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CD36, a multifunctional protein, is involved in cardiac long chain fatty acid (LCFA) metabolism and in the etiology of heart diseases, yet the functional impact of Cd36 gene variants remains unclear. In 7-week-old spontaneously hypertensive rats (SHR), which, like humans, carry numerous mutations in Cd36, we tested the hypothesis that their restricted cardiac LCFA utilization occurs prior to hypertrophy due to defective CD36 post-translational modifications (PTM), as assessed by ex vivo perfusion of (13)C-labeled substrates and biochemical techniques. Compared to their controls, SHR hearts displayed a lower (i) contribution of LCFA to β-oxidation (-40%) and triglycerides (+2.8 folds), which was not explained by transcriptional changes or malonyl-CoA level, a recognized β-oxidation inhibitor, and (ii) membrane-associated CD36 protein level, but unchanged distribution. Other results demonstrate alterations in CD36 PTM in SHR hearts, specifically by N-glycosylation, and the importance of O-linked-β-N-acetylglucosamine for its membrane recruitment and role in LCFA use in the heart., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Children are growing people. When they are suffering from cancer, they are often malnourished. Their nutritional care must be adapted and form an integral part of the overall treatment. The diet of Léa, a young girl suffering from neuroblastoma, was enriched and adjusted in order to take into account the side effects of her treatment.

Danon disease is an X-linked lysosomal disorder, characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation. We report a family with a novel mutation, in which the mother and her three sons were affected with various clinical presentations. A massive hypertrophy of the left ventricle was the predominant feature in the three male patients, with different degrees of severity of cardiac symptoms, from isolated palpitations to cardiac failure and sudden death. Muscle pain and weakness were also variable, but constantly associated with increased plasma CK levels. Finally, the male patients had variable degree of a mental retardation. The mother had an attenuated phenotype, limited to a mild hypertrophic cardiomyopathy with premature ventricular contractions diagnosed during her 40's. Microscopy examination of skeletal muscle biopsy, performed in the youngest patient, demonstrated atrophic myofibers with intracytoplasmic vacuoles suggesting lysosomal glycogen storage disease. Immunohistochemistry analyses in muscle specimen showed no detectable Lysosomal-Associated Membrane Protein-2 (LAMP-2), in keeping with the diagnosis of Danon disease. However, a very low expression of a shortened LAMP-2 protein could be evidenced by Western-blot in the patient's fibroblasts. Molecular investigations identified a novel splicing mutation (IVS6 + 1delG) in the LAMP-2 gene. This case report highlights the intrafamilial variability of Danon disease phenotype. In this case, morphological examination of muscle biopsy, showing lysosomal storage myopathy, and immunohistochemistry analyses can provide key elements for orienting etiologic investigations.

Fabry disease is an X-linked recessive lysosomal storage disorder caused by α-galactosidase A deficiency. Although the disease presents in childhood, diagnosis is often delayed to adulthood or missed, presumably due to the lack of specificity of the symptoms and to the absence of major complication during the paediatric years. We report a 9-year-old boy known to have a Fabry disease who presented an episode of priapism. Successful treatment was achieved by repeated corporeal aspiration under general anaesthesia. This case is the fifth report of priapism in children with Fabry disease, suggesting that priapism may be a severe vascular complication of the disease during infancy. This report emphasizes the importance of an early diagnosis and treatment of Fabry disease, including enzyme replacement therapy, to prevent major disease-associated morbidity and to optimize patient outcomes., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

