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Anales de Pediatria Jan 2022Inborn errors of metabolism are a highly heterogeneous group of orphan diseases. Diet therapy and enzyme and coenzyme replacement are the most frequently used treatment....
INTRODUCTION
Inborn errors of metabolism are a highly heterogeneous group of orphan diseases. Diet therapy and enzyme and coenzyme replacement are the most frequently used treatment. There are few patients and published studies about inborn errors of metabolism. The main objective of this study was to describe the effectiveness of orphan drugs in inborn errors of metabolism in paediatric patients.
MATERIAL AND METHODS
Retrospective descriptive study of 24 months on patients diagnosed with inborn errors of metabolism during childhood and who attended the pharmacy clinic or Day-Care Unit of a 630-bed general hospital.
RESULTS
The study included 15 patients with a median age of 17.8 years and were treated with nine different drugs: sapropterin, sodium phenylbutyrate, miglustat, velaglucerase, sebelipase, idursulfase, 5-hydroxytryptophan, succinate, and riboflavin. Seven different inborn errors of metabolism were observed: phenylketonuria, defects of the urea cycle, Gaucher, Nieman-Pick, Hunter's disease, along with acid lipase deficiency, and mitochondrial diseases. Orphan drugs used for the treatment of inborn errors of metabolism accounted for 1.3% of hospital drug costs. Some orphan drugs achieved asymptomatic patients, but others just produced a modest symptomatic improvement. Most patients showed good tolerance to the treatment.
CONCLUSIONS
Orphan drugs used in inborn errors of metabolism had an easy to manage toxicity profile, with many disparities in effectiveness. These drugs have a high economic impact. The cost-effectiveness ratio for orphan drugs is a controversial issue due to their high cost and the inconclusive clinical evidence.
Topics: Adolescent; Child; Humans; Metabolic Diseases; Metabolism, Inborn Errors; Orphan Drug Production; Rare Diseases; Retrospective Studies
PubMed: 34992005
DOI: 10.1016/j.anpede.2020.09.014 -
BMJ Case Reports Jan 2022Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited inborn error of metabolism, which presents with various severity depending...
Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited inborn error of metabolism, which presents with various severity depending on the level of residual enzyme activity. In neonates, it can present with recurrent hypoventilation episodes, persistent encephalopathy with or without microcephaly. MTHFR deficiency also results in hyperhomocysteinemia, homocystinuria and hypomethionemia. We report a male neonate with severe MTHFR deficiency presenting to us on third week of life with progressive encephalopathy, microcephaly, seizures, central hypoventilation. There was similar history in the previous sibling. The patient's blood lactate, ammonia, tandem mass spectrometry for amino acids and acyl carnitine were normal. He remained encephalopathic with progressive increase in need of respiratory support in spite of supportive treatment and metabolic cocktail consisting of riboflavin, pyridoxine, coenzyme Q and carnitine. This neonate had novel homozygous mutation, which results in MTHFR deficiency. In newborn with hypoventilation or recurrent apnoea with encephalopathy and microcephaly, MTHFR deficiency should be considered as a differential diagnosis. Mutation study helps in confirming diagnosis; however, extended newborn metabolic screening with homocysteine level could help in early diagnosis of these cases.
Topics: Homocystinuria; Humans; Hypoventilation; Infant, Newborn; Male; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Spasticity; Psychotic Disorders
PubMed: 34983810
DOI: 10.1136/bcr-2021-246431 -
ELife Dec 2021Many animals are dependent on microbial partners that provide essential nutrients lacking from their diet. Ticks, whose diet consists exclusively on vertebrate blood,...
