Treatment of experimental hyperchloremic metabolic acidosis in horses with enteral electrolyte solution containing sodium acetate.

Introduction: In adult horses, the development and evaluation of enteral electrolyte solutions containing sodium acetate for correcting hyperchloremic metabolic acidosis are still lacking, although these electrolyte and acid-base imbalances are commonly observed. The objective of this study was to evaluate the alkalinizing effect of two enteral electrolyte solutions containing different concentrations of acetate, administered via nasogastric tube in continuous flow, in adult horses with experimental hyperchloremic metabolic acidosis. Methods: Six mares aged between 3 and 10 years were used in a 6×2 crossover design, with each animal receiving both treatments. The horses were subjected to a protocol to induce hyperchloremic metabolic acidosis. They then received one of two treatments: HighAcetate (81.4 mmol/L) and LowAcetate (22.7 mmol/L) at an infusion rate of 15 mL/kg/h for 12 h. Plasma, serum, and urinary biochemical assessments; hematocrit; urinary volume, pH, and specific gravity; and blood gas analysis were measured at the following time points: T-12 h (beginning of the 12-h fast), T0h (end of fasting and beginning of the acidosis induction phase), every 2 h during the hyperchloremic metabolic acidosis induction phase (Ti2h and Ti4h), every 2 h during the 12-h enteral hydration phase (Tt2h, Tt4h, Tt6h, Tt8h, Tt10h, and Tt12h), with one sample taken at T24h (24 h after the start of acidosis induction) and another at T36h (36 h after the start of acidosis induction). Data were analyzed using descriptive statistics and analysis of variance based on a factorial design of repeated measures, with Tukey's post-hoc test or the Kruskal-Wallis test with Dunn's post-hoc test for non-parametric tests. Results: At the end of the induction phase, the animals developed moderate to severe hyperchloremic metabolic acidosis. The HighAcetate solution effectively corrected electrolyte and acid-base imbalances before the end of the treatment phase (Tt12h), while the LowAcetate solution was not effective in correcting those changes. Conclusion: The HighAcetate (81.4 mmol/L) solution is deemed an effective and safe alternative for the treatment of hyperchloremic metabolic acidosis in horses.

L-2 hydroxyglutaric aciduria: report of a Mexican-Mayan patient with the mutation c.569C>T and response to vitamin supplements and levocarnitine.

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by pathogenic variants in the L2HGDH gene which encodes mitochondrial 2-hydroxyglutarate dehydrogenase. Here, we report a case of L2HGA in a Mexican-Mayan patient with a homozygous mutation at L2HGDH gene and clinical response to vitamin supplements and levocarnitine. Case report: A 17-year-old, right-handed female patient with long-term history of seizures, developmental delay and ataxia was referred to a movement disorders specialist for the evaluation of tremor. Her brain MRI showed typical findings of L2HGA. The diagnosis was corroborated with elevated levels of 2-hydroxyglutaric acid in urine and genetic test which revealed a homozygous genetic known variant c.569C>T in exon 5 of L2HGDH gene. She was treated with levocarnitine and vitamin supplements, showing improvement in tremor and gait. Discussion: To our knowledge this is the first report of a Mexican patient with L2HGA. This case adds information about a rare condition in a different ethnic group and supports the findings of other authors which encountered symptomatic improvement with the use of flavin adenine dinucleotide (and its precursor riboflavin), and levocarnitine. Highlights: We report the first case of Mexican-Mayan patient with L2HGA showing a missense homozygous mutation in L2HGDH gene, and improvement of symptoms with vitamin supplements and levocarnitine.

L-2-Hydroxyglutaric Acid Administration to Neonatal Rats Elicits Marked Neurochemical Alterations and Long-Term Neurobehavioral Disabilities Mediated by Oxidative Stress.