NMR spectroscopy of urine samples is able to diagnose many inborn errors of metabolism (IEM). However, urinary metabolites have a poor stability, requiring special care for routine analysis (storage of urine at -20 or -80 degrees C, fast transport). The aim of our study was to investigate the reliability of dried urine filter paper for urine storage and transport and to evaluate the ability of NMR to detect several IEM using this method. Urine samples from five healthy subjects were analyzed by (1)H NMR following different storage conditions (-20 vs 4 degrees C vs dried on filter paper) and at different time points (24 h, 48 h, 96 h, and 7 days). Urine pattern of fresh urine was considered as a reference. We analyzed the conservation of some amino acids and organic acids using Bland and Altman plot with intraclass correlation coefficient determination. Then, we evaluated the use of filter paper to detect four different IEM (methylmalonic and isovaleric acidurias, ornithine transcarbamylase deficiency, and cystinuria). Analysis of urine samples from healthy subjects revealed a high stability of studied molecules (ICC > 0.8) even after 7 days of storage on filter paper. Moreover, an excellent preservation of metabolites specifically accumulated in IEM was observed when analysis of dried urine filter paper was compared to fresh urine (coefficient of variation < 15%). This preliminary study demonstrates that storage of dried urine on filter paper is reliable for (1)H NMR spectroscopy analysis. Preservation of urine molecules over time using that method is convenient for routine clinical practice.

Background: Human metapneumovirus (hMPV), a recently identified respiratory virus, is a leading cause of acute respiratory tract infection in children during winter. The aims of this study were to outline epidemiological and clinical presentations of hMPV infectious diseases in young children., Patients and Methods: A prospective study was conducted from November 2007 to April2008 in children under 2 years of age admitted to the University Children's Hospital of Tours, France, for acute respiratory infection. Nasopharyngeal aspirates were systematically tested for several respiratory viruses. Epidemiological and clinical characteristics of hMPV-infected children were compared to those of patients with respiratory syncytial virus (RSV) and other viral (OTH) infections., Results: A total of 374 children were enrolled in this study. Viral investigations detected 22 (6 %) hMPV infections, 177 (47 %) RSV infections, and 175 (47 %) presumed or demonstrated other viruses. The hMPV infection had a seasonal peak in December, similar to RSV, and was uncommon after January. Most of the patients infected with hMPV were under 1 year of age and bronchiolitis was the predominant diagnosis in 90 % of these patients with clinical symptoms of a lower respiratory tract infection. The severity of the disease, estimated from the requirement of respiratory or nutritional assistance, was similar to those of RSV patients, but was higher than those in the OTH group. hMPV was more frequently detected in patients with chronic pathology, such as bronchopulmonary dysplasia, congenital heart defect, or neuromuscular disorders, and in patients who had been previously admitted for bronchiolitis., Conclusion: These results highlight that hMPV plays an important role in seasonal acute respiratory tract infections in children during winter, with a severity similar to RSV infections., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Objectives: Mitochondrial respiratory chain deficiencies are known for their high clinical variability. Difficult to diagnose, the prevalence of these diseases is probably underestimated., Methods: We report 18 children diagnosed with respiratory chain deficiency at the Tours University Hospital over the past 10 years., Results: Three clinical profiles can be distinguished depending on the age at onset of the first symptoms: the neonatal period (4 cases), between 1 month and 2 years of age (10 cases), and after 10 years (4 cases). However, no clinical feature appears specific of any age group. In contrast, respiratory chain analysis on liver biopsy was very informative for all our patients at any age and with any clinical presentation, even with predominant neurological symptoms., Conclusions: These biochemical analyses support the diagnosis of mitochondrial disorders in view of molecular analysis, which nevertheless frequently remains inconclusive. These investigations should benefit from the new molecular screening technologies based on DNA chips that can identify the genomic mutations responsible for these severe and relatively frequent diseases.

We report the case of a 9-year-old girl with a long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. This enzyme participates in mitochondrial fatty acid B-oxidation. Genetic fatty acid oxidation defects induce cellular energetic deficiency, and thus early life-threatening manifestations. An appropriate diet prevents these severe disorders. Nevertheless, LCHAD deficiency is the only B-oxidation enzymatic disorder that induces a chorioretinopathy, predominating at the posterior pole. We describe the first case of bilateral macular choroidal neovascularization. One eye presented a fibrovascular lesion. The other eye presented an active neovascularization stabilized by two dynamic phototherapies. The specificity of choroidal degeneration related to LCHAD deficiency remains unknown. Reviewing of literature and biochemical mechanisms suggests that fatty acid oxidative stress rather than a mitochondrial energetic defect is involved. For practical purposes, this report emphasizes the importance of ophthalmological follow-up of these patients.