Many animals are dependent on microbial partners that provide essential nutrients lacking from their diet. Ticks, whose diet consists exclusively on vertebrate blood, rely on maternally inherited bacterial symbionts to supply B vitamins. While previously studied tick species consistently harbor a single lineage of those nutritional symbionts, we evidence here that the invasive tick harbors a unique dual-partner nutritional system between an ancestral symbiont, , and a more recently acquired symbiont, . Using metagenomics, we show that exhibits extensive genome erosion that endangers the nutritional symbiotic interactions. Its genome includes folate and riboflavin biosynthesis pathways but deprived functional biotin biosynthesis on account of massive pseudogenization. Co-symbiosis compensates this deficiency since the genome encompasses an intact biotin operon, which was primarily acquired via lateral gene transfer from unrelated intracellular bacteria commonly infecting arthropods. Thus, in , a mosaic of co-evolved symbionts incorporating gene combinations of distant phylogenetic origins emerged to prevent the collapse of an ancestral nutritional symbiosis. Such dual endosymbiosis was never reported in other blood feeders but was recently documented in agricultural pests feeding on plant sap, suggesting that it may be a key mechanism for advanced adaptation of arthropods to specialized diets.
Topics: Animals; Francisella; Gene Transfer, Horizontal; Ixodidae; Rickettsiales; Symbiosis; Vitamin B Complex
PubMed: 34951405
DOI: 10.7554/eLife.72747 -
Nutrients Nov 2021High-fitness individuals have been suggested to be at risk of a poor vitamin B2 (riboflavin) status due to a potentially higher vitamin B2 demand, as measured by the... (Clinical Trial)
Clinical Trial
High-fitness individuals have been suggested to be at risk of a poor vitamin B2 (riboflavin) status due to a potentially higher vitamin B2 demand, as measured by the erythrocyte glutathione reductase (EGR) activation coefficient (EGRAC). Longer-term exercise interventions have been shown to result in a lower vitamin B2 status, but studies are contradictory. Short-term exercise effects potentially contribute to discrepancies between studies but have only been tested in limited study populations. This study investigated if vitamin B2 status, measured by EGRAC, is affected by a single exercise bout in females who differ in fitness levels, and that represents long-term physical activity. At baseline and overnight after a 60-min cycling bout at 70% V·Opeak, EGR activity and EGRAC were measured in 31 young female adults, divided into a high-fit (V·Opeak ≥ 47 mL/kg/min, N = 15) and low-fit (V·Opeak ≤ 37 mL/kg/min, N = 16) group. A single exercise bout significantly increased EGR activity in high-fit and low-fit females (P = 0.006). This response was not affected by fitness level (P = 0.256). The effect of exercise on EGRAC was not significant (P = 0.079) and not influenced by EGR activity. The exercise response of EGRAC was not significantly different between high-fit and low-fit females (P = 0.141). Thus, a single exercise bout increased EGR activity, but did not affect EGRAC, indicating that vitamin B2 status was not affected. The exercise response on EGRAC and EGR did not differ between high-fit and low-fit females.
Topics: Adolescent; Adult; Exercise; Female; Healthy Volunteers; Humans; Nutritional Status; Physical Fitness; Riboflavin; Riboflavin Deficiency; Young Adult
PubMed: 34836352
DOI: 10.3390/nu13114097 -
Frontiers in Neurology 2021Late-onset multiple acyl-CoA dehydrogenase deficiency (LO-MADD) describes a curable autosomal recessive genetic disease caused by mutations that result in defects in...
Late-onset multiple acyl-CoA dehydrogenase deficiency (LO-MADD) describes a curable autosomal recessive genetic disease caused by mutations that result in defects in ETF-ubiquinone oxidoreductase. Almost all patients are responsive to riboflavin. This study describes the clinical presentations and genetic characteristics of five LO-MADD patients. From 2018 to 2021, we collected clinical and genetic data on five patients diagnosed with LO-MADD at our hospital and retrospectively analyzed their clinical characteristics, laboratory examination, electromyography, muscle biopsy, genetic analysis, and outcome data. This study included three males and two females with mean onset age of 37.8 years. Fluctuating exercise intolerance was the most common presentation. Serum creatine kinase (CK) levels were significantly elevated in all patients, and plasma acylcarnitine profiles revealed an increase in long-chain acylcarnitine species in three cases. The urinary organic acid study revealed a high level of hydroxyglutaric acid in all patients. Electrophysiology demonstrated myogenic impairment. Muscle biopsies revealed lipid storage myopathy. Molecular analysis identified nine mutations (three novels and six reported) in . Exercise intolerance and muscle weakness were dramatically improved in all patients treated with riboflavin (100 mg) daily following diagnosis. LO-MADD is caused by variants and responds well to riboflavin. Three novel pathogenic variants were identified, expanding their spectrum in the Chinese population and facilitating future interpretation and analysis of mutations.