L-2-Hydroxyglutaric aciduria (L-2-HGA) is an inherited neurometabolic disorder caused by deficient activity of L-2-hydroxyglutarate dehydrogenase. L-2-Hydroxyglutaric acid (L-2-HG) accumulation in the brain and biological fluids is the biochemical hallmark of this disease. Patients present exclusively neurological symptoms and brain abnormalities, particularly in the cerebral cortex, basal ganglia, and cerebellum. Since the pathogenesis of this disorder is still poorly established, we investigated the short-lived effects of an intracerebroventricular injection of L-2-HG to neonatal rats on redox homeostasis in the cerebellum, which is mostly affected in this disorder. We also determined immunohistochemical landmarks of neuronal viability (NeuN), astrogliosis (S100B and GFAP), microglia activation (Iba1), and myelination (MBP and CNPase) in the cerebral cortex and striatum following L-2-HG administration. Finally, the neuromotor development and cognitive abilities were examined. L-2-HG elicited oxidative stress in the cerebellum 6 h after its injection, which was verified by increased reactive oxygen species production, lipid oxidative damage, and altered antioxidant defenses (decreased concentrations of reduced glutathione and increased glutathione peroxidase and superoxide dismutase activities). L-2-HG also decreased the content of NeuN, MBP, and CNPase, and increased S100B, GFAP, and Iba1 in the cerebral cortex and striatum at postnatal days 15 and 75, implying long-standing neuronal loss, demyelination, astrocyte reactivity, and increased inflammatory response, respectively. Finally, L-2-HG administration caused a delay in neuromotor development and a deficit of cognition in adult animals. Importantly, the antioxidant melatonin prevented L-2-HG-induced deleterious neurochemical, immunohistochemical, and behavioral effects, indicating that oxidative stress may be central to the pathogenesis of brain damage in L-2-HGA.

Disruption of mitochondrial bioenergetics, calcium retention capacity and cell viability caused by D-2-hydroxyglutaric acid in the heart.

Accumulation of D-2-hydroxyglutaric acid (D-2-HG) is the biochemical hallmark of D-2-hydroxyglutaric aciduria type I and, particularly, of D-2-hydroxyglutaric aciduria type II (D2HGA2). D2HGA2 is a metabolic inherited disease caused by gain-of-function mutations in the gene isocitrate dehydrogenase 2. It is clinically characterized by neurological abnormalities and a severe cardiomyopathy whose pathogenesis is still poorly established. The present work investigated the potential cardiotoxicity D-2-HG, by studying its in vitro effects on a large spectrum of bioenergetics parameters in heart of young rats and in cultivated H9c2 cardiac myoblasts. D-2-HG impaired cellular respiration in purified mitochondrial preparations and crude homogenates from heart of young rats, as well as in digitonin-permeabilized H9c2 cells. ATP production and the activities of cytochrome c oxidase (complex IV), alpha-ketoglutarate dehydrogenase, citrate synthase and creatine kinase were also inhibited by D-2-HG, whereas the activities of complexes I, II and II-III of the respiratory chain, glutamate, succinate and malate dehydrogenases were not altered. We also found that this organic acid compromised mitochondrial Ca2+ retention capacity in heart mitochondrial preparations and H9c2 myoblasts. Finally, D-2-HG reduced the viability of H9c2 cardiac myoblasts, as determined by the MTT test and by propidium iodide incorporation. Noteworthy, L-2-hydroxyglutaric acid did not change some of these measurements (complex IV and creatine kinase activities) in heart preparations, indicating a selective inhibitory effect of the enantiomer D. In conclusion, it is presumed that D-2-HG-disrupts mitochondrial bioenergetics and Ca2+ retention capacity, which may be involved in the cardiomyopathy commonly observed in D2HGA2.

[Aciduria argininosuccínica: informe de un caso de inicio neonatal]. / Argininosuccinic aciduria: Neonatal case report.

Urea cycle defects are inborn errors of metabolism produced by a defect in one of the enzymes responsible for the detoxification of ammonia, which generates its accumulation in the body. The clinical manifestations can present early, with high morbidity and mortality, or late onset. The heterogeneity of the symptoms and the lack of clinical suspicion in neonates leads to a wrong diagnosis, which can be confused with neonatal sepsis or cerebral hemorrhages. The increase in plasma ammonia in the biochemical examination orients his diagnosis towards a defect of the urea cycle. Argininosuccinic aciduria is the third most frequent defect of the urea cycle, and is caused by a argininosuccinate lyase deficiency. A neonatal onset case report is presented. The objective is to emphasize its diagnostic suspicion, and to propose early diagnostic tools such as its incorporation into the neonatal metabolic screening.

