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Molecular Genetics and Metabolism... Dec 2022Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disease caused by a defect in electron transfer flavoprotein alpha (ETFA), ETF beta (ETFB),...
Clinical and molecular investigation of 37 Japanese patients with multiple acyl-CoA dehydrogenase deficiency: p.Y507D in , a common Japanese variant, causes a mortal phenotype.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disease caused by a defect in electron transfer flavoprotein alpha (ETFA), ETF beta (ETFB), or ETF dehydrogenase (ETFDH), and riboflavin metabolism disorders have recently been reported to present as mimicking MADD. MADD is roughly classified into neonatal (type 1 or 2) and later-onset (type 3) forms. To identify clinicogenetic characteristics in Japan, we investigated 37 Japanese patients with MADD diagnosed from 1997 to 2020. The causes of MADD were ETFDH deficiency in 26 patients, ETFA deficiency in four, ETFB deficiency in six, and riboflavin metabolism disorder in one. All 15 patients with the neonatal-onset type died by 2 years of age, while five of 22 patients with the later-onset form died by 3 years of age. Furthermore, 8 of 15 patients with the later-onset form of ETFDH deficiency treated with riboflavin were riboflavin non-responders. p.Y507D in was identified as the most common variant (9 of 48 alleles, 18.8%). Of two patients with a homozygous p.Y507D variant, one experienced disease onset and died in the neonatal period, while the other experienced disease onset at two months of age and died at two years old, suggesting that the p.Y507D variant results in fatal outcomes. Our study concluded that more than half of Japanese patients with MADD died by three years old, and more than half of patients with the later-onset form had poor responsiveness to riboflavin, partly due to the unique Japanese p.Y507D variant in .
PubMed: 36406819
DOI: 10.1016/j.ymgmr.2022.100940 -
The Journal of Biological Chemistry Dec 2022Extracellular hydrolysis of flavin-adenine dinucleotide (FAD) and flavin mononucleotide (FMN) to riboflavin is thought to be important for cellular uptake of vitamin B...
Extracellular hydrolysis of flavin-adenine dinucleotide (FAD) and flavin mononucleotide (FMN) to riboflavin is thought to be important for cellular uptake of vitamin B because FAD and FMN are hydrophilic and do not pass the plasma membrane. However, it is not clear whether FAD and FMN are hydrolyzed by cell surface enzymes for vitamin B uptake. Here, we show that in human cells, FAD, a major form of vitamin B in plasma, is hydrolyzed by CD73 (also called ecto-5' nucleotidase) to FMN. Then, FMN is hydrolyzed by alkaline phosphatase to riboflavin, which is efficiently imported into cells. We determined that this two-step hydrolysis process is impaired on the surface of glycosylphosphatidylinositol (GPI)-deficient cells due to the lack of these GPI-anchored enzymes. During culture of GPI-deficient cells with FAD or FMN, we found that hydrolysis of these forms of vitamin B was impaired, and intracellular levels of vitamin B were significantly decreased compared with those in GPI-restored cells, leading to decreased formation of vitamin B-dependent pyridoxal 5'-phosphate and mitochondrial dysfunction. Collectively, these results suggest that inefficient uptake of vitamin B might account for mitochondrial dysfunction seen in some cases of inherited GPI deficiency.
Topics: Humans; Riboflavin; Flavin-Adenine Dinucleotide; Alkaline Phosphatase; 5'-Nucleotidase; Flavin Mononucleotide; Hydrolysis; Vitamins
PubMed: 36309091
DOI: 10.1016/j.jbc.2022.102640 -
JCI Insight Oct 2022Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis...
Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.
Topics: Adult; Animals; Humans; Thiamine; Caenorhabditis elegans; Dihydrolipoamide Dehydrogenase; Thioctic Acid; Riboflavin; Carnitine; Pyruvates; Adenosine Triphosphate
PubMed: 36278487
DOI: 10.1172/jci.insight.156222 -
The American Journal of Clinical... Dec 2022
Topics: Adult; Humans; Riboflavin Deficiency; Vitamin B 6; Riboflavin; Pyridoxine; Genotype; Vitamins; Methylenetetrahydrofolate Reductase (NADPH2)
PubMed: 36264295
DOI: 10.1093/ajcn/nqac269 -
The American Journal of Clinical... Dec 2022The generation of the active form of vitamin B-6, pyridoxal 5'-phosphate (PLP), in tissues is dependent upon riboflavin as flavin mononucleotide, but whether this... (Clinical Trial)
Clinical Trial
BACKGROUND
The generation of the active form of vitamin B-6, pyridoxal 5'-phosphate (PLP), in tissues is dependent upon riboflavin as flavin mononucleotide, but whether this interaction is important for maintaining vitamin B-6 status is unclear.
OBJECTIVE
To investigate vitamin B-6 and riboflavin status, their metabolic interaction, and relationship with methylenetetrahydrofolate reductase (MTHFR) genotype in adulthood.