Pompe disease is an autosomal recessive glycogen storage disorder caused by acid-alpha-glucosidase deficiency. The infantile form is usually fatal by 1 year of age in the absence of specific therapy. We report the cardiac follow-up of a 4-month-old boy treated with enzyme replacement therapy (ERT) for 8 months. The patient had no cardiac failure at the age of 1 year. Before starting ERT, ECG showed a shortened PR interval, with huge QRS complexes and biventricular hypertrophy; echocardiography demonstrated major hypertrophic cardiomyopathy. The QRS voltage (SV1+RV6) decreased from 13 to 2.9 mV after 32 weeks of ERT, suggesting a progressive reduction of cardiac hypertrophy and intracellular glycogen excess. The PR interval increased from 60 to 90 ms. A block of the right bundle branch appeared after 13 weeks of treatment. The indexed left ventricular mass decreased from 240 to 90 g/m2 after 30 weeks of ERT. The left ventricular ejection fraction decreased transitorily between the 5th and the 15 th weeks of treatment. In summary, ERT is an efficient therapeutic approach for the cardiomyopathy of infantile Pompe disease. However, the possible occurrence of a right bundle branch block and a transitory alteration in the ejection fraction highlight the importance of cardiac follow-up.

Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA beta-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in the myocardial utilization of CHOs for energy production and anaplerosis in 12-wk-old peroxisome proliferator-activating receptor-alpha (PPARalpha) null mice (a model of FA beta-oxidation defects). Carbon-13 methodology was used to assess substrate flux through energy-yielding pathways in hearts perfused ex vivo at two workloads with a physiological substrate mixture mimicking the fed state, and real-time RT-quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. When compared with that from control C57BL/6 mice, isolated working hearts from PPARalpha null mice displayed an impaired capacity to withstand a rise in preload (mimicking an increased venous return as it occurs during exercise) as reflected by a 20% decline in the aortic flow rate. At the metabolic level, beyond the expected shift from FA (5-fold down) to CHO (1.5-fold up; P < 0.001) at both preloads, PPARalpha null hearts also displayed 1) a significantly greater contribution of exogenous lactate and glucose and/or glycogen (2-fold up) to endogenous pyruvate formation, whereas that of exogenous pyruvate remained unchanged and 2) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was affected differently by preloads in control and PPARalpha null mouse hearts, suggesting a restricted reserve for the latter hearts to enhance glycolysis when the energy demand is increased. Alterations in the expression of some glycolysis-related genes suggest potential mechanisms involved in this defective CHO metabolism. Collectively, our data highlight the importance of metabolic alterations in CHO metabolism associated with FA oxidation defects as a factor that may predispose the heart to decompensation under stress conditions even in the fed state.

Introduction: Medium-chain fatty acids (MCFAs) have physical and metabolic properties that are distinct from those of long-chain fatty acids, which make them a readily available cellular energy source. These properties have been used advantageously in the clinics for more than 50 years for treating lipid absorption disorders, undernourished patients, and more recently subjects with long-chain fatty acid oxidation defects. In these latter subjects, nutritional interventions with MCFA-containing triglycerides have been shown to improve clinical symptoms, particularly cardiomyopathies., Potential Benefits of Mcfa Metabolism in Cardiac Diseases: There is, however, only a limited number of studies that have considered the potential use of MCFAs as metabolic therapy for cardiac diseases in general. Nevertheless, current experimental evidence does support the notion that the diseased heart is energy deficient and that alterations in myocardial energy substrate metabolism contribute to contractile dysfunction and cardiac disease development and progression. Hence, this article will review current literature on MCFAs with a specific emphasis on their metabolism and potential benefits for the heart. It will include practical considerations about the potential clinical application of MCFA therapy for the management of patients with cardiac diseases.