Los defectos del ciclo de la urea son enfermedades metabólicas hereditarias que se producen por defecto en una de las enzimas encargadas de la desintoxicación del amonio, lo que genera su acumulación en el organismo. Las manifestaciones clínicas pueden presentarse en la etapa neonatal, con morbimortalidad elevada, o de forma tardía. La heterogeneidad de los síntomas y la falta de sospecha clínica en neonatos conducen a un diagnóstico erróneo y se puede confundir con sepsis neonatal o hemorragias cerebrales. El aumento de amonio plasmático en el examen bioquímico orienta su diagnóstico hacia un defecto del ciclo de la urea. La aciduria argininosuccínica es el tercer defecto más frecuente del ciclo de la urea y es causada por deficiencia de la enzima argininosuccínico liasa. Se presenta el informe de un caso de inicio neonatal. Los objetivos son enfatizar en su sospecha diagnóstica y proponer herramientas diagnósticas tempranas, como su incorporación a la pesquisa metabólica neonatal.

Aciduria argininosuccínica: informe de un caso de inicio neonatal / Argininosuccinic aciduria: Neonatal case report

Los defectos del ciclo de la urea son enfermedades metabólicas hereditarias que se producen por defecto en una de las enzimas encargadas de la desintoxicación del amonio, lo que genera su acumulación en el organismo. Las manifestaciones clínicas pueden presentarse en la etapa neonatal, con morbimortalidad elevada, o de forma tardía. La heterogeneidad de los síntomas y la falta de sospecha clínica en neonatos conducen a un diagnóstico erróneo y se puede confundir con sepsis neonatal o hemorragias cerebrales. El aumento de amonio plasmático en el examen bioquímico orienta su diagnóstico hacia un defecto del ciclo de la urea.La aciduria argininosuccínica es el tercer defecto más frecuente del ciclo de la urea y es causada por deficiencia de la enzima argininosuccínico liasa. Se presenta el informe de un caso de inicio neonatal. Los objetivos son enfatizar en su sospecha diagnóstica y proponer herramientas diagnósticas tempranas, como su incorporación a la pesquisa metabólica neonatal.

Urea cycle defects are inborn errors of metabolism produced by a defect in one of the enzymes responsible for the detoxification of ammonia, which generates its accumulation in the body. The clinical manifestations can present early, with high morbidity and mortality, or late onset. The heterogeneity of the symptoms and the lack of clinical suspicion in neonates leads to a wrong diagnosis, which can be confused with neonatal sepsis or cerebral hemorrhages. The increase in plasma ammonia in the biochemical examination orients his diagnosis towards a defect of the urea cycle.Argininosuccinic aciduria is the third most frequent defect of the urea cycle, and is caused by a argininosuccinate lyase deficiency. A neonatal onset case report is presented. The objective is to emphasize its diagnostic suspicion, and to propose early diagnostic tools such as its incorporation into the neonatal metabolic screening.

Clinical and Nutritional Evolution of 24 Patients with Glutaric Aciduria Type 1 in Follow-up at a Center Specialized in Inborn Errors of Metabolism in Chile

Abstract Introduction: Glutaric Aciduria Type 1 (GA-1) is produced by the enzymatic deficiency of glutaryl-CoA-dehydrogenase (GCDH), leading to the accumulation of glutaric acid (GA). 90% of patients without early treatment present acute encephalopathic crisis (AEC), followed by disabling neurological symptoms. The treatment consists of a low lysine (Lys) diet, protein substitute lys-free, tryptophan-reduced (PS) and L-carnitine. Objectives: Describe the clinical and nutritional evolution of a cohort of GA-1 patients at a national referral center in Chile. Methodology: Retrospective study of 24 patients diagnosed with GA-1 between 1998-2020 and referred to the Institute of Nutrition and Food Technology (INTA) of University of Chile. Results: Age at diagnosis was 19±27 months; 10/24 presented AEC and neurological sequelae. The cases without AEC (14/24) 8 presented neurological compromise: psychomotor development delay, abnormal movements and pyramidal syndrome. Nutritional evaluation: 12/24 were malnourished by deficiency, <6 years old group (12/24): 11 cases were found to have Lys and PS, ≥6 years old (12/24): 9/12 did not receive PS. All had normal free carnitine levels. Conclusion: GA-1 has variable symptoms with neurological involvement AEC or insidious start. Is essential to maintain a long-term follow-up and consider its inclusion in neonatal screening programs.

Elevated levels of BDNF and cathepsin-d as possible peripheral markers of neurodegeneration in plasma of patients with glutaric acidemia type I.

Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.

Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?

