Riboflavin Therapy Research Articles

Brown-Vialetto-van Laere syndrome: A riboflavin responsive neuronopathy of infancy with singular features

We report the case of a previously healthy child presenting at 6 months of age with mild feeding difficulties and then developing hypotonia, progressive bulbar palsy with respiratory compromise and lower motor neuron signs, causing her to spend 4 months in the Paediatric Intensive Care Unit.Neurophysiological studies demonstrated a motor neuronopathy involving anterior horn cells and cranial nerve nuclei and abnormal brainstem auditory evoked potentials, leading to a diagnosis of Brown-Vialetto-van Laere Syndrome, confirmed by genetic testing (SLC52A3). Magnetic Resonance Imaging showed signal changes in the dorsal column of the spinal cord. She developed a coarse face and abnormal hair pattern.Sustained clinical improvement has been observed during almost 4 years of high-dose riboflavin therapy.

Modified-release capsules containing sodium riboflavin 5′-phosphate

Introduction: The focus of this work was to produce delayed-release capsules containing riboflavin (vitamin B2, as API) layered pellets. Riboflavin therapy is indicated in patients with a riboflavin deficiency, which usually occurs in conjunction with malabsorption, alcoholism or a protein-calorie deficiency and rarely as the sole vitamin deficiency. Riboflavin is readily absorbed from the upper gastrointestinal tract by a specific transport mechanism. The dissolution rate of coated capsules was controlled through the coating of the capsules and the thickness of the coating layer.Methods: The core pellets (Cellet 300) were loaded with a 10% aqueous solution of sodium riboflavin 5′-phosphate by a layering technique in a coating pan. Hard capsules were filled with riboflavin layered pellets and coated with Eudragit NE polymer with different coating layer thicknesses. The dissolution was tested in gastric and intestinal fluids with the half-change method. The dissolution profiles were analyzed with the use of different mathematical models and an attempt was made to predict the optimum coating film thickness that ensures the required degree and rate of dissolution.Results: A new solid dosage form was developed which can enhance the bioavailability of riboflavin. RRSBW distribution and the Chapman–Richards growth function were used to fit the dissolution profiles. Statistical analysis indicated that the best products were described by the Chapman–Richards equation. The results were utilized to create a theoretical model suitable for prediction of the optimum film thickness that ensures the required release of riboflavin.

Brown‐Vialetto‐Van Laere and Fazio Londe syndromes: defects of riboflavin transport with biochemical similarities to multiple acyl‐CoA dehydrogenation defects (MADD)