Background: Menkes disease is a rare X-linked disorder due to a defect in intracellular copper transport. Clinical symptoms appear during the first months of life, with a progressive developmental delay leading to death within a few years. Diagnosis is confirmed by the demonstration of copper retention in fibroblasts and/or DNA testing. However, these investigations are complexes and time consuming., Case Report: We report 1 case of Menkes disease with neonatal onset, diagnosed on multiple organ failure, hypothermia, and major central nervous system damage, leading to death in a few weeks. The diagnosis, suggested by the clinical features, was rapidly supported by the microscopic examination of the hairs, showing pili torti, and the demonstration of severely decreased levels of plasma copper and ceruloplasmin. Diagnosis was further confirmed by the demonstration of an increased copper uptake and retention in fibroblasts., Conclusion: This report highlights the clinical variability of Menkes disease with the possibility of a neonatal onset. Microscopic examination of the hairs and the determination of copper and ceruloplasmin plasma levels are simple and inexpensive investigations, which can provide rapidly valuable information to support this diagnosis.

Background: The mucopolysaccharidoses (MPS) form a group of heterogeneous hereditary lysosomal storage diseases, distinguished by facial dysmorphy in gargoyle-like facies. The enzymatic deficiency involves the degradation of glycosaminoglycans, whose accumulation manifests in severe general and ophthalmologic problems., Cases Report: We report the cases of two 18-month-old girls consulting for corneal clouding and photophobia. The diagnosis was made based on the facial dysmorphy, then biologically corroborated: Scheie's syndrome (MPS type I-S) and Hurler's syndrome (MPS type I-H). The corneal clouding was isolated or associated with bilateral disc swelling. Enzyme replacement therapy was instituted in both cases while waiting for bone marrow transplantation, with a better prognosis in the first case because of the type of MPS and the less severe neurological involvement., Discussion: The accumulation of glycosaminoglycans in ocular tissues can involve stromal opacities, glaucoma, retinopathy, and optic nerve swelling. Whereas the ophthalmological involvement is often secondary, it can lead the ophthalmologist to the diagnosis of MPS. The early diagnosis of MPS, before the onset of neurological signs, is vital, since treatment can stop disease progression., Conclusion: Better knowledge of the clinical signs of MPS on the part of the ophthalmologists could improve the prognosis of these patients.

Unlabelled: "Air swallowing" described as being part of functional gastrointestinal disorders in "Rome criteria" in 1999 is often misdiagnosed, particularly in non-mentally deficient children., Aims: To recognize "air swallowing" child and to describe any progress according to the treatment., Population and Methods: This retrospective study reports 13 cases of children without mental deficiency or neuromuscular disease. Clinical elements and precise histories are detailed and we have contacted consulting doctors or families for news., Results: Ten boys and 3 girls, from 2,5 years to 10 years old, were referred for long lasting pain or abdominal distension. Numerous laboratory investigations were always normal. Diagnosis relied upon the observation of air swallowing and X-Rays views of gastric distension. Air swallowing was observed 7 times, 9 children had twitches and 3 language troubles. In 10 cases, X-rays showed gastric and colic distension. Three children have Chilaïditi syndrome. Favourable results followed in 12 cases after an average of 28 months of treatment. One case was lost for follow-up. Treatment was long, often disappointing and required the intervention of a psychiatrist, a paediatrician and (temporarily) a speech therapist., Conclusion: Pathological childhood aerophagia is often underdiagnosed and deserves to be better known by paediatricians, psychiatrists and surgeons. A late diagnosis leads to many negative results and causes anxiety. An early diagnosis should lead to a multidisciplinary care.