Abstract Genetic homocystinurias are a group of inborn errors of metabolism that result in the massive excretion of homocysteine (Hcy) in the urine due to Hcy accumulation in the body, usually causing neurological and cardiovascular complications. The three most frequent causes are classical homocystinuria [deficiency of cystathionine beta-synthase (CBS)], methylmalonic aciduria with homocystinuria, cblC type (cblC deficiency) and severe methylenetetrahydrofolate reductase (MTHFR) deficiency. In this review, we highlight the similarities and differences among these disorders. Briefly, their joint manifestation is the accumulation of tHcy, however, the other sulfur amino acids show various and even invers profiles. Vascular disease, developmental delay and seizures are found in all homocystinurias, nevertheless, the complications of CNS differ in a wide variety of presentations and severities and are apparently less pronounced in CBS deficiency. Moreover, patients with remethylation defects typically do not present ectopia lentis and bone disturbances, tall stature and osteoporosis. Whereas hematological alterations, such as megaloblastic anemia, thrombocytopenia neutropenia and life-threatening microangiopathy, are specific findings of cblC deficiency.

Oxidative damage in glutaric aciduria type I patients and the protective effects of l-carnitine treatment.

The deficiency of the enzyme glutaryl-CoA dehydrogenase, known as glutaric acidemia type I (GA-I), leads to the accumulation of glutaric acid (GA) and glutarilcarnitine (C5DC) in the tissues and body fluids, unleashing important neurotoxic effects. l-carnitine (l-car) is recommended for the treatment of GA-I, aiming to induce the excretion of toxic metabolites. l-car has also demonstrated an important role as antioxidant and anti-inflammatory in some neurometabolic diseases. This study evaluated GA-I patients at diagnosis moment and treated the oxidative damage to lipids, proteins, and the inflammatory profile, as well as in vivo and in vitro DNA damage, reactive nitrogen species (RNS), and antioxidant capacity, verifying if the actual treatment with l-car (100 mg kg-1 day-1 ) is able to protect the organism against these processes. Significant increases of GA and C5DC were observed in GA-I patients. A deficiency of carnitine in patients before the supplementation was found. GA-I patients presented significantly increased levels of isoprostanes, di-tyrosine, urinary oxidized guanine species, and the RNS, as well as a reduced antioxidant capacity. The l-car supplementation induced beneficial effects reducing these biomarkers levels and increasing the antioxidant capacity. GA, in three different concentrations, significantly induced DNA damage in vitro, and the l-car was able to prevent this damage. Significant increases of pro-inflammatory cytokines IL-6, IL-8, GM-CSF, and TNF-α were shown in patients. Thus, the beneficial effects of l-car presented in the treatment of GA-I are due not only by increasing the excretion of accumulated toxic metabolites, but also by preventing oxidative damage.

Fractional excretion of electrolytes and paradoxical aciduria in dairy cows with left displaced abomasum / Excreção fracionada de eletrólitos em acidúria paradoxal em vacas leiteiras com deslocamento de abomaso à esquerda

The fractional excretion of electrolytes is used to assess renal function and interpret electrolyte and acid-base imbalances. Left displaced abomasum is a common disorder in dairy cows, which causes hypokalemic, hypochloremic metabolic alkalosis. There is limited information on fractional excretion of electrolytes in cows with displaced abomasum. This study aimed to measure the fractional excretion of sodium, potassium, and chloride and paradoxical aciduria in dairy cows with displaced abomasum. Blood and urine samples were collected from 30 dairy cows before and 24, 48, and 72 h after surgery. The cows were divided into two groups (G1: laparoscopy and G2: laparotomy) with 15 cows each. The concentrations of chloride, sodium, potassium, and creatinine were measured in serum and urine. Urinary pH and packed cell volume were measured. Fractional excretion of sodium, potassium, and chloride and urinary strong ion difference [SID]urine were calculated using published formulas. Cows in both groups showed hypokalemic, metabolic alkalosis before surgery; however, hypochloremia was observed only in G2. Potassium concentration significantly increased 24, 48, and 72 h after surgery in G1 and 48 and 72 h after surgery in G2. There were no significant changes in fractional excretion of sodium, chloride, and potassium and urinary pH and [SID]urine between treatments and time points. Paradoxical aciduria was observed before and 24 h following surgery in G1. Fractional excretion and urinary SID are valuable tools to understand hypochloremic, hypokalemic alkalosis in dairy cows with displaced abomasum, as well as paradoxical aciduria and return of abomasal flux.(AU)