Riboflavin-responsive defects of electron transfer were firstdescribed in the 1980s as mild variant forms of MADD orglutaric acidemia type II (Gregersen et al 1982; Amendt andRhead 1986). Some of these patients were shown to havedefects in ETF and ETF dehydrogenase but a number ofpatients remained in whom the biochemical and moleculardefects remained elusive (Roettger et al 1992). It was pos-tulated that these patients may have defect(s) of riboflavintransport or abnormalities in downstream flavin metabolismto form the active FAD/FMN cofactors required for facili-tating electron transfer. Treatment of some of these patientswith high dose riboflavin tended to normalize the abnormalmetabolite profiles. Treatment with high dose riboflavin wasalso subjectively claimed to improve the clinical phenotype,a difficult judgment given the mild and intermittent natureof the phenotype. The phenotype of most of the cases ofriboflavin-responsive MADD was that of stress-inducedmyopathy (de Visser et al 1986; DiDonato et al 1989).Recently, the genetic basis for Brown-Vialetto-Van Laeresyndrome(BVVLS) wasidentified asapreviouslyunknownopen reading frame C20orf54 (Green et al 2010). This genewas subsequently shown to encode a riboflavin transporterand the gene is now renamed SLC52A3 encoding humanriboflavin transporter 2 (hRFT2). At around the same time, adominantly inherited mutation in SLC52A1encoding humanriboflavin transporter 1 (hRFT1) was identified in theclinically normal mother of a neonate with complex neuro-logical disease and a MADD metabolite profile whichresponded dramatically to riboflavin therapy. It is presumedthat the neonate was riboflavin deficient secondarily to thematernal haploinsufficiency and from increased riboflavindemand during pregnancy (Ho et al 2011). Bosch and cow-orkersandothersextendedthephenotypeofSLC52A3defectsto include patients with Fazio Londe syndrome, which waspreviouslyconsideredtobeanoverlappingclinicalphenotypebut without a molecular basis (Bosch et al 2011). Anand andcoworkers added an additional riboflavin-responsive BVVLScase to the data base (Anand et al 2012). In this volume ofJIMD, Haack et al 2012, demonstrating the power of wholeexome sequencing identified disease-causing mutations in athird riboflavin transporter in an individual with BVVLS.They identified mutations in SLC52A2 and exquisitely dem-onstrate a functional defect of hRFT3, the gene product. Thispresent case also highlights the likely mechanisms of diseasephenotype in BVVLS.The clinical phenotype of BVVLS is not what wewould immediately associate with defects of electrontransfer such as MADD. For this reason, it is importantfor investigators to recognize this phenotype as it wouldappear that these defects of riboflavin transport areeminently treatable with high dose riboflavin therapy.BVVLS is rare and has been reported in about 60patients in total but may be under diagnosed. It presentsprimarily with a severe sensorineural deafness. The ageof onset is from infancy to the third decade. During therelentless progress, lower motor neuron limb signs leadto neuropathy and are accompanied by cerebellar ataxia,optic atrophy, retinal pigmentary changes, mental retar-dation and psychiatric abnormalities. Death is usually aresult of diaphragmatic paralysis (Dipti et al 2005).

O03 High-dose riboflavin therapy in Brown-Vialetto-Van Laere syndrome: clinical and biochemical improvement

O03 High-dose riboflavin therapy in Brown-Vialetto-Van Laere syndrome: clinical and biochemical improvement A.R. Foley, A.A. Broomfield, A. Pandraud, J.O. Johnson, A.B. Singleton, I.P. Hargreaves, J.M. Land, S. Grunewald, S. Rahman, P. Clayton, H. Houlden, M.M. Reilly, F. Muntoni. Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK; Department of Clinical and Molecular Genetics, UCL Institute of Child Health, London, UK; MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA; Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK; Metabolic Medicine Unit, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK

Update on clinical aspects and treatment of selected vitamin‐responsive disorders II (riboflavin and CoQ10)

Riboflavin and ubiquinone (Coenzyme Q(10), CoQ(10)) deficiencies are heterogeneous groups of autosomal recessive conditions affecting both children and adults. Riboflavin (vitamin B(2))-derived cofactors are essential for the function of numerous dehydrogenases. Genetic defects of the riboflavin transport have been detected in Brown-Vialetto-Van Laere and Fazio-Londe syndromes (C20orf54), and haploinsufficiency of GPR172B has been proposed in one patient to cause persistent riboflavin deficiency. Mutations in the electron tranferring fravoprotein genes (ETFA/ETFB) and its dehydrogenase (ETFDH) are causative for multiple acyl-CoA dehydrogenase deficiency. Mutations in ACAD9, encoding the acyl-CoA dehydrogenase 9 protein were recently reported in mitochondrial disease with respiratory chain complex I deficiency. All these conditions may respond to riboflavin therapy. CoQ(10) is a lipid-soluble component of the cell membranes, where it functions as a mobile electron and proton carrier, but also participates in other cellular processes as a potent antioxidant, and by influencing pyrimidine metabolism. The increasing number of molecular defects in enzymes of the CoQ(10) biosynthetic pathways (PDSS1, PDSS2, COQ2, COQ6, COQ9, CABC1/ADCK3) underlies the importance of these conditions. The clinical heterogeneity may reflect blocks at different levels in the complex biosynthetic pathway. Despite the identification of several primary CoQ(10) deficiency genes, the number of reported patients is still low, and no true genotype-phenotype correlations are known which makes the genetic diagnosis still difficult. Additionally to primary CoQ(10) deficiencies, where the mutation impairs a protein directly involved in CoQ(10) biosynthesis, we can differentiate secondary deficiencies. CoQ(10) supplementation may be beneficial in both primary and secondary deficiencies and therefore the early recognition of these diseases is of utmost importance.

Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency

NADPH-cytochrome P450 oxidoreductase (CYPOR) is essential for electron donation to microsomal cytochrome P450-mediated monooxygenation in such diverse physiological processes as drug metabolism (approximately 85-90% of therapeutic drugs), steroid biosynthesis, and bioactive metabolite production (vitamin D and retinoic acid metabolites). Expressed by a single gene, CYPOR's role with these multiple redox partners renders it a model for understanding protein-protein interactions at the structural level. Polymorphisms in human CYPOR have been shown to lead to defects in bone development and steroidogenesis, resulting in sexual dimorphisms, the severity of which differs significantly depending on the degree of CYPOR impairment. The atomic structure of human CYPOR is presented, with structures of two naturally occurring missense mutations, V492E and R457H. The overall structures of these CYPOR variants are similar to wild type. However, in both variants, local disruption of H bonding and salt bridging, involving the FAD pyrophosphate moiety, leads to weaker FAD binding, unstable protein, and loss of catalytic activity, which can be rescued by cofactor addition. The modes of polypeptide unfolding in these two variants differ significantly, as revealed by limited trypsin digestion: V492E is less stable but unfolds locally and gradually, whereas R457H is more stable but unfolds globally. FAD addition to either variant prevents trypsin digestion, supporting the role of the cofactor in conferring stability to CYPOR structure. Thus, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy in utero, if predicted prenatally, or rescued postnatally in less severe cases.

Comparison of the effects of dietary factors in the management and prophylaxis of migraine.

Migraine is defined as a disorder characterized by intermittent headache episodes, accompanied with nausea, photophobia and/or phonophobia. Pharmacological therapy is in accordance with the severity of pain and may include acute, prophylactic and most commonly both approaches. The aim of the acute therapy is stopping or alleviating the attack or progression of the pain and, in case of a migraine attack that has started, lessening the pain. Preventive therapy aims to reduce attack frequency and severity. This study was designed to evaluate the effect of dietary factors in the management and prophylaxis of migraine in cases diagnosed as having migraine disorder according to the 2003-IHS criteria. Fifty consecutive Turkish patients (13 men, 37 women) with diagnosis of migraine were randomly divided into two groups for treatment protocols with the written approval of the ethics committee. The cases in the first group (K) were treated with metoprolol, vitamin B(2) (riboflavin), and naproxen sodium just at the aura or at the beginning of the attacks. The cases in the second group (D) were also supplied with a comprehensive dietary list arranged by our algology clinic in addition to the same medication protocol. There were no demographic differences between the cases (P > 0.05). VAS scores were lower in group D than group K (P < 0.01), and also the migraine attack frequencies and monthly amounts of analgesic consumed amounts were also statistically significantly less. It was concluded that beta-blocker and riboflavin therapy supplemented with a convenient diet with appropriate alternatives in patients with migraine disorder was associated with statistically significant decreases in headache frequency, intensity, duration and medication intake.

Riboflavin and Ultraviolet A Collagen Crosslinking of the Cornea for the Treatment of Keratitis

