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Cleveland Clinic Journal of Medicine Oct 2016Certain vitamin and mineral deficiencies may be recognized by their cutaneous signs. This case-based article reviews deficiencies of zinc and vitamins A, B, B, B, and C,... (Review)
Review
Certain vitamin and mineral deficiencies may be recognized by their cutaneous signs. This case-based article reviews deficiencies of zinc and vitamins A, B, B, B, and C, discussing their consequences and skin findings.
Topics: Adolescent; Aged; Ascorbic Acid Deficiency; Female; Humans; Middle Aged; Niacin; Riboflavin Deficiency; Skin Diseases; Vitamin A Deficiency; Vitamin B 6 Deficiency; Zinc
PubMed: 27726828
DOI: 10.3949/ccjm.83a.15061 -
The Journal of Nutrition Mar 2015Thiamin deficiency in infancy is the underlying cause of beriberi, which can be fatal without rapid treatment. Reports of thiamin deficiency are common in Cambodia;... (Observational Study)
Observational Study
BACKGROUND
Thiamin deficiency in infancy is the underlying cause of beriberi, which can be fatal without rapid treatment. Reports of thiamin deficiency are common in Cambodia; however, population representative data are unavailable. Because B-complex vitamin deficiencies commonly occur in combination, riboflavin was also investigated.
OBJECTIVE
We determined the biomarker status of thiamin and riboflavin in women of childbearing age in rural and urban Cambodia.
METHODS
We measured thiamin (erythrocyte thiamin diphosphate; TDP) and riboflavin (erythrocyte glutathione reductase activity coefficient; EGRac) status in a representative sample of Cambodian women (aged 20-45 y) in urban Phnom Penh (n = 146) and rural Prey Veng (n = 156), Cambodia, and, for comparison purposes, in a convenience sample of women in urban Vancouver, British Columbia, Canada (n = 49).
RESULTS
Thiamin insufficiency (TDP ≤ 90 nmol/L) was common among both urban (39%) and rural (59%) Cambodian women (P < 0.001), whereas <20% of Vancouver women were thiamin insufficient (P < 0.001). The prevalence of suboptimal and deficient riboflavin status (EGRac ≥ 1.3) was 89%, 92%, and 70% among women in Phnom Penh, Prey Veng, and Vancouver, respectively (P < 0.001).
CONCLUSIONS
Suboptimal status of both thiamin and riboflavin were common in Cambodian women, with substantially higher rates among women living in rural Prey Veng than in urban Phnom Penh. Strategies may be needed to improve the thiamin and riboflavin status of women in Cambodia. The unexpected finding of high riboflavin inadequacy status in Vancouver women warrants further investigation.
Topics: Adult; Cambodia; Canada; Cross-Sectional Studies; Erythrocytes; Female; Humans; Middle Aged; Nutritional Status; Riboflavin; Riboflavin Deficiency; Rural Population; Thiamine; Thiamine Deficiency; Thiamine Pyrophosphate; Urban Population; Young Adult
PubMed: 25733481
DOI: 10.3945/jn.114.203604 -
Molecular Syndromology Apr 2023Succinate dehydrogenase deficiency, also known as mitochondrial complex II deficiency, is a rare inborn error of metabolism, accounting for approximately 2% of...
INTRODUCTION
Succinate dehydrogenase deficiency, also known as mitochondrial complex II deficiency, is a rare inborn error of metabolism, accounting for approximately 2% of mitochondrial disease. Mutations in the four genes and have been reported resulting in diverse clinical presentations. The vast majority of clinically affected individuals reported in the literature harbor genetic variants within the gene and present with a Leigh syndrome phenotype, clinically defined as a subacute necrotizing encephalopathy.
