Focus: Rare Disease: Neuromonitoring in Rare Disorders of Metabolism

Inborn errors of metabolism (IEM) are a unique class of genetic diseases due to mutations in genes involved in key metabolic pathways. The combined incidence of IEM has been estimated to be as high as 1:1000. Urea Cycle disorders (UCD), one class of IEM, can present with cerebral edema and represent a possible target to explore the utility of different neuromonitoring techniques during an hyperammonemic crisis. The last two decades have brought advances in the early identification and comprehensive management of UCD, including further understanding of neuroimaging patterns associated with neurocognitive function. Nonetheless, very important questions remain about the potential acute neurotoxic effects of hyperammonemia to better understand how to treat and prevent secondary brain injury. In this review, we describe existing neuromonitoring techniques that have been used in rare metabolic disorders to assess and allow amelioration of ongoing brain injury. Directions of future research should be focused on identifying new diagnostic approaches in the management of metabolic crises to optimize care and reduce long term morbidity and mortality in patients with IEM.     

Novel Developments in Metabolic Disorders of Purine and Pyrimidine Metabolism and Therapeutic Applications of Their Analogs

The biennial 15^th symposium on Purine and Pyrimidine metabolism was held in Madrid, June 2013 (PP13). During the meeting, several novel developments on the diagnosis, pathophysiology, and treatment of several inborn errors of purine and pyrimidine metabolism were presented. These ranged from new drugs for gout to enzyme replacement therapies for mitochondrial diseases. A relatively novel aspect in this meeting was the interest in purine and pyrimidine metabolism in nonmammalian systems, such as parasites, mycoplasms, and bacteria. Development of novel analogs for parasite infections, cardiovascular diseases, inflammatory diseases, and cancer were also discussed.     

筛选选择性降解玉米秸皮的菌株

目的:筛选能选择性降解玉米秸皮的菌株,用于玉米秸皮生物机械法制浆的研究。方法:采用Bavendamm-PDA平板对玉米种植地土壤内的真菌进行初筛选,之后采用玉米秸皮降解实验对产生棕色变色圈的菌株和实验室现有白腐菌进行复筛选。结果:筛选到4株能在Bavendamm-PDA平板上产生棕色变色圈的菌株;降解实验显示杂色云芝引起了最大31.76%的重量损失,重量损失最小的菌株为粗毛栓菌lg-9;除杂色云芝和白耙齿菌降低了玉米秸皮苯醇抽出物外,其他处理样均增加;碳水化合物测定结果表明白耙齿菌处理样综纤维素的损失最大,且各种菌株所引起的综纤维素损失中,纤维素和聚戊糖损失所占的比例有很大差别。结论:粗毛栓菌lg-9对玉米秸皮木素降解的选择性最强,之后为Sd、黄袍原毛平革菌-14和黄袍原毛平革菌-25。     

An HPLC-Based Assay of Adenylosuccinate Lyase in Erythrocytes

ADSL deficiency is a disorder of purine metabolism with a broad clinical spectrum. A rapid and simple HPLC-based assay to measure ADSL activity in erythrocytes was developed. The suitability of DBSs was assessed. ADSL activity was measured in erythrocyte lysates and DBS using succinyl-AMP as the substrate. Detection and quantification were performed using isocratic ion-pairing reversed-phase HPLC with UV-detection. Reference values in erythrocyte lysates were established. The intra- and interassay variations were 2% and 8%, respectively. ADSL deficiency was easily recognized. ADSL activity in DBS was highly unstable, disqualifying DBS for diagnostic procedures.     

Common Chromosomal Fragile Site Gene WWOX in Metabolic Disorders and Tumors

WWOX, a gene that spans the second most common chromosomal fragile site (FRA16D), often exhibits homozygous deletions and translocation breakpoints under multiple cellular stresses induced by extrinsic or intrinsic factors, such as hypoxia, UV, and DNA damage regents. Loss of WWOX is closely related to genomic instability, tumorigenesis, cancer progression and therapy resistance. WWOX heterozygous knockout mice show an increased incidence of spontaneous or induced tumors. WWOX can interact via the WW domain with proteins that possess proline PPxY motifs and is involved in a variety of cellular processes. Accumulating evidence has shown that WWOX that contains a short-chain dehydrogenase/reductase (SDR) domain is involved in steroid metabolism and bone development. Reduced or lost expression of WWOX will lead to development of metabolic disease. In this review, we focus on the roles of WWOX in metabolic disorders and tumors.     