To describe riboflavin and ultraviolet light (UV) collagen crosslinking as an effective treatment for infectious keratitis. A 25-year-old previously healthy female contact lens user was diagnosed with unilateral severe keratitis with unclear pathogenesis, although the clinical presentation suggested acanthamoeba as the infectious agent. A 4-mm diameter, annular, semi-opaque infiltrate was found on the paracentral parts of the cornea in the left eye (OS). Laboratory examinations for bacteria, herpes simplex, and acanthamoeba were performed, but no specific pathogen could be detected. Best corrected visual acuity (BCVA) at presentation was 20/1000. Treatment was initialized with broad-spectrum antibiotics also covering acanthamoeba. During the first month of treatment the keratitis progressed and the corneal thickness diminished. Therefore, treatment with riboflavin and UV collagen crosslinking was initiated. After riboflavin and UV collagen crosslinking therapy, there was a rapid decrease of pain and necrotic material. Reepithelialization of the cornea started within a few days and was complete within a month. After 2 months, the wound had healed completely. Nine months after the UV treatment, BCVA was 20/30. This case illustrates the positive effects of riboflavin and UV collagen crosslinking on presumed infectious keratitis with a satisfactory final visual outcome. This may be a promising new treatment for keratitis, although this remains to be elucidated in detail in future studies. Until more data are available this treatment should only be considered in therapy-refractive keratitis or ulceration and not in the first line of defence since it may have cytotoxic side effects.

Impeded Electron Transfer From a Pathogenic FMN Domain Mutant of Methionine Synthase Reductase and Its Responsiveness to Flavin Supplementation

Methionine synthase reductase (MSR) is a diflavin oxidoreductase that transfers electrons from NADPH to oxidized cobalamin and plays a vital role in repairing inactive cobalamin-dependent methionine synthase. MSR deficiency is a recessive genetic disorder affecting folate and methionine metabolism and is characterized by elevated levels of plasma homocysteine. In this study, we have examined the molecular basis of MSR dysfunction associated with a patient mutation, A129T, which is housed in the FMN binding domain and is adjacent to a cluster of conserved acidic residues found in diflavin oxidoreductases. We show that the substitution of alanine with threonine destabilizes FMN binding without affecting the NADPH coenzyme specificity or affinity, indicating that the mutation's effects may be confined to the FMN module. The A129T MSR mutant transfers electrons to ferricyanide as efficiently as wild type MSR but the rate of cytochrome c, 2,6-dichloroindophenol, and menadione reduction is decreased 10-15 fold. The mutant is depleted in FMN and reactivates methionine synthase with 8% of the efficiency of wild type MSR. Reconstitution of A129T MSR with FMN partially restores its ability to reduce cytochrome c and to reactivate methionine synthase. Hydrogen-deuterium exchange mass spectrometric studies localize changes in backbone amide exchange rates to peptides in the FMN-binding domain. Together, our results reveal that the primary biochemical penalty associated with the A129T MSR mutant is its lower FMN content, provide insights into the distinct roles of the FAD and FMN centers in human MSR for delivering electrons to various electron acceptors, and suggest that patients harboring the A129T mutation may be responsive to riboflavin therapy.

Ethylmalonic Encephalopathy: Clinical and Biochemical Observations

Ethylmalonic encephalopathy (EE) is a rare, recently defined inborn error of metabolism which affects the brain, gastrointestinal system and peripheral blood vessels and is characterized by a unique constellation of clinical and biochemical features. A 7-month-old male, who presented with psychomotor retardation, chronic diarrhea and relapsing petechiae is described with the objective of highlighting the biochemical and neuroradiological features of this disorder as well as the effect of high-dose riboflavin therapy. Urinary organic acid analysis revealed markedly increased excretion of ethylmalonic acid, isobutyrylglycine, 2-methylbutyrylglycine and isovalerylglycine. Acylcarnitine analysis in dried blood spots showed increased butyrylcarnitine. Short-chain acyl-CoA dehydrogenase (SCAD) activity in muscle was normal as were mitochondrial OXPHOS enzyme activities in cultured skin fibroblasts. In skeletal muscle the catalytic activity of complex II was decreased. Brain MRI revealed bilateral and symmetrical atrophy in the fronto-temporal areas, massive enlargement of the subarachnoid spaces and hyperdensities on T (2) sequences of the basal ganglia. Mutation analysis of the ETHE1 gene demonstrated homozygosity for the Arg163Gly mutation, confirming the diagnosis of EE at a molecular level. On repeat MRI, a significant deterioration was seen, correlating well with the clinical deterioration of the patient.