A excreção fracionada de eletrólitos é calculada para verificar a função renal e auxiliar na interpretação de distúrbios eletrolíticos e ácido-base. O deslocamento de abomaso à esquerda é frequente em vacas leiteiras, ocasionado alcalose hipoclorêmica e hipocalêmica. Há pouca informação na literatura sobre excreção fracionada de eletrólitos em vacas com deslocamento de abomaso. Este estudo objetivou mensurar a excreção fracionada de sódio, potássio e cloro e a acidúria paradoxal em vacas leiteiras com deslocamento abomasal. Amostras sanguíneas e urinárias foram coletadas de 30 vacas antes e 24, 48 e 72 horas após operação. As vacas foram divididas em dois grupos (G1: laparoscopia e G2: laparotomia) com 15 animais cada. As concentrações de cloro, sódio, potássio e creatinina foram dosadas no soro e urina. Mensurou-se pH urinário e o hematócrito. A excreção fracionada e diferença de íons fortes urinário [SID]urina foram calculados utilizando fórmulas publicadas. Vacas de ambos os grupos apresentaram alcalose hipocalêmica antes da operação. Não houve alterações significativas na excreção fracionada de sódio, potássio e cloro, no pH urinário e na [SID]urina entre os tratamentos e momentos. Acidúria paradoxal foi observada no G1 antes e 24h após operação. A excreção fracionada e [SID]urina são ferramentas importantes para interpretar a alcalose hipoclorêmica e hipocalêmica em vacas leiteiras com deslocamento de abomaso, como também a acidúria paradoxal e o retorno do fluxo abomasal.(AU)

Fractional excretion of electrolytes and paradoxical aciduria in dairy cows with left displaced abomasum / Excreção fracionada de eletrólitos em acidúria paradoxal em vacas leiteiras com deslocamento de abomaso à esquerda

The fractional excretion of electrolytes is used to assess renal function and interpret electrolyte and acid-base imbalances. Left displaced abomasum is a common disorder in dairy cows, which causes hypokalemic, hypochloremic metabolic alkalosis. There is limited information on fractional excretion of electrolytes in cows with displaced abomasum. This study aimed to measure the fractional excretion of sodium, potassium, and chloride and paradoxical aciduria in dairy cows with displaced abomasum. Blood and urine samples were collected from 30 dairy cows before and 24, 48, and 72 h after surgery. The cows were divided into two groups (G1: laparoscopy and G2: laparotomy) with 15 cows each. The concentrations of chloride, sodium, potassium, and creatinine were measured in serum and urine. Urinary pH and packed cell volume were measured. Fractional excretion of sodium, potassium, and chloride and urinary strong ion difference [SID]urine were calculated using published formulas. Cows in both groups showed hypokalemic, metabolic alkalosis before surgery; however, hypochloremia was observed only in G2. Potassium concentration significantly increased 24, 48, and 72 h after surgery in G1 and 48 and 72 h after surgery in G2. There were no significant changes in fractional excretion of sodium, chloride, and potassium and urinary pH and [SID]urine between treatments and time points. Paradoxical aciduria was observed before and 24 h following surgery in G1. Fractional excretion and urinary SID are valuable tools to understand hypochloremic, hypokalemic alkalosis in dairy cows with displaced abomasum, as well as paradoxical aciduria and return of abomasal flux.(AU)

A excreção fracionada de eletrólitos é calculada para verificar a função renal e auxiliar na interpretação de distúrbios eletrolíticos e ácido-base. O deslocamento de abomaso à esquerda é frequente em vacas leiteiras, ocasionado alcalose hipoclorêmica e hipocalêmica. Há pouca informação na literatura sobre excreção fracionada de eletrólitos em vacas com deslocamento de abomaso. Este estudo objetivou mensurar a excreção fracionada de sódio, potássio e cloro e a acidúria paradoxal em vacas leiteiras com deslocamento abomasal. Amostras sanguíneas e urinárias foram coletadas de 30 vacas antes e 24, 48 e 72 horas após operação. As vacas foram divididas em dois grupos (G1: laparoscopia e G2: laparotomia) com 15 animais cada. As concentrações de cloro, sódio, potássio e creatinina foram dosadas no soro e urina. Mensurou-se pH urinário e o hematócrito. A excreção fracionada e diferença de íons fortes urinário [SID]urina foram calculados utilizando fórmulas publicadas. Vacas de ambos os grupos apresentaram alcalose hipocalêmica antes da operação. Não houve alterações significativas na excreção fracionada de sódio, potássio e cloro, no pH urinário e na [SID]urina entre os tratamentos e momentos. Acidúria paradoxal foi observada no G1 antes e 24h após operação. A excreção fracionada e [SID]urina são ferramentas importantes para interpretar a alcalose hipoclorêmica e hipocalêmica em vacas leiteiras com deslocamento de abomaso, como também a acidúria paradoxal e o retorno do fluxo abomasal.(AU)

Experimental Evidence that In Vivo Intracerebral Administration of L-2-Hydroxyglutaric Acid to Neonatal Rats Provokes Disruption of Redox Status and Histopathological Abnormalities in the Brain.

Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. L-2-HG markedly induced the generation of reactive oxygen species (increase of 2',7'-dichloroflurescein-DCFH-oxidation), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione-GSH) and sulfhydryl content in the cerebral cortex. Alterations of the activities of various antioxidant enzymes were also observed in the cerebral cortex and striatum following L-2-HG administration. Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients.

Novel contiguous gene deletion in peruvian girl with Trichothiodystrophy type 4 and glutaric aciduria type 3.

Trichothiodystrophy type 4 is a rare autosomal recessive and ectodermal disorder, characterized by dry, brittle, sparse and sulfur-deficient hair and other features like intellectual disability, ichthyotic skin and short stature, caused by a homozygous mutation in MPLKIP gene. Glutaric aciduria type 3 is caused by a homozygous mutation in SUGCT gene with no distinctive phenotype. Both genes are localized on chromosome 7 (7p14). We report an 8-year-old female with short stature, microcephaly, development delay, intellectual disability and hair characterized for dark, short, coarse, sparse and brittle associated to classical trichorrhexis microscopy pattern. Chromosome microarray analysis showed a 125 kb homozygous pathogenic deletion, which includes genes MPLKIP and SUGCT, not described before. This is the first case described in Peru of a novel contiguous gene deletion of Trichothiodystrophy type 4 and Glutaric aciduria type 3 performed by chromosome microarray analysis, highlighting the contribution and importance of molecular technologies on diagnosis of rare genetic conditions.

Fractional excretion of electrolytes and paradoxical aciduria in dairy cows with left displaced abomasum

ABSTRACT: The fractional excretion of electrolytes is used to assess renal function and interpret electrolyte and acid-base imbalances. Left displaced abomasum is a common disorder in dairy cows, which causes hypokalemic, hypochloremic metabolic alkalosis. There is limited information on fractional excretion of electrolytes in cows with displaced abomasum. This study aimed to measure the fractional excretion of sodium, potassium, and chloride and paradoxical aciduria in dairy cows with displaced abomasum. Blood and urine samples were collected from 30 dairy cows before and 24, 48, and 72 h after surgery. The cows were divided into two groups (G1: laparoscopy and G2: laparotomy) with 15 cows each. The concentrations of chloride, sodium, potassium, and creatinine were measured in serum and urine. Urinary pH and packed cell volume were measured. Fractional excretion of sodium, potassium, and chloride and urinary strong ion difference [SID]urine were calculated using published formulas. Cows in both groups showed hypokalemic, metabolic alkalosis before surgery; however, hypochloremia was observed only in G2. Potassium concentration significantly increased 24, 48, and 72 h after surgery in G1 and 48 and 72 h after surgery in G2. There were no significant changes in fractional excretion of sodium, chloride, and potassium and urinary pH and [SID]urine between treatments and time points. Paradoxical aciduria was observed before and 24 h following surgery in G1. Fractional excretion and urinary SID are valuable tools to understand hypochloremic, hypokalemic alkalosis in dairy cows with displaced abomasum, as well as paradoxical aciduria and return of abomasal flux.

RESUMO: A excreção fracionada de eletrólitos é calculada para verificar a função renal e auxiliar na interpretação de distúrbios eletrolíticos e ácido-base. O deslocamento de abomaso à esquerda é frequente em vacas leiteiras, ocasionado alcalose hipoclorêmica e hipocalêmica. Há pouca informação na literatura sobre excreção fracionada de eletrólitos em vacas com deslocamento de abomaso. Este estudo objetivou mensurar a excreção fracionada de sódio, potássio e cloro e a acidúria paradoxal em vacas leiteiras com deslocamento abomasal. Amostras sanguíneas e urinárias foram coletadas de 30 vacas antes e 24, 48 e 72 horas após operação. As vacas foram divididas em dois grupos (G1: laparoscopia e G2: laparotomia) com 15 animais cada. As concentrações de cloro, sódio, potássio e creatinina foram dosadas no soro e urina. Mensurou-se pH urinário e o hematócrito. A excreção fracionada e diferença de íons fortes urinário [SID]urina foram calculados utilizando fórmulas publicadas. Vacas de ambos os grupos apresentaram alcalose hipocalêmica antes da operação. Não houve alterações significativas na excreção fracionada de sódio, potássio e cloro, no pH urinário e na [SID]urina entre os tratamentos e momentos. Acidúria paradoxal foi observada no G1 antes e 24h após operação. A excreção fracionada e [SID]urina são ferramentas importantes para interpretar a alcalose hipoclorêmica e hipocalêmica em vacas leiteiras com deslocamento de abomaso, como também a acidúria paradoxal e o retorno do fluxo abomasal.