CASE REPORT
Herein, we report the first case of a 7-year-old child who was diagnosed as having succinate dehydrogenase deficiency. The affected child presented at 1 year of age with encephalopathy and developmental regression following viral illnesses. MRI changes supported a clinical diagnosis of Leigh syndrome and c.1328C>Q and c.872A>C variants were identified as compound heterozygous. Mitochondrial cocktail treatment including L-carnitine, riboflavin, thiamine, biotin, and ubiquinone was started. Mild clinical improvement was observed after treatment. He is now unable to walk and speak. The second patient, a 21-year-old woman, presented with generalized muscle weakness, easy fatigability, and cardiomyopathy. Investigations revealed increased lactate level of 67.4 mg/dL (4.5-19.8) with repeatedly increased plasma alanine levels 1,272 µmol/L (200-579). We administered carnitine, coenzyme, riboflavin, and thiamine for empirical therapy with the suspicion of mitochondrial disease. Clinical exome sequencing revealed compound heterozygous variants NM_004168.4:c.1945_1946del (p.Leu649GlufsTer4) at exon 15 of the gene and NM_004168.4:c.1909-12_1909-11del at intron 14 of gene.
DISCUSSION AND CONCLUSION
There are several very different presentations including Leigh syndrome, epileptic encephalopathy, and cardiomyopathy. Some cases present following viral illness; this feature is not specific to mitochondrial complex II deficiency and occurs in many other mitochondrial disease presentations. There is no cure for complex II deficiency, though some reported patients showed clinical improvement following riboflavin therapy. Riboflavin is not the only therapeutic intervention that is available to patients with an isolated complex II deficiency and various other compounds have shown promise in the treatment of symptoms, including L-carnitine and ubiquinone. Treatment alternatives such as parabenzoquinone EPI-743 and rapamycin are under study in the treatment of the disease.
PubMed: 37064335
DOI: 10.1159/000527538 -
International Journal of Molecular... Jul 2020Inborn errors of Riboflavin (Rf) transport and metabolism have been recently related to severe human neuromuscular disorders, as resulting in profound alteration of... (Review)
Review
Inborn errors of Riboflavin (Rf) transport and metabolism have been recently related to severe human neuromuscular disorders, as resulting in profound alteration of human flavoproteome and, therefore, of cellular bioenergetics. This explains why the interest in studying the "flavin world", a topic which has not been intensively investigated before, has increased much over the last few years. This also prompts basic questions concerning how Rf transporters and FAD (flavin adenine dinucleotide) -forming enzymes work in humans, and how they can create a coordinated network ensuring the maintenance of intracellular flavoproteome. The concept of a coordinated cellular "flavin network", introduced long ago studying humans suffering for Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), has been, later on, addressed in model organisms and more recently in cell models. In the frame of the underlying relevance of a correct supply of Rf in humans and of a better understanding of the molecular rationale of Rf therapy in patients, this review wants to deal with theories and existing experimental models in the aim to potentiate possible therapeutic interventions in Rf-related neuromuscular diseases.
Topics: Flavoproteins; Humans; Models, Biological; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Proteins; Neuromuscular Diseases; Riboflavin; Riboflavin Deficiency
PubMed: 32722651
DOI: 10.3390/ijms21155310 -
American Journal of Human Genetics Jun 2016Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular... (Comparative Study)
Comparative Study
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.
Topics: Adult; Blotting, Western; Case-Control Studies; Cells, Cultured; Electron Transport; Female; Fibroblasts; Flavin-Adenine Dinucleotide; Frameshift Mutation; Gene Expression Profiling; Humans; Infant; Infant, Newborn; Liver; Male; Mitochondrial Diseases; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle, Skeletal; Mutagenesis, Site-Directed; Nucleotidyltransferases; Protein Binding; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Riboflavin; Skin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Vitamin B Complex; Young Adult
PubMed: 27259049
DOI: 10.1016/j.ajhg.2016.04.006 -
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 -
CNS Neuroscience & Therapeutics Oct 2012To explore risk factors for stroke independent of hypertension and the relationship between riboflavin kinase (RFK) and stroke.
AIMS
To explore risk factors for stroke independent of hypertension and the relationship between riboflavin kinase (RFK) and stroke.
METHODS
Gene expression profiling in the brains of spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP) was comparatively analyzed by gene chips. The differentially expressed gene RFK was further verified by q-PCR and Western blot. The protective role of RFK-regulated flavins (including riboflavin, flavin mononucleotide, and flavin adenine dinucleotide) in stroke was observed in middle cerebral artery occlusion (MCAO) mice. Influence of flavins on apoptosis and death in oxygen and glucose deprivation (OGD)-treated neurons was examined by flow cytometry. Bax and Bcl-2 proteins were detected by Western blot.