Coordinated and reversible reduction of enzymes involved in terminal oxidative metabolism in skeletal muscle mitochondria from a riboflavin‐responsive, multiple acyl‐CoA dehydrogenase deficiency patient

In this case report we studied alterations in mitochondrial proteins in a patient suffering from recurrent profound muscle weakness, associated with ethylmalonic-adipic aciduria, who had benefited from high dose of riboflavin treatment. Morphological and biochemical alterations included muscle lipid accumulation, low muscle carnitine content, reduction in fatty acid beta-oxidation and reduced activity of complexes I and II of the respiratory chain. Riboflavin therapy partially or totally reversed these symptoms and increased the level of muscle flavin adenine dinucleotide, suggesting that aberrant flavin cofactor metabolism accounted for the disease. Proteomic investigation of muscle mitochondria revealed decrease or absence of several flavoenzymes, enzymes related to flavin cofactor-dependent mitochondrial pathways and mitochondrial or mitochondria-associated calcium-binding proteins. All these deficiencies were completely rescued after riboflavin treatment. This study indicates for the first time a profound involvement of riboflavin/flavin cofactors in modulating the level of a number of functionally coordinated polypeptides involved in fatty acyl-CoA and amino acid metabolism, extending the number of enzymatic pathways altered in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.

Vitamin B2 Interference with TDx Drugs-of-Abuse Assays

Migraine is a headache condition found in significant frequency in the general population. One recent study has shown that riboflavin, Vitamin B2, is an effective prophylactic treatment for this headache condition. One subject in a recent study conducted by the Division of Forensic Toxicology, Armed Forces Institute of Pathology (AFIP) was taking 200 mg of riboflavin twice daily for the prevention of migraine headaches. When that subject's urine was tested using Abbott TDx drugs-of-abuse assays a number of tests resulted in a MX BKG error and all samples had BLK I values greater than those observed with normal urine specimens. The MX BKG error occurs when the BLK I value is greater than the upper limit determined by the manufacturer for a particular assay. High BLK I values may result if the specimen being analyzed contains a fluorophore that will compete with the fluorescein-labeled antibody used in the assay. This error serves as a notification that an interfering substance may be present and the assay is not performing according to manufacturer-specifications. Upon termination of riboflavin therapy the subject's BLK I values began to decrease within 60 h of the last 200 mg dose. A second subject began chronic riboflavin use to confirm this interferent effect. Elevated BLK I values resulted within 3 h of a single 200 mg dose and MX BKG errors occurred 1 h after a second 400 mg dose. No false negative results were noted with either subject (both subjects used butalbital and the first subject also used hydrocodone and diazepam during the study), suggesting that riboflavin is not an adulterant. Riboflavin use, however, does interfere with the TDx DAU assays and may result in quantitative values being determined which are of questionable validity in the face of an elevated BLK I value or may result in only an MX BKG error and no quantitative value reported. It is unclear if the interfering fluorophore is simply riboflavin itself or a combination of riboflavin and its metabolic products. Results obtained on urine samples collected from individuals using prophylactic riboflavin for migraine prevention and analyzed by TDx may be of questionable validity. Such samples may require analysis utilizing another immunoassay technique that does not employ a fluorescein-labeled antibody.

Mitochondrial myopathy with tRNA Leu(UUR) mutation and complex I deficiency responsive to riboflavin

Deficiency of complex I (reduced nicotinamide adenine dinucleotide dehydrogenase–ubiquinone oxidoreductase) of the mitochondrial respiratory chain may be seen as a pure myopathy or as a neuromuscular disorder at presentation. Efficacy of long- term therapy for these disorders is yet to be established. We report the case of a female patient with complex I deficiency and skeletal myopathy, who has had a sustained clinical response to riboflavin during 3 years of therapy. Molecular studies found no mutations in the putative flavin mononucleotide binding site in the 51 kd subunit of complex I, but a T-to-C transition at nucleotide 3250 in the mitochondrial DNA tRNA Leu(UUR) gene was identified. This mutation has been reported in one other family in that five members had fatigue with or without muscle weakness. There were also five cases of unexplained infant deaths in that family and two cases in the family reported here. Riboflavin therapy should be attempted in all patients with complex I deficiency when the clinical presentation is one of isolated skeletal myopathy. (J Pediatr 1997;130:138-45)

Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy

The clinical phenotype of multiple acyl-CoA dehydrogenase deficiency in infancy is characterized by recurrent episodes of hypoketotic hypoglycemia and lipid storage myopathy. Brain damage has been described only as a consequence of severe and protracted hypoglycemia. We describe a child who experienced normal physical and psychomotor development until the age of 3 years, who then developed progressive intention tremors, dysarthria, ataxia, and spastic tetraparesis. Episodes of acute metabolic distress were never observed. Magnetic resonance imaging disclosed abnormal signals within the white mater of the brain and cerebellum, suggesting leukodystrophy. Gas chromatography/mass spectrometry analysis revealed abnormally high levels of glutaric acid, dicarboxylic acids, and glycine derivatives in urine. Riboflavin therapy was initiated at 4 years of age, when the patient had already lost control of trunk and head posture. Consistent improvement rapidly occurred after riboflavin supplementation. Glutaric aciduria type II may cause brain damage, in spite of the absence of acute metabolic distress, and should be considered in the differential diagnosis of leukodystrophies.

A riboflavin-responsive lipid storage myopathy due to multiple acyl-CoA dehydrogenase deficiency: An adult case

A 62-year-old man was admitted to our hospital because of easy fatigability of the lower limbs during walking. The biopsied muscle specimen showed excessive lipid accumulation. The carnitine concentration in the muscle was at the lower level of the normal range. Organic acid urinalysis was consistent with the diagnosis of multiple acyl-CoA dehydrogenase deficiency or glutaric acidemia type II. In cultured lymphoblastoid cells from this patient there was impaired β-oxidation, but the activities of acyl-CoA dehydrogenases were normal. Riboflavin therapy resulted in a dramatic improvement in both clinical and biochemical aspects. In this patient, the defect in coenzyme binding to electron transfer flavoprotein (ETF) or ETF-dehydrogenase was suspected. In the adult case of lipid storage myopathy, multiple acyl-CoA dehydrogenase deficiency should be suspected as one of its pathogenesis and riboflavin therapy should be considered.

Methaemoglobin reductase deficiency in dogs

Erythrocyte methaemoglobin reductase deficiency is described in a toy Alaskan Eskimo dog, a miniature poodle dog and a cocker/poodle cross dog. Blood methaemoglobin contents ranged from 19% to 36% of total haemoglobin, with methaemoglobin reductase values between 13% and 33% of normal. There appeared to be a negative linear correlation between erythrocyte methaemoglobin content and methaemoglobin reductase activity. A single intravenous injection of methylene blue (1 mg/kg body weight) resulted in a dramatic decrease in methaemoglobin content within 1 hour when given to two of the deficient dogs in the present study. Following the disappearance of methylene blue from blood, methaemoglobin content increased linearly at 3.2% and 2.5% per day in these dogs, suggesting that about 3.0% of erythrocyte haemoglobin is normally oxidised to methaemoglobin each day in dogs, as has been estimated in humans. Oral riboflavin therapy was not effective in reducing blood methaemoglobin content in deficient dogs.