PubMed: 34819910
DOI: 10.3389/fneur.2021.747360 -
European Journal of Human Genetics :... Aug 2022Mitochondrial flavin adenine dinucleotide (FAD) transporter deficiencies are new entities recently reported to cause a neuro-myopathic phenotype. We report three...
Mitochondrial flavin adenine dinucleotide (FAD) transporter deficiencies are new entities recently reported to cause a neuro-myopathic phenotype. We report three patients from two unrelated families who presented primarily with hypoketotic hypoglycemia. They all had acylcarnitine profiles suggestive of multiple acyl-CoA dehydrogenase deficiency (MADD) with negative next-generation sequencing of electron-transfer flavoprotein genes (ETFA, ETFB, and ETFDH). Whole exome sequencing revealed a homozygous c.272 G > T (p.Gly91Val) variant in exon 2 of the SLC25A32 gene. The three patients shared the same variant, and they all demonstrated similar clinical and biochemical improvement with riboflavin supplementation. To date, these are the first patients to be reported with hypoketotic hypoglycemia without the neuromuscular phenotype previously reported in patients with SLC25A32 deficiency.
Topics: Electron-Transferring Flavoproteins; Humans; Hypoglycemia; Iron-Sulfur Proteins; Membrane Transport Proteins; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Mutation; Oxidoreductases Acting on CH-NH Group Donors; Riboflavin
PubMed: 34764427
DOI: 10.1038/s41431-021-00995-7 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2021To investigate the incidence rate, clinical and gene mutation characteristics of multiple acyl-CoA dehydrogenase deficiency (MADD) in newborns in Zhejiang province. A...
To investigate the incidence rate, clinical and gene mutation characteristics of multiple acyl-CoA dehydrogenase deficiency (MADD) in newborns in Zhejiang province. A total of 3 896 789 newborns were screened for MADD using tandem mass spectrometry in Zhejiang Neonatal Screening Center during January 2009 and December 2020. Patients of MADD were confirmed by urine organic acid and electron transferring flavoprotein (or electron transferring flavoprotein dehydrogenase () gene detection. MADD patients were given diet and life management, supplemented with L-carnitine, riboflavin and coenzyme Q 10 treatment, and their growth and intellectual development were evaluated during the followed up.Thirteen patients with MADD were diagnosed, with an incidence of 1/299 753. One patient was type Ⅱ, and the rest were type Ⅲ. Patients were followed up for 1 case died, 4 cases had acute metabolic disorders with hypoglycemia as the main manifestation due to infection, 1 case had hypotonia, and the rest 7 cases developed well. Patients had raised levels of C4-C18:1 acylcarnitines in the initial screening. Thirteen children were genetically tested, 1 case with compound heterozygous mutation in the gene, 1 case with homozygous mutation in the gene, 1 case with compound heterozygous mutation in the gene, 8 cases with compound heterozygous mutation and 1 case with homozygous mutation in the gene, 1 case that only 1 locus of gene was detected. The c.250G>A was the hotspot mutation in this study.The clinical manifestations of MADD are highly heterogeneous. The neonatal-onset form is serious, and late onset form usually has no obvious clinical symptoms. C4-C18:1 acylcarnitines usually increased in the initial screening, and the hotspot gene mutation is c.250G>A.
