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      Aciduria glutárica tipo II. A propósito de un caso Translated title: Type II glutaric aciduria. Case report


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          Resumen: Los errores innatos del metabolismo son un conjunto de enfermedades que convergen en la presencia de mutaciones que se expresan en enzimas y proteínas de transporte, entre otros, que generan un bloqueo en las rutas del metabolismo desencadenando alteraciones bioquímicas. La aciduria glutárica tipo II es una alteración de la oxidación de los ácidos grasos y aminoácidos que comprenden trastornos de complejidad variable, desde la presentación neonatal grave hasta una enfermedad leve de la infancia o la edad adulta con descompensación metabólica episódica, debilidad muscular e insuficiencia respiratoria. Caso clínico: Se presenta un recién nacido pretérmino de 32 semanas con dificultad respiratoria, quien presenta acidosis metabólica inicialmente descompensada, la cual posteriormente se compensa, manteniendo una brecha aniónica normal durante toda su hospitalización. En este tipo de patologías es importante un alto grado de sospecha clínica para establecer un diagnóstico precoz y lograr instaurar el tratamiento oportuno.

          Translated abstract

          Summary: Inborn errors of metabolism are a set of diseases that converge in the presence of mutations expressed in enzymes and transport proteins, among others, that generate a blockage in metabolic routes, triggering biochemical alterations. Glutaric aciduria type II is a disturbance in the oxidation of fatty and amino acids, comprising disorders that may vary in complexity from a severe neonatal presentation to a mild illness in childhood or adulthood with episodic metabolic alterations, muscle weakness, and respiratory failure. Clinical case: A 32-weekold preterm newborn with respiratory distress, whom initially presented a decompensated metabolic acidosis, which subsequently compensates, and maintains a normal anion gap throughout his hospitalization. A high clinical suspicion is important to reach diagnosis and establish immediate treatment.

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          Most cited references18

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          Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

          Background Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases. Methods All 350 cases of late-onset MADD reported in the literature to date have been analyzed and evaluated with respect to age at presentation, diagnostic delay, biochemical features and diagnostic parameters as well as response to treatment. Results Mean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remained asymptomatic until a maximum age of 14 years. Diagnosis may be difficult as a relevant number of patients do not display typical biochemical patterns of urine organic acids and blood acylcarnitines during times of wellbeing. The vast majority of patients carry mutations in the ETFDH gene (93%), while mutations in the ETFA (5%) and ETFB (2%) genes are the exceptions. Almost all patients with late-onset MADD (98%) are clearly responsive to riboflavin. Conclusions Late-onset MADD is probably an underdiagnosed disease and should be considered in all patients with acute or chronic muscular symptoms or acute metabolic decompensation with hypoglycemia, acidosis, encephalopathy and hepatopathy. This may not only prevent patients from invasive diagnostic procedures such as muscle biopsies, but also help to avoid fatal metabolic decompensations.
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            Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency

            Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.
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              Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency: A retrospective and laboratory cohort study.

              Multiple acyl-CoA dehydrogenase deficiency (MADD) is an ultra-rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes. We performed a retrospective nationwide cohort study; then developed an MADD-disease severity scoring system (MADD-DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD-DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts. Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD-DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD-DS3 scores of patients in our cohort ranged from 0 to 29. FAO flux and [U-13 C]C2-, C5-, and [U-13 C]C16-acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all P < .05) and strongly correlated to MADD-DS3 scores (oleate: r = -.86; myristate: r = -.91; [U-13 C]C2-acylcarnitine: r = -.96; C5-acylcarnitine: r = .97; [U-13 C]C16-acylcarnitine: r = .98, all P < .01). Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD-patients and were correlated to MADD-DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow-up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs.

                Author and article information

                Archivos Venezolanos de Puericultura y Pediatría
                Arch Venez Puer Ped
                Sociedad Venezolana de Puericultura y Pediatría (Caracas, Distrito Capital, Venezuela )
                September 2020
                : 83
                : 3
                : 86-88
                [2] Caracas orgnameCentro Médico Docente La Trinidad orgdiv1Unidad de Terapia Intensiva Neonatal Venezuela
                [1] Caracas orgnameCentro Médico Docente La Trinidad Venezuela
                S0004-06492020000300086 S0004-0649(20)08300300086

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                : 30 August 2020
                : 30 July 2020
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 18, Pages: 3

                SciELO Venezuela

                Caso Clínico

                neonatal screening,Aciduria glutárica,error innato metabolismo,pesquisa neonatal,Glutaric aciduria,Inborn errors of metabolism


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