An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency.

Riboflavin transporter deficiency (RTD) is a rare neurological condition that encompasses the Brown-Vialetto-Van Laere and Fazio-Londe syndromes since the discovery of pathogenic mutations in the SLC52A2 and SLC52A3 genes that encode human riboflavin transporters RFVT2 and RFVT3. Patients present with a deteriorating progression of peripheral and cranial neuropathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory compromise which when left untreated can be fatal. Considerable progress in the clinical and genetic diagnosis of RTDs has been made in recent years and has permitted the successful lifesaving treatment of many patients with high dose riboflavin supplementation. In this review, we first outline the importance of riboflavin and its efficient transmembrane transport in human physiology. Reports on 109 patients with a genetically confirmed diagnosis of RTD are then summarized in order to highlight commonly presenting clinical features and possible differences between patients with pathogenic SLC52A2 (RTD2) or SLC52A3 (RTD3) mutations. Finally, we focus attention on recent work with different models of RTD that have revealed possible pathomechanisms contributing to neurodegeneration in patients.

Adequate vitamin B12 and riboflavin status from menus alone in residential care facilities in the Lower Mainland, British Columbia.

Older adults have potential increased risk of nutrient deficiencies because of age-related decreased dietary intake and malabsorption; it is important to ensure nutrient needs are met to avoid adverse health outcomes. B vitamins are of particular interest: vitamin B12 deficiency can cause irreversible neurodegeneration; there is mandatory folic acid fortification in Canada; and suboptimal riboflavin status has been reported among older adults in the United Kingdom. In this exploratory secondary analysis study we assessed vitamin B12 and riboflavin biochemical status (via microparticle enzyme immunoassay and erythrocyte glutathione reductase activity coefficient (EGRac), respectively), and the vitamin B12, riboflavin, and folate content of menus served to a convenience sample of older adults (≥65 years) from 5 residential care facilities within the Lower Mainland of British Columbia, Canada. Diet was assessed from customized 28-day cycle meal plans. Participants (n = 207; 53 men and 154 women) were aged 86 ± 7 years, largely of European descent (92%), and nonsmokers (95%). The menus served had a low prevalence of inadequacy for vitamin B12 and riboflavin (only 4% and 1% of menus contained less than the estimated average requirement (EAR), respectively), but 93% contained less than the EAR for folate. Mean ± SD serum total vitamin B12 concentration was 422 ± 209 pmol/L, and EGRac was 1.30 ± 0.19. The majority of older adults in residential care were provided with adequate vitamin B12 and riboflavin menu amounts, and only 5% were vitamin B12 deficient (<148 pmol/L). However, 26% were riboflavin deficient (EGRac ≥ 1.4), which may warrant further investigation.

Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience.

INTRODUCTION: Riboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in the brain. In 2010 it was demonstrated that mutations in the riboflavin transporter genes SLC52A2 (coding for RFVT2) and SLC52A3 (coding for RFVT3) cause a neurodegenerative disorder formerly known as Brown-Vialetto-Van Laere (BVVL) syndrome, now renamed to riboflavin transporter deficiency. Five years after the diagnosis of the first patient we performed a review of the literature to study the presentation, treatment and outcome of patients with a molecularly confirmed diagnosis of a riboflavin transporter deficiency. METHOD: A search was performed in Medline, Pubmed using the search terms 'Brown-Vialetto-Van Laere syndrome' and 'riboflavin transporter' and articles were screened for case reports of patients with a molecular diagnosis of a riboflavin transporter deficiency. RESULTS: Reports on a total of 70 patients with a molecular diagnosis of a RFVT2 or RTVT3 deficiency were retrieved. The riboflavin transporter deficiencies present with weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties and respiratory difficulties which are caused by a sensorimotor axonal neuropathy and cranial neuropathy. Biochemical abnormalities may be absent and the diagnosis can only be made or rejected by molecular analysis of all genes. Treatment with oral supplementation of riboflavin is lifesaving. Therefore, if a riboflavin transporter deficiency is suspected, treatment must be started immediately without first awaiting the results of molecular diagnostics.

Suspected outbreak of riboflavin deficiency among populations reliant on food assistance: a case study of drought-stricken Karamoja, Uganda, 2009-2010.