Topics: Child; Follow-Up Studies; Humans; Infant, Newborn; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Mutation; Neonatal Screening; Riboflavin
PubMed: 34704421
DOI: 10.3724/zdxbyxb-2021-0261 -
Nutrients Oct 2021This study analyzed and evaluated the nutritional intake and nutrition quotient for adults (NQ-A) among 21 disabled national athletes preparing for the Tokyo Paralympic...
This study analyzed and evaluated the nutritional intake and nutrition quotient for adults (NQ-A) among 21 disabled national athletes preparing for the Tokyo Paralympic competition. A 24-h recall nutrition survey was conducted on the second day of training and one day of the weekend (holidays) to analyze daily nutritional intake. Dietary information was analyzed using the NQ-A questionnaire, which comprises 21 items. The athletes were divided into three groups based on the NQ-A score (High, Middle, Low). A comparative analysis of dietary intake of disabled athletes with the recommended dietary intake amount (RDA) was performed. The intake of carbohydrates (166.9%), proteins (112.3%), vitamin E (112.0%), thiamine (124.6%), riboflavin (100.2%), vitamin B6 (110.6%), vitamin B12 (120.7%), sodium (216.6%), phosphorus (118.3%), iron (146.5%), iodine (143.2%), and selenium (114.2%) was higher than the Korean-recommended amount. In particular, as the results of comparing dietary intake between the three groups showed, the low NQ-A score group had significantly lower intake compared to the %RDA for vitamin E (67.1%), C (26.3%), and Potassium (42.8%). However, with most nutrients, nutritional intake deficiency was not shown to be a problem.
Topics: Adult; Athletes; Diet; Dietary Carbohydrates; Dietary Proteins; Disabled Persons; Eating; Energy Intake; Female; Humans; Male; Middle Aged; Nutrition Surveys; Nutritional Requirements; Nutritional Status; Potassium, Dietary; Republic of Korea; Sports; Tokyo; Vitamin E; Vitamins; Young Adult
PubMed: 34684631
DOI: 10.3390/nu13103631 -
The Plant Journal : For Cell and... Dec 2021The riboflavin derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are essential cofactors for enzymes in multiple cellular processes....
The riboflavin derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are essential cofactors for enzymes in multiple cellular processes. Characterizing mutants with impaired riboflavin metabolism can help clarify the role of riboflavin in plant development. Here, we characterized a rice (Oryza sativa) white and lesion-mimic (wll1) mutant, which displays a lesion-mimic phenotype with white leaves, chlorophyll loss, chloroplast defects, excess reactive oxygen species (ROS) accumulation, decreased photosystem protein levels, changes in expression of chloroplast development and photosynthesis genes, and cell death. Map-based cloning and complementation test revealed that WLL1 encodes lumazine synthase, which participates in riboflavin biosynthesis. Indeed, the wll1 mutant showed riboflavin deficiency, and application of FAD rescued the wll1 phenotype. In addition, transcriptome analysis showed that cytokinin metabolism was significantly affected in wll1 mutant, which had increased cytokinin and δ-aminolevulinic acid contents. Furthermore, WLL1 and riboflavin synthase (RS) formed a complex, and the rs mutant had a similar phenotype to the wll1 mutant. Taken together, our findings revealed that WLL1 and RS play pivotal roles in riboflavin biosynthesis, which is necessary for ROS balance and chloroplast development in rice.
Topics: Chlorophyll; Chloroplasts; Cytokinins; DNA Damage; Evolution, Molecular; Flavin-Adenine Dinucleotide; Gene Expression Regulation, Plant; Multienzyme Complexes; Mutation; Oryza; Phenotype; Phylogeny; Plant Leaves; Plant Proteins; Plants, Genetically Modified; Reactive Oxygen Species; Riboflavin; Two-Hybrid System Techniques
PubMed: 34628678
DOI: 10.1111/tpj.15537