BMI and Metabolic Disorders in South Korean Adults: 1998 Korea National Health and Nutrition Survey

Objective: The prevalence of overweight, obesity, and metabolic disorders and their relationship with BMI were studied in South Korean adults. The appropriate BMI categories for overweight and obesity for Koreans were evaluated. Research Methods and Procedures: The 1998 Korea National Health and Nutrition Examination Survey was the first such survey, to our knowledge, conducted on a cross‐sectional and nationally representative population. The survey provided data on body weight; height; fasting serum glucose; triacylglycerol; total, low‐density lipoprotein, and high‐density lipoprotein cholesterol; blood pressure; and various other questions that were incorporated into this study. A total of 39, 060 persons over the age of 1 year from 12, 283 households participated in the Health and Nutrition Interview Survey. Of these, 10, 876 people over the age of 10 years old participated in the Health Examination. We analyzed data from 7962 adults over the age of 20 years old. Results: The overweight (BMI, ≥25.0 to <30.0) and obesity (BMI, ≥30) rates were low among Korean adults: 23.4% and 1.7% in men and 24.9% and 3.2% in women, respectively. However, the prevalences of diabetes, hypertension, and abnormal concentrations of serum triacylglycerol and total, low‐density lipoprotein, and high‐density lipoprotein cholesterol were high at 10.5%, 27.1%, 29.0%, 34.5%, 28.4%, and 37.4%, respectively. These disorders were age dependent, and, in general, there was a strong linear relationship between BMI and the disorders. The relative risk of disorders doubled at a BMI of 23.0 to 24.0 and tripled at a BMI of 26.0, compared with a baseline BMI of 18.5 to 22.0. Discussion: High rates of diabetes, hypertension, and dyslipidemia were noted in middle‐aged and elderly Koreans even at relatively low BMI. It might be appropriate to lower the BMI classification from the current ≥25.0 for overweight and ≥30.0 for obesity for this group of Koreans.     

Putative Mechanisms Underlying the Beneficial Effects of Polyphenols in Murine Models of Metabolic Disorders in Relation to Gut Microbiota

The beneficial effects of polyphenols on metabolic disorders have been extensively reported. The interaction of these compounds with the gut microbiota has been the focus of recent studies. In this review, we explored the fundamental mechanisms underlying the beneficial effects of polyphenols in relation to the gut microbiota in murine models of metabolic disorders. We analyzed the effects of polyphenols on three murine models of metabolic disorders, namely, models of a high-fat diet (HFD)-induced metabolic disorder, dextran sulfate sodium (DSS)-induced colitis, and a metabolic disorder not associated with HFD or DSS. Regardless of the model, polyphenols ameliorated the effects of metabolic disorders by alleviating intestinal oxidative stress, improving inflammatory status, and improving intestinal barrier function, as well as by modulating gut microbiota, for example, by increasing the abundance of short-chain fatty acid-producing bacteria. Consequently, polyphenols reduce circulating lipopolysaccharide levels, thereby improving inflammatory status and alleviating oxidative imbalance at the lesion sites. In conclusion, polyphenols likely act by regulating intestinal functions, including the gut microbiota, and may be a safe and suitable therapeutic agent for various metabolic disorders.     

Evaluation of oxidative stress markers and cardiovascular risk factors in Fabry Disease patients

Fabry Disease, an X-linked inborn error of metabolism, is characterized by progressive renal insufficiency, with cardio and cerebrovascular involvement. Homocysteine (Hcy) is considered a risk factor for vascular diseases, but the mechanisms by which it produces cardiovascular damage are still poorly understood. Regarding the vascular involvement in FD patients, the analysis of factors related to thromboembolic events could be useful to improving our understanding of the disease. The aim of this study was to evaluate plasma Hcy and other parameters involved in the methionine cycle, as well as oxidative stress markers. The sample consisted of a group of 10 male FD patients and a control group of 8 healthy individuals, paired by age. Venous blood was collected for Hcy determination, molecular analysis, identification of thiobarbituric acid reactive substances, total glutathione and antioxidant enzymes activity, as well as vitamins quantification. Comparative analysis of FD patients versus the control group indicated hyperhomocysteinemia in 8 of the 10 FD patients, as well as a significant increase in overall glutathione levels and catalase activity. It is inferred that FD patients, apart from activation of the antioxidant system, present increased levels of plasma Hcy, although this is probably unrelated to common alterations in the methionine cycle.     