BACKGROUND: In 2009, a humanitarian response was launched to address a food security and livelihoods crisis in Karamoja, Uganda. During a polio immunization campaign in mid-August 2009, health workers in Nakapiripit District reported a concern about an increase in mouth sores, or angular stomatitis (AS) and gum ulcerations, among children in one village, and an investigation was launched. OBJECTIVE: This article describes the investigation, lessons learned, and provides guidance for monitoring micronutrient deficiencies among populations receiving food assistance. DESIGN: An investigation into a suspected outbreak of riboflavin (vitamin B2) deficiency was initiated, including a rapid assessment, mass screening, a convenience sample collection of blood specimens (n = 58 symptomatic cases and n = 18 asymptomatic individuals), and analysis of the general food ration (70% ration). RESULTS: Findings showed signs of AS in only 399 (0.2%) of 179,172 screened individuals, including adults and children. Biochemical analysis confirmed riboflavin deficiency in 84.5% of specimens from symptomatic individuals and 94.4% of specimens from asymptomatic individuals. Ration distribution data showed that 55% of distributions provided less than half the riboflavin RDA. CONCLUSION: Evidence was insufficient to confirm an actual outbreak of riboflavin deficiency, though the present investigation adds further documentation that micronutrient deficiencies continue to persist among populations in emergency settings. This article describes challenges, lessons learned, and guidance for monitoring micronutrient deficiencies among food assistance recipients, including: ongoing nutrition monitoring and surveillance; training and sensitization about micronutrient deficiencies, sensitization of the population about locally-available food, and identifying ways to improve micronutrient interventions.

Effects of methodological variation on assessment of riboflavin status using the erythrocyte glutathione reductase activation coefficient assay.

Riboflavin status is usually measured as the in vitro stimulation with flavin adenine dinucleotide of the erythrocyte enzyme glutathione reductase, and expressed as an erythrocyte glutathione reductase activation coefficient (EGRAC). This method is used for the National Diet and Nutrition Surveys (NDNS) of the UK. In the period between the 1990 and 2003 surveys of UK adults, the estimated prevalence of riboflavin deficiency, expressed as an EGRAC value > or = 1.30, increased from 2 to 46 % in males and from 1 to 34 % in females. We hypothesised that subtle but important differences in the detail of the methodology between the two NDNS accounted for this difference. We carried out an evaluation of the performance of the methods used in the two NDNS and compared against an 'in-house' method, using blood samples collected from a riboflavin intervention study. Results indicated that the method used for the 1990 NDNS gave a significantly lower mean EGRAC value than both the 2003 NDNS method and the 'in-house' method (P < 0.0001). The key differences between the methods relate to the concentration of FAD used in the assay and the duration of the period of incubation of FAD with enzyme. The details of the EGRAC method should be standardised for use in different laboratories and over time. Additionally, it is proposed that consideration be given to re-evaluating the basis of the EGRAC threshold for riboflavin deficiency.

Organic acid concentrations in amniotic fluid found in normal and Down syndrome pregnancies.

INTRODUCTION: Organic acids were examined from normal and Down syndrome pregnancies to identify possible differences between the amniotic fluid from fetuses with Down Syndrome compared with that of normal fetuses. MATERIALS AND METHODS: Amniotic fluids were obtained from prior amniocenteses. Forty-one normal and 22 Down syndrome specimens were assayed using gas chromatography/mass spectrometry. RESULTS AND DISCUSSION: 5-hydroxycaproate, methylsuccinate, alpha-ketoglutarate, and adipate were significantly elevated in Down syndrome, suggesting riboflavin deficiency. Phenylpyruvate was also significantly elevated in fetuses with Down syndrome. Phenylpyruvate inhibits the metabolism of tetrahydrobiopterin, which is necessary for neurotransmitter metabolism. Elevated phenylpyruvate is consistent with previous research, suggesting a disturbance of tetrahydrobiopterin metabolism in Down syndrome. CONCLUSION: Organic acid markers for B2 deficiency are elevated in the amniotic fluid of fetuses with Down syndrome. Elevation of phenylpyruvate may impair neurotransmitter metabolism. Organic acid markers for B12 levels are not different between the Down syndrome and normal group.