The mitochondrial trifunctional protein (MTP) catalyzes the last three steps in the long-chain fatty acid beta-oxidation pathway. We report herein a patient with an inherited MTP deficiency and hypoparathyroidism that were both revealed at 4 months of age. Although parathyroid function appeared to be normalized following nutritional management of the fatty acid beta-oxidation defect, persistent gland dysfunction was suggested by frequent mild episodes of hypocalcaemia without increase in plasma intact parathyroid hormone (iPTH) levels during recurrent fasting-induced episodes of rhabdomyolysis and by our finding of a bilateral cataract at 5 years of age. An acute provocation test conducted to stimulate iPTH release with sodium bicarbonate infusion resulted in a subnormal rise in iPTH release, which further supported a partial hypoparathyroidism. This case is the third report of inherited MTP deficiency associated with hypoparathyroidism, thus raising the possibility of a link between these two rare disorders.

Background/aims: The aim of this study was to delineate the specific clinical, biological and liver morphological alterations of the hepatocerebral syndrome due to alterations in the deoxyguanosine kinase gene, a rare and severe form of mitochondrial DNA depletion syndrome., Methods: We report seven cases from three unrelated families with the same mutation in the deoxyguanosine kinase gene., Results: All the patients presented in the first weeks of life with hepatomegaly and progressive liver failure that led to death few months later. Major psychomotor delay and multidirectional nystagmus were reported shortly after onset of the disease. Severe hyperlactacidaemia was constant. Histological examination of the liver disclosed a multifocal injury of hepatocytes with irregular foamy steatosis, cholestasis, and fibrosis, associated with different degrees of hepatosiderosis and glycogen depletion. Liver respiratory chain activities were abnormal in all analysed patients and the amount of liver mitochondrial DNA was severely decreased. An identical homozygous 4bp GATT duplication was identified in the deoxyguanosine kinase gene of all the cases., Conclusions: These patients, together with patients reported in the literature, permit to delineate the specific features of the hepatocerebral form of mitochondrial DNA depletion syndrome and to differentiate them from other causes of neonatal liver failure.

The spontaneously hypertensive rat (SHR) is a model of cardiomyopathy characterized by a restricted use of exogenous long-chain fatty acid (LCFA) for energy production. The aims of the present study were to document the functional and metabolic response of the SHR heart under conditions of increased energy demand and the effects of a medium-chain fatty acid (MCFA; octanoate) supplementation in this situation. Hearts were perfused ex vivo in a working mode with physiological concentrations of substrates and hormones and subjected to an adrenergic stimulation (epinephrine, 10 microM). (13)C-labeled substrates were used to assess substrate selection for energy production. Compared with control Wistar rat hearts, SHR hearts showed an impaired response to the adrenergic stimulation as reflected by 1) a smaller increase in contractility and developed pressure, 2) a faster decline in the aortic flow, and 3) greater cardiac tissue damage (lactate dehydrogenase release: 1,577 +/- 118 vs. 825 +/- 44 mU/min, P < 0.01). At the metabolic level, SHR hearts presented 1) a reduced exogenous LCFA contribution to the citric acid cycle flux (16 +/- 1 vs. 44 +/- 4%, P < 0.001) and an enhanced contribution of endogenous substrates (20 +/- 4 vs. 1 +/- 4%, P < 0.01); and 2) an increased lactate production from glycolysis, with a greater lactate-to-pyruvate production ratio. Addition of 0.2 mM octanoate reduced lactate dehydrogenase release (1,145 +/- 155 vs. 1,890 +/- 89 mU/min, P < 0.001) and increased exogenous fatty acid contribution to energy metabolism (23.7 +/- 1.3 vs. 15.8 +/- 0.8%, P < 0.01), which was accompanied by an equivalent decrease in unlabeled endogenous substrate contribution, possibly triglycerides (11.6 +/- 1.5 vs. 19.0 +/- 1.2%, P < 0.01). Taken altogether, these results demonstrate that the SHR heart shows an impaired capacity to withstand an acute adrenergic stress, which can be improved by increasing the contribution of exogenous fatty acid oxidation to energy production by MCFA supplementation.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. This condition usually presents in neonates or children. This report describes the clinical case of a 21 year old woman who was diagnosed in adulthood during the course of an unexplained coma. After recovery from the coma, she presented very unusual neuropsychological disorders involving memory and the meaning of certain words, suggesting a semantic deficit. The discovery of OTCD in adulthood is rare and the neuropsychological consequences may be unique.