A newborn screening method for cerebrotendinous xanthomatosis using bile alcohol glucuronides and metabolite ratios

Cerebrotendinous xanthomatosis (CTX) is a treatable neurodegenerative metabolic disorder of bile acid synthesis in which symptoms can be prevented if treatment with chenodeoxycholic acid supplementation is initiated early in life, making CTX an excellent candidate for newborn screening. We developed a new dried blood spot (DBS) screening assay for this disorder on the basis of different ratios between the accumulating cholestanetetrol glucuronide (tetrol) and specific bile acids/bile acid intermediates, without the need for derivatization. A quarter-inch DBS punch was extracted with methanol, internal standards were added, and after concentration the extract was injected into the tandem mass spectrometer using a 2 min flow injection analysis for which specific transitions were measured for cholestanetetrol glucuronide, taurochenodeoxycholic acid (t-CDCA), and taurotrihydroxycholestanoic acid (t-THCA). A proof-of-principle experiment was performed using 217 Guthrie cards from healthy term/preterm newborns, CTX patients, and Zellweger patients. Using two calculated biomarkers, tetrol:t-CDCA and t-THCA:tetrol, this straightforward method achieved an excellent separation between DBSs of CTX patients and those of controls, Zellweger patients, and newborns with cholestasis. The results of this small pilot study indicate that the tetrol:t-CDCA ratio is an excellent derived biomarker for CTX that has the potential to be used in neonatal screening programs.     

Population energy use scales positively with body size in natural aquatic microcosms

Aim  We test the 'energetic equivalence rule' (EER) – the idea that the amount of energy used by a population per unit area per unit time is independent of body mass – in meio-invertebrate communities from a series of natural, multitrophic aquatic 'rock pool' microcosms. Our study represents the first rigorous test of the EER at local scales of observation in a community of naturally coexisting species.
Location  Discovery Bay, Jamaica.
Method  We estimated population energy use (PEU) for every occurrence of every species of meio-invertebrate fauna found in each of 29 microcosms (233 observations of 31 species) using estimates of population density obtained in January 2005 in combination with published metabolism–mass relations for closely related taxa.
Results  In the rock pool system as a whole, population density decreased ( ancova : b  = –0.38 (–0.55 to –0.19), r ² = 0.19, P  < 0.001) and PEU increased with body mass ( ancova : b  = 0.55 (0.36–0.73), r ² = 0.28, P  < 0.001).
Main conclusions  The positive PEU–body mass relation found here suggests that larger organisms are energetically dominant and points to the importance of size-structured competition in these systems. Our results contrast those obtained in the few other previously published tests of the EER and challenge the idea that all species use similar amounts of energy regardless of their size.     

Metabolic engineering for the production of plant isoquinoline alkaloids

Several plant isoquinoline alkaloids (PIAs) possess powerful pharmaceutical and biotechnological properties. Thus, PIA metabolism and its fascinating molecules, including morphine, colchicine and galanthamine, have attracted the attention of both the industry and researchers involved in plant science, biochemistry, chemical bioengineering and medicine. Currently, access and availability of high‐value PIAs [commercialized (e.g. galanthamine) or not (e.g. narciclasine)] is limited by low concentration in nature, lack of cultivation or geographic access, seasonal production and risk of overharvesting wild plant species. Nevertheless, most commercial PIAs are still extracted from plant sources. Efforts to improve the production of PIA have largely been impaired by the lack of knowledge on PIA metabolism. With the development and integration of next‐generation sequencing technologies, high‐throughput proteomics and metabolomics analyses and bioinformatics, systems biology was used to unravel metabolic pathways allowing the use of metabolic engineering and synthetic biology approaches to increase production of valuable PIAs. Metabolic engineering provides opportunity to overcome issues related to restricted availability, diversification and productivity of plant alkaloids. Engineered plant, plant cells and microbial cell cultures can act as biofactories by offering their metabolic machinery for the purpose of optimizing the conditions and increasing the productivity of a specific alkaloid. In this article, is presented an update on the production of PIA in engineered plant, plant cell cultures and heterologous micro‐organisms.     

Possible role for protein kinase C in the pathogenesis of inborn errors of metabolism

Protein kinase C (PKC) is a ubiquitous enzyme family implicated in the regulation of a large number of short- and long-term intracellular processes. It is hypothesized that modulation of PKC activity may represent, at least in part, a functional link between mutations (genotype) that lead to the pathological accumulation of naturally occurring compounds that affect PKC activity and perturbation of PKC-mediated substrate phosphorylation and cellular function in the corresponding diseases (phenotype). This model provides a unifying putative mechanism by which the phenotypic expression of some inborn errors of metabolism may be explained. Recent studies in a cell-free system of human skin fibroblasts support the hypothesis that alteration of PKC activity may represent the functional link between accumulation of sphingolipids and fatty acyl-CoA esters, and perturbation of cell function in sphingolipidoses and fatty acid oxidation defects, respectively. Further studies will elucidate the effects of these alterations on PKC-mediated short- and long-term cellular functions in these diseases, as well as the possible role of PKC in the pathogensis of other diseases. © 1995 Wiley-Liss, Inc.     