METHODS
Data from 5612 adults aged 18-102 y were drawn from the Irish National Adult Nutrition Survey (NANS; population-based sample) and the Trinity-Ulster Department of Agriculture (TUDA) and Genovit cohorts (volunteer samples). Plasma PLP and erythrocyte glutathione reductase activation coefficient (EGRac), as a functional indicator of riboflavin, were determined.
RESULTS
Older (≥65 y) compared with younger (<65 y) adults had significantly lower PLP concentrations (P < 0.001). A stepwise decrease in plasma PLP was observed across riboflavin categories, from optimal (EGRac ≤1.26), to suboptimal (EGRac: 1.27-1.39), to deficient (EGRac ≥1.40) status, an effect most pronounced in older adults (mean ± SEM: 76.4 ± 0.9 vs 65.0 ± 1.1 vs 55.4 ± 1.2 nmol/L; P < 0.001). In individuals with the variant MTHFR 677TT genotype combined with riboflavin deficiency, compared with non-TT (CC/CT) genotype participants with sufficient riboflavin, we observed PLP concentrations of 52.1 ± 2.9 compared with 76.8 ±0.7 nmol/L (P < 0.001). In participants with available dietary data (i.e., NANS cohort, n = 936), PLP was associated with vitamin B-6 intake (nonstandardized regression coefficient β: 2.49; 95% CI 1.75, 3.24; P < 0.001), supplement use (β: 81.72; 95% CI: 66.01, 97.43; P < 0.001), fortified food (β: 12.49; 95% CI: 2.08, 22.91; P = 0.019), and EGRac (β: -65.81; 95% CI: -99.08, -32.54; P < 0.001), along with BMI (β: -1.81; 95% CI: -3.31, -0.30; P = 0.019).
CONCLUSIONS
These results are consistent with the known metabolic dependency of PLP on flavin mononucleotide (FMN) and suggest that riboflavin may be the limiting nutrient for maintaining vitamin B-6 status, particularly in individuals with the MTHFR 677TT genotype. Randomized trials are necessary to investigate the PLP response to riboflavin intervention within the dietary range. The TUDA study and the NANS are registered at www.ClinicalTrials.gov as NCT02664584 (27 January 2016) and NCT03374748 (15 December 2017), respectively.Clinical Trial Registry details: Trinity-Ulster-Department of Agriculture (TUDA) study, ClinicalTrials.gov no. NCT02664584 (January 27th 2016); National Adult Nutrition Survey (NANS), ClinicalTrials.gov no. NCT03374748 (December 15th 2017).
Topics: Adult; Aged; Humans; Flavin Mononucleotide; Genotype; Methylenetetrahydrofolate Reductase (NADPH2); Pyridoxal Phosphate; Riboflavin; Vitamin B 12; Vitamin B 6; Vitamins
PubMed: 36264281
DOI: 10.1093/ajcn/nqac240 -
Nutrients Sep 2022The importance of B complex vitamins starts early in the human life cycle and continues across its different stages. At the same time, numerous reports have emphasized... (Review)
Review
The importance of B complex vitamins starts early in the human life cycle and continues across its different stages. At the same time, numerous reports have emphasized the critical role of adequate B complex intake. Most studies examined such issues concerning a specific vitamin B or life stage, with the majority reporting the effect of either excess or deficiency. Deep insight into the orchestration of the eight different B vitamins requirements is reviewed across the human life cycle, beginning from fertility and pregnancy and reaching adulthood and senility, emphasizing interactions among them and underlying action mechanisms. The effect of sex is also reviewed for each vitamin at each life stage to highlight the different daily requirements and/or outcomes. Thiamine, riboflavin, niacin, pyridoxine, and folic acid are crucial for maternal and fetal health. During infancy and childhood, B vitamins are integrated with physical and psychological development that have a pivotal impact on one's overall health in adolescence and adulthood. A higher intake of B vitamins in the elderly is also associated with preventing some aging problems, especially those related to inflammation. All supplementation should be carefully monitored to avoid toxicity and hypervitaminosis. More research should be invested in studying each vitamin individually concerning nutritional disparities in each life stage, with extensive attention paid to cultural differences and lifestyles.
Topics: Adolescent; Adult; Aged; Child; Female; Folic Acid; Humans; Male; Niacin; Pantothenic Acid; Pregnancy; Pyridoxine; Riboflavin; Sex Characteristics; Thiamine; Vitamin B 12; Vitamin B Complex
PubMed: 36235591
DOI: 10.3390/nu14193940 -
Asia Pacific Journal of Clinical... 2022Congenital heart disease (CHD) is the common congenital malformations in children and cause malnutrition. We determine the association between dietary nutrient intake...
BACKGROUND AND OBJECTIVES
Congenital heart disease (CHD) is the common congenital malformations in children and cause malnutrition. We determine the association between dietary nutrient intake and nutritional status of children with CHD.
METHODS AND STUDY DESIGN
428 children of age 1-10 years with CHD admitted. The dietary nutrient intake was recorded after 3 days of 24-h recall. The growth and nutritional status of children were evaluated using anthropometric measurements and z-scores.