Inborn Errors of Ketone Body Metabolism and Transport: An Update for the Clinic and for Clinical Laboratories

Abstract Major progress occurred in understanding inborn errors of ketone body transport and metabolism between the International Congresses on Inborn Errors of Metabolism in Barcelona (2013) and Rio de Janeiro (2017). These conditions impair either ketogenesis (presenting as episodes of hypoketotic hypoglycemia) or ketolysis (presenting as ketoacidotic episodes); for both groups, immediate intravenous glucose administration is the most critical and (mHGGCS, HMGCS2) effective treatment measure. Ketogenesis Deficiencies: New biomarkers were described for mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHGGCS, HMGCS2) deficiency. New patient series refined clinical knowledge of 3-hydroxy-3-methylglutaryl-CoA lyase (HGGCL, HMGCL) deficiency. Although affected humans have not been described, two animal model phenotypes are pertinent: zebrafish deficient in monocarboxylate transporter 7 (MCT7, slc16a6) (decreased ketone body exit from hepatocytes) or mice lacking D-3-hydroxy-n-butyrate dehydrogenase (BDH1, BDH1) (isolated hyperacetoacetatemia; fatty liver). Ketolysis Deficiencies: Monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency is a newly described defect of ketone body transport, joining deficiencies of succinyl-CoA:3-oxoacid CoA transferase (SCOT, OXCT1) and methylacetoacetyl-CoA thiolase (MAT, ACAT1). Some heterozygotes for MCT1 or SCOT deficiency develop ketoacidosis.

Mimicking Ketonuria in the Ketogenesis Defect 3-Hydroxy-3-MethylglutarylCoenzyme A Lyase Deficiency: An Artefact in the Analysis of Urinary Organic Acids

Abstract 3-Hydroxy-3-methylglutaryl-coenzyme A lyase (HMGCL, HMGCL) deficiency is a rare inborn error of ketogenesis. Even if the ketogenic enzyme is fully disrupted, an elevated signal for the ketone body acetoacetic acid is a frequent observation in the analysis of urinary organic acids, at least if derivatization is performed by methylation. We provide an explanation for this phenomenon and trace it back to degradation of the derivatized 3-hydroxy-3-methylglutaric acid and high temperature of the injector of the gas chromatograph.

Aproximación físico-química a las alteraciones ácido base en la orina de ovinos con alcalosis hipoclorémica / Physical-chemical approach to acid-base alterations in the urine of sheep with hypochloremic alkalosis / Aproximação físico-química às alterações ácido base na urina de ovinos com alcalose hipoclórica

Resumen La aproximación físico-química para determinar el pH urinario es relativamente nueva y no se ha usado en condiciones patológicas en animales. En el presente artículo, el objetivo principal fue demostrar la validez de esta teoría en la orina de ovinos con alcalosis metabólica hipoclorémica. Se realizó un estudio de tipo experimental para la inducción de la alcalosis metabólica hipoclorémica en ovinos. Durante el periodo de control y de inducción se determinaron en la orina: pH calculado, pH medido, excreción neta de ácido, amonio y diferencia de iones fuertes en la orina (SID) cada 24 h hasta el desarrollo de la aciduria paradójica o el deterioro físico de los sujetos. Se determinó la correlación de Pearson (p) entre el pH medido y calculado a partir del modelo del SID en la orina. Se observó una correlación alta entre el pH urinario medido y el calculado usando el SID calculado con base en la excreción neta de ácido (p = 0,874). La correlación entre SID calculado y pH en orina fue significativa (p = 0,839). Sin embargo, la correlación entre el SID y el pH medido de la orina fue moderada (p = 0,588). Se concluye que existe una alta correlación entre el pH calculado a partir del SID usando la excreción neta de ácido y el pH medido en la orina de ovinos con alcalosis metabólica hipoclorémica. Esto indica que el pH urinario depende fuertemente del SID y, por lo tanto, la reducción en el pH puede ser explicada por la disminución del SID.