Improving Influenza Vaccination Coverage in the Pediatric Asthma Population: The Case for Combined Methodologies

The Advisory Committee on Immunization Practices recommends annual influenza vaccine for pediatric asthma patients. Despite considerable risk for influenza complications in pediatric asthma patients, including hospitalization and death, influenza vaccination among children with asthma remains low, especially among low-income pediatric asthma patients. Multiple interventions have been attempted to increase immunization in the pediatric asthma population, including recall and reminders, parent/patient education, and physician education. More recently, information technology methods have been employed, including electronic alerts and computerized physician order entry/clinical decision support interventions. Each of these interventions, as well as a recent legislative intervention, has evidence of effectiveness, but none achieved the Healthy People 2020 vaccination goals of 80 percent for this population. This goal may be achievable with a combination of these methodologies and strategies that increase access to care for underserved patients.     

Prevalence of the Metabolic Syndrome in a Bulgarian Female Population Referred for Bone Density Testing

Objective: To investigate the prevalence of the metabolic syndrome in Bulgarian women referred for bone density screening. Research Methods and Procedures: This was a cross‐sectional clinical study. Subjects were 444 consecutive 30‐ to 75‐year‐old Bulgarian women recruited from the outpatients referred for bone density testing (mean age, 52.67 ± 15.19 years; mean BMI, 26.10 ± 5.71 kg/m²). Height (centimeters), weight (kilograms), and blood pressure were measured. BMI and waist‐to‐hip ratio were calculated. Fasting plasma glucose, blood lipids, and immunoreactive insulinemia (Bayer Corp.‐Diagnostics Div., Tarrytown, NY) were determined. Body composition was analyzed by bioimpedance on a leg‐to‐leg analyser (Tanita TBF‐215; Tanita Corporation, Tokyo, Japan). Results: Of all women, 56.76% had a BMI > 25 kg/m², 45.95% had a waist circumference > 88 cm, and 64.64% had a waist‐to‐hip ratio > 0.8; 59.90% had hypertension; 4.05% had fasting plasma glucose > 7.0 mM, and 42.79% had fasting morning immunoreactive insulinemia = 16 UI/liter; 23.65% had hypercholesterolemia; and 26.35% had hypertriglyceridemia. The prevalence of the metabolic syndrome in this sample, as defined by the National Cholesterol and Education Program‐Adult Treatment Panel III, was 34.91%, and by the modified World Health Organization definition was 37.16%. Discussion: We concluded that Bulgarian women 30 to 75 years old referred for bone density testing have a high prevalence of the metabolic syndrome. Therefore, large‐scale prevention programs are needed in this field.     

肠道菌群与代谢性综合征的关系及其运动干预效果的研究进展

人体肠道是一个复杂的微生态系统,栖息着数量、种类繁多的微生物,其中数目最庞大的微生物为肠道菌群,肠道微生物群落被认为是人体中的第二个基因组.诸多研究表明它们影响着机体许多功能,与代谢性疾病的发生有重要联系.运动干预能极大地改善肠道菌群和促进宿主的健康.通过查阅最近几年肠道菌群与代谢性综合征的资料,探索肠道菌群与代谢性综...     

Combinatorial CRISPR-Cas9 Metabolic Screens Reveal Critical Redox Control Points Dependent on the KEAP1-NRF2 Regulatory Axis

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Thirteen Years Experience with Selective Screening for Disorders in Purine and Pyrimidine Metabolism

Purine and pyrimidine disorders represent a heterogeneous group with variable clinical symptoms and low prevalence rate. In the last thirteen years, we have studied urine/plasma specimens from about 1600 patients and we have identified 35 patients: eight patients with adenylosuccinate lyase deficiency, eight patients with hypoxanthine-guanine phosphoribosyltransferase deficiency, one patient with purine nucleoside phosphorylase deficiency, ten patients with xanthine dehydrogenase deficiency, six patients with molybdenum cofactor deficiency and two patients with dihydropyrimidine dehydrogenase deficiency.

Despite low incidence of these diseases, our findings highlight the importance of including the purine and pyrimidine analysis in the selective screening for inborn errors of metabolism in specialized laboratories, where amino acid and organic acid disorders are simultaneously investigated.