Malonyl coenzyme A decarboxylase deficiency with a novel mutation.

Malonyl-CoA, a product of acetyl-CoA carboxylase is a metabolic intermediate in lipogenic tissues that include liver and adipose tissue, where it is involved in the de novo fatty acid synthesis and elongation. Malonyl-CoA decarboxylase (MLYCD, E.C.4.1.1.9), a 55-kDa enzyme catalyses the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide, thus providing a route for disposal of malonyl-CoA from mitochondria and peroxisomes, whereas in the cytosol, the malonyl-CoA pool is regulated by the balance of MLYCD and acetyl-CoA carboxylase activities. So far, 34 cases with different MLYCD gene defects comprising point mutations, stop codons, and frameshift mutations have been reported in the literature. Here, we describe the follow-up of a patient affected by malonic aciduria upon neonatal onset. Molecular analysis showed novel homozygous mutations in the MLYCD gene. Our findings expand the number of reported cases and add a novel variant to the repertoire of MLYCD mutations.

Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities.

Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin-glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.

Un trastorno poco frecuente del ciclo de la urea en un recién nacido: deficiencia de N-acetilglutamato sintasa / A rare urea cycle disorder in a neonate: N-acetylglutamate synthetase deficiency

Los trastornos del ciclo de la urea (TCU) son enfermedades hereditarias con un posible desenlace desfavorable por hiperamoniemia grave. Se informa de una bebé con deficiencia de N-acetilglutamato sintasa (NAGS), quien tenía succión débil e hipotonicidad. Al examinarla, se observó hepatomegalia. El hemograma, los análisis y la gasometría eran normales, y las proteínas de la fase aguda, negativas. En los análisis, no se observaron cetonas en sangre, pero sí concentraciones elevadas de amoníaco. Las pruebas metabólicas no fueron concluyentes. Se inició el tratamiento de emergencia inmediatamente y recibió el alta el día 15 después del ingreso. Se confirmó deficiencia de NAGS mediante análisis de ADN. La paciente no tiene restricciones alimentarias ni toma medicamentos, excepto N-carbamil glutamato (NCG). La deficiencia de NAGS es el único TCU que puede tratarse específica y eficazmente con NCG. La detección temprana permite iniciar un tratamiento temprano y evitar los efectos devastadores de la hiperamoniemia

Urea cycle disorders (UCD), are genetically inherited diseases that may have a poor outcome due to to profound hyperammonemia. We report the case of a baby girl diagnosed as N-acetylglutamate synthase (NAGS) deficiency.The patient was evaluated due to diminished sucking and hypotonicity. Physical examination showed hepatomegaly. Complete blood count, biochemical values and blood gas analyses were normal, acute phase reactants were negative. Further laboratory analyses showed no ketones in blood and highly elevated ammonia. Metabolic tests were inconclusive. Emergency treatment was initiated immediately and she was discharged on the 15th day of admission. NAGS deficiency was confirmed by DNA-analysis. She is now without any dietary restriction or other medication, except N-carbamylglutamate (NCG).NAGS deficiency is the only UCD which can be specifically and effectively treated by NCG. Early recognition of disease will lead to early treatment that may prohibit devastating effects of hyperammonemia

A rare urea cycle disorder in a neonate: N-acetylglutamate synthetase deficiency. / Un trastorno poco frecuente del ciclo de la urea en un recién nacido: deficiencia de N-acetilglutamato sintasa.

Urea cycle disorders (UCD), are genetically inherited diseases that may have a poor outcome due to to profound hyperammonemia. We report the case of a baby girl diagnosed as N-acetylglutamate synthase (NAGS) deficiency. The patient was evaluated due to diminished sucking and hypotonicity. Physical examination showed hepatomegaly. Complete blood count, biochemical values and blood gas analyses were normal, acute phase reactants were negative. Further laboratory analyses showed no ketones in blood and highly elevated ammonia. Metabolic tests were inconclusive. Emergency treatment was initiated immediately and she was discharged on the 15th day of admission. NAGS deficiency was confirmed by DNA-analysis. She is now without any dietary restriction or other medication, except N-carbamylglutamate (NCG). NAGS deficiency is the only UCD which can be specifically and effectively treated by NCG. Early recognition of disease will lead to early treatment that may prohibit devastating effects of hyperammonemia.

Los trastornos del ciclo de la urea (TCU) son enfermedades hereditarias con un posible desenlace desfavorable por hiperamoniemia grave. Se informa de una bebé con deficiencia de N-acetilglutamato sintasa (NAGS), quien tenía succión débil e hipotonicidad. Al examinarla, se observó hepatomegalia. El hemograma, los análisis y la gasometría eran normales, y las proteínas de la fase aguda, negativas. En los análisis, no se observaron cetonas en sangre, pero sí concentraciones elevadas de amoníaco. Las pruebas metabólicas no fueron concluyentes. Se inició el tratamiento de emergencia inmediatamente y recibió el alta el día 15 después del ingreso. Se confirmó deficiencia de NAGS mediante análisis de ADN. La paciente no tiene restricciones alimentarias ni toma medicamentos, excepto N-carbamil glutamato (NCG). La deficiencia de NAGS es el único TCU que puede tratarse específica y eficazmente con NCG. La detección temprana permite iniciar un tratamiento temprano y evitar los efectos devastadores de la hiperamoniemia.