RESULTS
Of the 76 differentially expressed genes, 41 genes were upregulated, and 35 genes were downregulated in SHRSP as compared with SHR. RFK was significantly downregulated in SHRSP. Flavins markedly decreased infarct area in MCAO mice, inhibited apoptosis and death in OGD-treated neurons, and decreased Bax protein expression.
CONCLUSIONS
Physiological downregulation of RFK may be a new potential risk factor for stroke, which probably affects the absorbance and utility of riboflavin and further destroys the protective effect of flavins on stroke. RFK might act as a therapeutic target for stroke.
Topics: Analysis of Variance; Animals; Apoptosis; Brain Infarction; Cells, Cultured; Cerebral Cortex; Dinitrocresols; Disease Models, Animal; Embryo, Mammalian; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Glucose; Hypoxia; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Inbred SHR; bcl-2-Associated X Protein
PubMed: 22925047
DOI: 10.1111/j.1755-5949.2012.00379.x -
Brain : a Journal of Neurology Dec 2018Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene...
Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.
Topics: Charcot-Marie-Tooth Disease; Child, Preschool; Disability Evaluation; Disease Progression; Female; Humans; Infant; Infant, Newborn; Male; Observer Variation; Psychometrics; Reproducibility of Results; Severity of Illness Index
PubMed: 30476010
DOI: 10.1093/brain/awy280 -
Orphanet Journal of Rare Diseases Jul 2018Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic...
BACKGROUND
Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.
RESULTS
We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.
CONCLUSIONS
Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
Topics: Acidosis; Activities of Daily Living; Acyl-CoA Dehydrogenase; Amino Acid Metabolism, Inborn Errors; Cardiomyopathy, Hypertrophic; Electron Transport Complex I; Female; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Prognosis; Riboflavin
PubMed: 30025539
DOI: 10.1186/s13023-018-0784-8 -
Nutrition Journal Jun 2021This study examined incidence rates, temporal trends, and demographic factors associated with vitamin deficiencies/disorders in all United States military personnel from...
BACKGROUND
This study examined incidence rates, temporal trends, and demographic factors associated with vitamin deficiencies/disorders in all United States military personnel from 1997 to 2015 (mean N = 1,382,266/year).
METHODS
Employing an ecological study design, the Defense Medical Epidemiological Database and specific International Classification of Diseases codes were used to determine incidence rates for clinically-diagnosed vitamin deficiencies/disorders. Associations with demographic factors were examined.
RESULTS
The overall incidence rate of vitamin deficiencies/disorders was 92.7 cases/100,000 person-years (p-yr). Highest rates were for vitamin D (53.7 cases/100,000 p-yr), other B-complex vitamins (20.2 cases, 100,000 p-yr), vitamin B anemia (7.6 cases/100,000 p-yr), deficiencies of "other vitamins" (5.9 cases/100,000 p-yr), and vitamin A (2.5 cases/100,000 p-yr). Thiamin, riboflavin, niacin, pyridoxine, folate, vitamin C, and vitamin K deficiencies and hypervitaminoses A and D had < 1 case/100,000 p-yr. Rates for vitamin D, other B-complex, "other vitamin", and thiamin deficiencies increased over time, while vitamin A and C deficiencies decreased. Women had higher incidence rates for all examined deficiencies/ disorders except niacin and vitamin C. Incidence rates rose with age in 8 of 15 deficiency/disorder categories and blacks had higher incidence rates in 9 of 15 deficiency/disorder categories.
CONCLUSIONS
The overall rate of clinically-diagnosed vitamin deficiencies and disorders was low but higher in women and minority subgroups. As for most illnesses, the diagnosed incidence of such disorders may be an underestimate of the actual incidence. These findings can guide clinical decision making with regard to testing for nutritional deficiencies and delivering public health information to at risk populations.
CLINICAL TRIAL REGISTRATION
(No. ISRCTN58987177 ). Registration date 9 October 2019.
Topics: Ascorbic Acid; Avitaminosis; Female; Humans; Military Personnel; United States; Vitamin A; Vitamins
PubMed: 34130698
DOI: 10.1186/s12937-021-00708-2