Abstract The physical-chemical approach to determine urinary pH is relatively new and has not yet been used in pathological conditions in animals. The main objective of this paper was to demonstrate the validity of this theory in the urine of sheep with hypochloremic metabolic alkalosis. An experimental-type study was conducted to induce hypochloremic metabolic alkalosis in sheep. During the control and induction periods, calculated pH, measured pH, net acid excretion, ammonium and strong ion difference (SID) in urine were examined every 24 hours until development of paradoxical aciduria or physical deterioration of subjects. Pearson's correlation (p) was determined between measured and calculated pH based on SID in urine. A high correlation between measured and calculated urine pH was observed using SID calculated from net acid excretion (p = 0.874). The correlation between calculated SID and urine pH was significant (p = 0.839). However, the correlation between SID and measured urine pH was moderate (p = 0.588). It is concluded that there is a high correlation between pH calculated from SID using net acid excretion and pH measured in the urine of sheep with hypochloremic metabolic alkalosis. This indicates that urine pH depends strongly on SID and, therefore, a reduction in pH can be explained by a decrease in SID.

Resumo A aproximação físico-química para determinar o pH urinário é relativamente nova e não tem sido usado em condições patológicas em animais. Neste artigo, o objetivo principal foi demonstrar a validez desta teoria na urina de ovinos com alcalose metabólica hipoclórica. Realizou-se um estudo de tipo experimental para a indução da alcalose metabólica hipoclórica em ovinos. Durante o período de controle e de indução determinaram na urina: pH calculado, pH medido, excreção neta de ácido, amônio e diferença de íons fortes na urina (SID) cada 24 horas hasta o desenvolvimento da aciduria paradoxal ou a deterioração física dos sujeitos. Determinou-se a correlação de Pearson (p) entre o pH medido e calculado a partir do modelo do SID na urina. Observou-se uma correlação alta entre o pH urinário medido e o calculado usando o SID calculado a partir da ex creção líquida de ácido (p = 0,874). A correlação entre SID calculado e pH em urina foi significativa (p = 0,839). Contudo, a correlação entre o SID e o pH medido da urina foi moderada (p = 0.588). Conclui-se que existe uma alta correlação entre o pH calculado a partir do SID usando a excreção líquida de ácido e o pH medido na urina de ovinos com alcalose metabólica hipoclórica. Isto indica que o pH urinário depende fortemente do SID e, portanto, a redução no pH pode ser explicada pela diminuição do SID.

α-Ketoadipic Acid and α-Aminoadipic Acid Cause Disturbance of Glutamatergic Neurotransmission and Induction of Oxidative Stress In Vitro in Brain of Adolescent Rats.

Tissue accumulation of α-ketoadipic (KAA) and α-aminoadipic (AAA) acids is the biochemical hallmark of α-ketoadipic aciduria. This inborn error of metabolism is currently considered a biochemical phenotype with uncertain clinical significance. Considering that KAA and AAA are structurally similar to α-ketoglutarate and glutamate, respectively, we investigated the in vitro effects of these compounds on glutamatergic neurotransmission in the brain of adolescent rats. Bioenergetics and redox homeostasis were also investigated because they represent fundamental systems for brain development and functioning. We first observed that AAA significantly decreased glutamate uptake, whereas glutamate dehydrogenase activity was markedly inhibited by KAA in a competitive fashion. In addition, AAA and more markedly KAA induced generation of reactive oxygen and nitrogen species (increase of 2',7'-dichloroflurescein (DCFH) oxidation and nitrite/nitrate levels), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione (GSH)) and aconitase activity. Furthermore, KAA-induced lipid peroxidation and GSH decrease were prevented by the antioxidants α-tocopherol, melatonin, and resveratrol, suggesting the involvement of reactive species in these effects. Noteworthy, the classical inhibitor of NMDA glutamate receptors MK-801 was not able to prevent KAA-induced and AAA-induced oxidative stress, determined by DCFH oxidation and GSH levels, making unlikely a secondary induction of oxidative stress through overstimulation of glutamate receptors. In contrast, KAA and AAA did not significantly change brain bioenergetic parameters. We speculate that disturbance of glutamatergic neurotransmission and redox homeostasis by KAA and AAA may play a role in those cases of α-ketoadipic aciduria that display neurological symptoms.