Dual Graph Partitioning Highlights a Small Group of Pseudoknot-Containing RNA Submotifs.

RNA molecules are composed of modular architectural units that define their unique structural and functional properties. Characterization of these building blocks can help interpret RNA structure/function relationships. We present an RNA secondary structure motif and submotif library using dual graph representation and partitioning. Dual graphs represent RNA helices as vertices and loops as edges. Unlike tree graphs, dual graphs can represent RNA pseudoknots (intertwined base pairs). For a representative set of RNA structures, we construct dual graphs from their secondary structures, and apply our partitioning algorithm to identify non-separable subgraphs (or blocks) without breaking pseudoknots. We report 56 subgraph blocks up to nine vertices; among them, 22 are frequently occurring, 15 of which contain pseudoknots. We then catalog atomic fragments corresponding to the subgraph blocks to define a library of building blocks that can be used for RNA design, which we call RAG-3Dual, as we have done for tree graphs. As an application, we analyze the distribution of these subgraph blocks within ribosomal RNAs of various prokaryotic and eukaryotic species to identify common subgraphs and possible ancestry relationships. Other applications of dual graph partitioning and motif library can be envisioned for RNA structure analysis and design.

Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R.

Hereditary coproporphyria (HCP) is an autosomal dominant acute hepatic porphyria due to the half-normal activity of the heme biosynthetic enzyme, coproporphyrinogen oxidase (CPOX). The enzyme catalyzes the step-wise oxidative decarboxylation of the heme precursor, coproporphyrinogen III, to protoporphyrinogen IX via a tricarboxylic intermediate, harderoporphyrinogen. In autosomal dominant HCP, the deficient enzymatic activity results primarily in the accumulation of coproporphyrin III. To date, only a few homozygous HCP patients have been described, most having Harderoporphyria, a rare variant due to specific CPOX mutations that alter enzyme residues D400-K404, most patients described to date having at least one K404E allele. Here, we describe a Turkish male infant, the product of a consanguineous union, who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. He was homoallelic for the CPOX missense mutation, c.980A>G (p.H327R), and had massively increased urinary uroporphyrins I and III (9,250 and 2,910 µM, respectively) and coproporphyrins I and III (895 and 19,400 µM, respectively). The patient expired at 5 months of age from an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site, thereby accounting for the Harderoporphyria phenotype.

Hair chromium concentration and chromium excretion in tannery workers.

Hair and urine samples were collected from 34 male tannery workers and from 12 normal adults. Eighteen of the workers dealt directly with chromium and the remaining 16 (controls) worked in the offices and kitchen of the same factory. All were found to be clinically healthy. Chromium was determined by flameless atomic absorption spectroscopy. When compared with normal adult values, urinary chromium concentration, Cr/Creatinine ratio, daily chromium excretion, and hair chromium, concentrations were significantly higher and urinary beta 2-microglobulin/Cre ratios significantly lower in both tannery workers and in controls. A significant negative correlation was found between urinary beta 2-microglobulin/Cre and Cr/Cre ratios of tannery workers and controls. A significant positive correlation was shown between hair chromium and urinary Cr/Cre values in all workers. No correlations between the duration of exposure to chromium and hair and urinary chromium values were found. Nevertheless, high values observed in workers with short exposures show that chromium is readily absorbed through the respiratory system.

Alterations of chromium metabolism and effect of chromium supplementation in Turner's syndrome patients.

This study was conducted to investigate chromium metabolism and the effect of chromium supplementation in patients with Turner's syndrome, a condition noted for its high incidence of diabetes. Oral glucose tolerance tests were performed in 14 patients 8 to 19 yr of age. Eight of the 14 subjects were given 30 g of brewer's yeast containing 50 micrograms of chromium every day for 8 wk and glucose tolerance tests repeated. Urine samples were collected before and after each glucose load. Serum lipids were also investigated. Before supplementation, urinary chromium/creatinine ratio was high, and the urinary chromium response to oral glucose tolerance test was absent. Cholesterol and/or triglyceride levels were high in three of the patients. After supplementation, a decrease in urinary Cr/Cre ratio, and an improvement in glucose area index total were noted. A decrease in cholesterol and/or triglyceride levels occurred in the three patients with high initial levels as well as an increase in high-density lipoprotein cholesterol. These findings indicate a state of chromium deficiency and support the hypothesis that chromium deficiency may have a role in the pathogenesis of the abnormal glucose tolerance tests encountered in Turner patients.