[Thiamin and ribovlavin status in populations of Arkhangelsk].

It was been performed the epidemiological study of Thiamine and Riboflavin status of 3579 inhabitants in Arkhangelsk. Establish by 49.6% man and 47.4% woman have lower provision of thiamin. Lack of riboflavin reveal by 23.6% man and 21.7% woman. The analysis of the effect of seasonality on vitamins content shown the worst thiamin level in examined population in January-February and in September-October. The worst Riboflavin content observed in examined population in December-January and in July-August.

[The vitamins and minerals provision of children living in different ecological-biogeochemical zones in Chuvashia]. / Obespechennost' vitaminami i mineral'nymi veshchestvami detei, prozhivaiushchikh v razlichnykh ékologo-biogeokhimicheskikh zonakh Chuvashskoi respubliki.

The results of investigation about providing 96 children at the age of 11-12 with vitamins in different ecological-biogeochemical zones of Chuvashia are presented in this article. The actual nutrition of children was estimated, by questionnaire-weight Pokrovsky's method and the level of excretion of vitamins B1, B2 and ascorbic acid with urine was studied by fluorescent method. The deficiency of riboflavin (66% in girls and 97% in boys) and ascorbic acid deficiency (30% in children) was revealed in the daily ration, the quantity of thiamin was sufficient. The providing the organism of children with investigated vitamins is low in Chuvashia. There is the link between ecological-biogeochemical characteristics of Chuvashia and providing with vitamins B1, B2 and C, their quantity in food being the same.

[Structural-functional damage to cellular membranes in deficiency of vitamins A, E, B2, B6, PP in children with calculous pyelonephritis]. / Strukturno-funktsional'noe narushenie kletochnykh membran pri defitsite v organizme vitaminov A, E, B2, B6, PP u detei s kal'kuleznym pielonefritom.

Lipids were studied in 150 patients with nephrolithiasis, calculous pyelonephritis; enzymes, LPO products, phospholipase in 111 patients; vitamins A and E in 136 patients, vitamins B2, B6 and PP in 146 patients in the course of the disease, at admission and after treatment. In acute purulent and aggravated chronic calculous pyelonephritis lysophospholipids levels rose manifolds. Activation of LPO products, phospholipase, organ-specific enzymes is closely associated with low provision of vitamins A, E, B2, B6, PP. Deficiency of these vitamins ranged from 76.8 to 94.6% in acute purulent calculous pyelonephritis in all the patients.

Riboflavin deficiency in cystic fibrosis: three case reports.

Three cases of clinical riboflavin deficiency are reported in children aged 2-10 years attending a regional Cystic Fibrosis clinic. Riboflavin deficiency presented as angular stomatitis in all three patients. Patients were confirmed to be riboflavin deficient by assaying the activity of erythrocyte glutathione reductase. Patients were not on routine supplements of water-soluble vitamins before presentation and were treated with riboflavin supplements as part of a water-soluble vitamin complex. At presentation, one patient had poor nutritional status, but two patients were adequately nourished, receiving overnight Gastrostomy feeds. Data on these two patients indicate an adequate dietary intake of riboflavin, suggesting a mechanism for increased requirements, inadequate absorption or utilization. Additional deficiencies of thiamin, pyridoxine and iron were also observed. This paper reports the occurrence of a vitamin deficiency not previously reported in the cystic fibrosis population.

The thiamin, riboflavin and pyridoxine status of patients on emergency admission to hospital.

The aim of this study was to assess the prevalence of thiamin, riboflavin and pyridoxine deficiencies at admission to an acute hospital. One hundred and twenty adult patients were selected at random from those admitted via the Accident and Emergency department over 3 days. Comparisons were made with a group of 80 healthy blood donors sequentially attending a local transfusion centre. The alcohol intake of 500 patients admitted sequentially via the same Accident and Emergency department was also assessed. Erythrocyte transketolase (ETK), glutathione reductase (EGR) and aspartate aminotransferase (EAA) coenzyme activation assays were used to determine thiamin, riboflavin and pyridoxine deficiencies. The prevalences of deficiency states in the inpatient group were 21, 2.7 and 32% for thiamin, riboflavin and pyridoxine deficiencies respectively with 49.2% being deficient in one or more vitamin. The mean alcohol intake in the group of patients in whom this was assessed was 9.7 units per week compared with 10 units per week amongst blood donors.

