (SR-BI) pathways. In the same way, HDL are also involved in the delivery of cholesterol to certain tissues, mainly steroidogenic organs. Apolipoprotein (apo) B and E containing-VLDL and chylomicron remnants bind with high affinity to the LDLR and the LDL receptor related protein (LRP) that mediates endocytosis of both particl...

SUMMARY BackgroundFaecal calprotectin is a reliable tool for predicting Crohn's disease (CD) relapse in patients with sustained remission. Prediction of relapse with faecal calprotectin has been less studied in patients with severe CD treated with anti-TNF.

Although growing evidence indicates that bioenergetic metabolism plays an important role in the progression of tumorigenesis, little information is available on the contribution of reprogramming of energy metabolism in cancer initiation. By applying a quantitative proteomic approach and targeted metabolomics, we find that specific metabolic modifications precede primary skin tumor formation. Using a multistage model of ultraviolet B (UVB) radiation-induced skin cancer, we show that glycolysis, tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation are decreased at a very early stage of photocarcinogenesis, while the distal part of the electron transport chain (ETC) is upregulated. Reductive glutamine metabolism and the activity of dihydroorotate dehydrogenase (DHODH) are both necessary for maintaining high ETC. Mice with decreased DHODH activity or impaired ETC failed to develop pre-malignant and malignant lesions. DHODH activity represents a major link between DNA repair efficiency and bioenergetic patterning during skin carcinogenesis.

BackgroundThis study aimed to determine the prevalence of genetic and environmental vascular risk factors in non diabetic patients with premature peripheral arterial disease, either peripheral arterial occlusive disease or thromboangiitis obliterans, the two main entities of peripheral arterial disease, and to established whether some of them are specifically associated with one or another of the premature peripheral arterial disease subgroups.Methods and ResultsThis study included 113 non diabetic patients with premature peripheral arterial disease (diagnosis <45-year old) presenting either a peripheral arterial occlusive disease (N = 64) or a thromboangiitis obliterans (N = 49), and 241 controls matched for age and gender. Both patient groups demonstrated common traits including cigarette smoking, low physical activity, decreased levels of HDL-cholesterol, apolipoprotein A–I, pyridoxal 5′-phosphate (active form of B6 vitamin) and zinc. Premature peripheral arterial occlusive disease was characterized by the presence of a family history of peripheral arterial and carotid artery diseases (OR 2.3 and 5.8 respectively, 95% CI), high lipoprotein (a) levels above 300 mg/L (OR 2.3, 95% CI), the presence of the factor V Leiden (OR 5.1, 95% CI) and the glycoprotein Ia807T,837T,873A allele (OR 2.3, 95% CI). In thromboangiitis obliterans group, more patients were regular consumers of cannabis (OR 3.5, 95% CI) and higher levels in plasma copper has been shown (OR 6.5, 95% CI).ConclusionsAccording to our results from a non exhaustive list of study parameters, we might hypothesize for 1) a genetic basis for premature peripheral arterial occlusive disease development and 2) the prevalence of environmental factors in the development of thromboangiitis obliterans (tobacco and cannabis). Moreover, for the first time, we demonstrated that the 807T/837T/873A allele of platelet glycoprotein Ia may confer an additional risk for development of peripheral atherosclerosis in premature peripheral arterial occlusive disease.

Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy‐one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16‐86). Eighty‐nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD—6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life‐threatening condition. Physicians working in adult care must be aware of late‐onset presentations given the implications for patients and their families.

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Medium-chain acyl-CoA deshydrogenase deficiency (MCADD) is the most frequent disorder of mitochondrial fatty acid oxidation (MFAO). We report a 3 year-old girl with enterovirus viremia who was referred after 36 hours of fasting with hypoketotic hypoglycemic coma and myolysis. Evolution was complicated by acute renal failure, increased serum levels of transaminases and hypoparathyroidism. Diagnosis of MCADD was supported by typical plasma acylcarnitine and urinary organic acid profiles, and confirmed by homozygosity for the common missense A985G mutation. Whereas myolysis is frequent in MFAO defects, it is rarely reported as a major accompanying sign in MCADD. Hypoparathyroidism has been previously reported in some MFAO deficiencies but has never been mentioned in association with MCADD. We review the possible mechanisms of hypoparathyroidism in MFAO deficiencies. Parathyroid glands and pancreas dysfunction should be screened in MFAO defects as these organs could be implicated in the clinical spectrum of the frequent A985G MCADD disease-causing mutation.