The availability of genetically modified mice requires the development of methods to assess heart function and metabolism in the intact beating organ. With the use of radioactive substrates and ex vivo perfusion of the mouse heart in the working mode, previous studies have documented glucose and fatty acid oxidation pathways. This study was aimed at characterizing the metabolism of other potentially important exogenous carbohydrate sources, namely, lactate and pyruvate. This was achieved by using (13)C-labeling methods. The mouse heart perfusion setup and buffer composition were optimized to reproduce conditions close to the in vivo milieu in terms of workload, cardiac functions, and substrate-hormone supply to the heart (11 mM glucose, 0.8 nM insulin, 50 microM carnitine, 1.5 mM lactate, 0.2 mM pyruvate, 5 nM epinephrine, 0.7 mM oleate, and 3% albumin). The use of three differentially (13)C-labeled carbohydrates and a (13)C-labeled long-chain fatty acid allowed the quantitative assessment of the metabolic origin and fate of tissue pyruvate as well as the relative contribution of substrates feeding acetyl-CoA (pyruvate and fatty acids) and oxaloacetate (pyruvate) for mitochondrial citrate synthesis. Beyond concurring with the notion that the mouse heart preferentially uses fatty acids for energy production (63.5 +/- 3.9%) and regulates its fuel selection according to the Randle cycle, our study reports for the first time in the mouse heart the following findings. First, exogenous lactate is the major carbohydrate contributing to pyruvate formation (42.0 +/- 2.3%). Second, lactate and pyruvate are constantly being taken up and released by the heart, supporting the concept of compartmentation of lactate and glucose metabolism. Finally, mitochondrial anaplerotic pyruvate carboxylation and citrate efflux represent 4.9 +/- 1.8 and 0.8 +/- 0.1%, respectively, of the citric acid cycle flux and are modulated by substrate supply. The described (13)C-labeling strategy combined with an experimental setup that enables continuous monitoring of physiological parameters offers a unique model to clarify the link between metabolic alterations, cardiac dysfunction, and disease development.

Objective: To describe three female patients of one family with different phenotypes of the same mutation of the ornithine transcarbamylase gene. X-linked inherited ornithine transcarbamylase deficiency is the most frequent urea cycle disorder. Many of the hemizygous males die during the neonatal period. Women, who are mostly healthy carriers, can also develop symptomatic hyperammonemia., Design: Case study., Setting: Intensive care unit and internal medicine unit at a university hospital., Patients: The 20-yr-old female propositus was hospitalized for unexplained coma. She had a history of headaches, recurrent vomiting, specific anorexia for high-protein foods, and an acute neurologic crisis with alleged food poisoning 8 yrs before. The present episode began with psychiatric symptoms and seizures treated by diazepam and valproate. This unexplained coma, associated with respiratory alkalosis and major brain swelling on brain computed tomography scan, revealed hyperammonemia leading to the diagnosis of ornithine transcarbamylase deficiency. Continuous venovenous hemodiafiltration and treatment with sodium benzoate and phenylbutyrate improved the situation. However, the patient had some neurologic sequelae. DNA studies have disclosed a pathogenic mutation in the ornithine transcarbamylase gene of the patient, her mother, and her sister. For the mother, the disease was overlooked despite the onset of unusual headaches and neurologic signs that mimicked a cerebral tumor 12 yrs before. The 28-yr-old sister of the propositus has always been asymptomatic, even during pregnancy., Conclusions: Diagnosis of urea cycle disorder should be considered in any patient with unexplained neurologic and psychiatric disorders with selective anorexia, even in adulthood. Unexplained coma with cerebral edema and respiratory alkalosis requires urgent measurement of ammonemia and metabolic work-up.