RESULTS
The prevalence of malnutrition was 37.6% in CHD. 57.8%, 12.6%, 43.8%, and 40.6% of children did not meet their requirements for energy, protein, fat, and carbohydrate, respectively. The prevalence of insufficient intake was 88.3% for calcium, 35.9% for magnesium, 21.9% for iron, and 12.5% for zinc. 15%-86% of children did not meet vitamin requirements. 85.2% and 53.9% of children did not meet their requirements for vitamin A and vitamin C. The prevalence of insufficient intake was 39.1% for thiamin, 24.2% for riboflavin, 15.6% for niacin and 28.1% for vitamin E. Compared with the normal nutrition group, malnutrition group had a relatively lower intake of proteins, iron, zinc and vitamin E.
CONCLUSIONS
An obvious deficiency of dietary nutrient intake was found among children with CHD, especially CHD with malnutrition. Dietary intake related to the nutritional status of children with CHD. The gap between actual consumption and recommendation indicates a need for improved nutritional counseling and monitoring. Early interventions targeting the dietary intakes of children with CHD may be a benefit for long-term effects associated with nutritional status.
Topics: Ascorbic Acid; Calcium; Carbohydrates; Child; Child, Preschool; Diet; Eating; Energy Intake; Heart Defects, Congenital; Humans; Infant; Iron; Magnesium; Malnutrition; Niacin; Nutritional Requirements; Nutritional Status; Riboflavin; Thiamine; Vitamin A; Vitamin E; Vitamins; Zinc
PubMed: 36173223
DOI: 10.6133/apjcn.202209_31(3).0019 -
Stem Cell Research Oct 2022Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is an inborn metabolic disorder that affects fatty acid oxidation and the catabolism of branched-chain amino...
Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is an inborn metabolic disorder that affects fatty acid oxidation and the catabolism of branched-chain amino acids, vitamins B and energy metabolism. In this study, the induced pluripotent stem cell (iPSC) line LZUSHi002-A from PBMCs of a 10-year-old male patient with ETFDH mutations using the episomal plasmids was established, which is an ideal in vitro model to understand the exact pathogenesis of MADD.
Topics: Male; Humans; Child; Induced Pluripotent Stem Cells; Electron-Transferring Flavoproteins; Oxidoreductases Acting on CH-NH Group Donors; Acyl-CoA Dehydrogenase; Iron-Sulfur Proteins; Riboflavin; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Mutation; Fatty Acids; Vitamins; Amino Acids, Branched-Chain; Guanine Nucleotide Exchange Factors; Death Domain Receptor Signaling Adaptor Proteins
PubMed: 36162333
DOI: 10.1016/j.scr.2022.102914 -
Neonatology 2022An increasing number of women of reproductive age follow vegan diets. Because vegan diets are deficient in a number of essential nutrients, guidelines address the...
An increasing number of women of reproductive age follow vegan diets. Because vegan diets are deficient in a number of essential nutrients, guidelines address the necessity of supplementations such as iron, zinc, and vitamin B12. However, the risk of riboflavin (vitamin B2) deficiency is not properly addressed. We report a case of a male neonate with a life-threatening hypoglycaemia and lactic acidosis due to severe riboflavin deficiency. The mother followed a strict vegan diet with intermittent use of supplements (folic acid, vitamin B12, vitamin D, omega 3). This case highlights the importance of adequate counselling of all pregnant women adhering to vegan diets to ensure sufficient intake of essential nutrients and vitamins, including riboflavin.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Male; Diet, Vegan
PubMed: 36122554
DOI: 10.1159/000526334 -
Frontiers in Pediatrics 2022We present a now 18-year-old female patient with a severe congenital myopathy phenotype, originally diagnosed as mitochondrial myopathy, however later revealed to...
We present a now 18-year-old female patient with a severe congenital myopathy phenotype, originally diagnosed as mitochondrial myopathy, however later revealed to constitute a -related myopathy based on genetic testing. After birth, floppiness, bradycardia and respiratory insufficiency ensued, and moderately reduced mitochondrial complex I activity was found in muscle tissue (tested at 3 weeks and 3 years of age, respectively). She was treated with riboflavin, carnitine, creatine and a ketogenic diet. At the age of 13 years, whole exome sequencing challenged the initial diagnosis by identifying two (compound heterozygous) variants affecting the highly conserved voltage sensor and pore regions of the voltage-gated sodium channel Na1.4: a known pathogenic loss of function (LOF) variant [c.4360C>T; p.(Arg1454Trp)] and a novel variant of uncertain significance [c.3615C>G; p.(Asn1205Lys)]. For this novel variant, a LOF effect was predicted by , clinical and functional evidence from paralog human sodium channels, and the variant was accordingly classified as likely pathogenic. The patient's phenotype is in line with the few published cases of autosomal recessive -related myopathy. There was limited benefit from treatment with salbutamol and acetazolamide, while pyridostigmine caused side effects at a minor dose. This report highlights the importance of genetic testing in severe myopathies particularly in regard to treatment options and the value of paralog information in evaluating ion channel variations.
PubMed: 36090556
DOI: 10.3389/fped.2022.944784