A case of glutaric acidemia type I: Effect of riboflavin and carnitine

Glutaric acidemia, type I, is an organic acidemia associated with a progressive neurologic disorder. 1 By 1 year of age, affected individuals generally have recurrent episodes of vomiting and lethargy associated with metabolic acidosis. Progressive neurologic defici ts include dysarthria, dystonia, and choreoathetosis. Most affected Children are also mentally retarded. The presumptive diagnosis of GA-I is made by gas chromatography-mass spectrometry of urine revealing peaks of glutaric acid and its principal metabolites 3-OH-glutarate and glutaconate. The enzyme deficiency, glutaryl CoA dehydrogenase, is demonstrable in leukocytes, fibroblasts, and hepatocytes. 2 Therapeutic approaches have included low-protein diets and diets low in tryptophan and lysine, the precursors of glutaryl CoA. 3 Riboflavin (as flavin adenine dinucleotide), a cofactor of glutaryl CoA dehydrogenase, has been given to enhance residual enzyme activity? L-Carnitine has been used to stimulate the formation and excretion of shortchain acylcarnitine derivatives of glutaric acid. 4 Finally, because of evidence of inhibition of synthesis of G A B A by glutaric acid and the presence of decreased G A B A in brains of affected individuals, the G A B A analog baclofen has been given) With these techniques, progression of symptoms has been arrested in a number of cases but little clinical improvement has resulted? -8 The present report concerns a boy with GA-I who had progressive dystonic cerebral palsy associated with basal ganglia degeneration and who responded to riboflavin and L-carnitine therapy with evidence of biochemical and clinical improvement.

Treatment of Cystinosis: Decrease in Content of Free Cystine in Leukocytes and Alleviation of Progressive Renal Failure by Treatment with Riboflavin

AbstractTwo patients with cystinosis were treated with riboflavin, resulting in a decrease in the content of free cystine and taurine in leukocytes. Riboflavin therapy was not sufficient to improve the renal function; however, the progression of renal failure was alleviated.

CARNITINE METABOLISM IN RECURRENT REYE SYNDROME DUE TO DEFECTIVE ACETYL-CoA DISPOSAL

A ten month old infant with multiple Reye Syndrome-like attacks excreted during the illness β-hydroxybutrate,acetoacetate and large amounts of the following dicarboxylic acids: adipate, suberate,sebacate, ethylmalonate and glutarate.Production of CO2 from(1-14C) and(U-14C)palmitate and(1-14C)butyrate was 83%, 5% and 50%, respectively. Acyl-CoA dehydrogenase was normal. Riboflavin therapy eliminated the dicarboxylic aciduria under ordinary load conditions. Carnitine metabolism was studied because plasma carnitine was low (22.2 μmol/l)and continued to decrease despite the apparent beneficial effect of riboflavin.Urinary free and short chain acylcarnitines (SCAC) were initially 17.1 and 108.9 μmol/1 (N:24.2 and 38.9),suggesting that hypocarnitinemia was due to urinary SCAC-loss (86-96% of total) although absolute losses (227 μmol/g cr)were only mildly elevated. Urine values normalized during i.v. glucose. After recovery from the attack and from dicarboxylic aciduria under riboflavin therapy, oral carnitine was given. This unveiled the persistence of the underlying defect, because SCAC excretion increased to 994 μmol/g cr. On a beef broth supplemented diet, SCAC excretion was 791-825 μmol/g cr. On a low-fat,low-protein diet without beef broth SCAC was 140 μmol/g cr.Acetylcarnitine was consistently the major urinary carnitine ester:1052 nanomol/ml (N:18.9) or 620 μmol/g cr. This compares with the acetylcarnitine excretion of adults after 60hrs. starvation! and suggests a partial block in the disposal of acetyl-CoA.Reye Syndrome-like attacks may be precipitated by mitochondrial trapping of CoA-SH as acetyl-CoA viz. acylCoA.

Multiple acyl-CoA dehydrogenase deficiency occurring in pregnancy and caused by a defect in riboflavin metabolism in the mother: Study of a kindred with seven deaths in infancy: Value of riboflavin therapy in preventing this syndrome

Seven infants in one kindred died: one was stillborn; the others, who were floppy at birth and were breast-fed, developed a disorder with the odor of sweaty feet and died in early infancy. In two further pregnancies, 3-hydroxvisovaleric, glutaric, and C6-C10-dicarboxylic acids were demonstrated in the mother's urine during the seventh month. Riboflavin therapy in the last trimester of pregnancy and a riboflavin-rich diet given the infants prevented this syndrome. The presence of abnormal erythrocyte glutathione-reductase activity in the mother while she excreted normal amounts of riboflavin in her urine indicates a probable disorder of riboflavin metabolism resulting in multiple acyl-CoA dehydrogenase deficiency.