Glutathione reductase deficiency in Saudi Arabia.

Glutathione reductase (GR) is a ubiquitous enzyme required for the conversion of oxidized glutathione (GSSG) to reduced glutathione (GSH) concomitantly oxidizing reduced nicotinamide adenine dinucleotide phosphate (NADPH) in a reaction essential for the stability and integrity of red cells. Mutations in the GR gene and nutritional deficiency of riboflavin, a co-factor required for the normal functioning of GR, can cause GR deficiency. We conducted a study on 1691 Saudi individuals to determine the overall frequency of GR deficiency and to identify whether the deficiency results from genetic or acquired causes or both. The activity of GR was measured in freshly prepared red cell haemolysate in the presence and absence of flavin adenine dinucleotide (FAD) and the activity coefficient (AC) was determined. Samples with low GR activity (> 2.0 IU/g haemoglobin) both in the presence and absence of FAD and an AC between 0.9 and 1.2 were considered GR-deficient. Samples with AC > or = 1.3 were considered riboflavin-deficient. The overall frequency of partial GR deficiency was 24.5% and 20.3% in males and females respectively. In addition, 17.8% of males and 22.4% of females suffered from GR deficiency due to riboflavin deficiency. This could be easily corrected by dietary supplementation with riboflavin. No cases of severe GR deficiency were identified.

Estado nutricional con respecto a vitamina B2 en un grupo de adultos, antes y después de la suplementación / Ribofavin nutritional status of a group of adults, before and after supplementation

Se evaluó el estado nutricional con respecto a vitamina B2 (riboflavina), en 61 mujeres y 15 varones, clínicamente sanos,universitarios de la Universidad Nacional de Buenos Aires, que no tomaban suplementos vitamínicos. Se calculó la ingesta de vitamina B2 mediante una encuesta dietética de 7 días. Se determinó, en hemolizado de glóbulos rojos, el grado de estimulación de la glutation reductasa eritrocitaria o coeficiente de actividad, que aumenta en la inadecuación nutricional a valores superiores a 1,30. En los individuos con valores de inadecuación se estudió el efecto de administración de 5 mg/día de riboflavina, durante una semana. Las ingestas de vitamina B2 (mg/día) fueron, en mujeres y varones, respectivamente: 1,19 ñ 0,44 y 1,65 ñ 0,74, representando 91,5 y 97,0 por ciento de las ingestas recomendadas, siendo inferiores a éstas en 75,4 por ciento de mujeres y en 53,3 por ciento de varones. Desde el punto de vista bioquímico el porcentaje de individuos con inadecuación fue 26,2 por ciento en las mujeres y 26,7 por ciento en los varones. En estos casos el índice se normalizó luego de la administración de la riboflavina (1,51 ñ 0,14 vs. 1,13 ñ 0,14; p < 0,0001). Estos datos indican deficiencia específica de vitamina B2, de menor incidencia que la reflejada por la ingesta diaria, que se relacionó con el bajo consumo de productos lácteos

Thiamin and riboflavin status of medical inpatients.

Thiamin status was assessed by erythrocyte transketolase activity (ETKA) and thiamin pyrophosphate effect (TPPE) and riboflavin status by erythrocyte glutathione reductase activity (EGRA) and activity coefficient (AC) in 165 medical inpatients in Ramathibodi Hospital. Based on TPPE > 15 per cent, 9 per cent of the medical inpatients had thiamin depletion. Most of them were patients with renal, cardiovascular, hematological and infectious diseases. Based on AC > or = 1.2, 17 per cent of these inpatients had riboflavin depletion. Most of them were patients with pulmonary, cardiovascular and hematological diseases. Only one patient with pulmonary disease had both thiamin and riboflavin depletion. The proportion of thiamin depletion (2/37) in subjects with thiamin supplementation (mean 32.4, median 6, mode 2 md/d) tended to be less than those without (9/98). But, subjects with riboflavin supplementation (mean 3.3, median 4, mode 1 md/d) had the proportion of riboflavin depletion (0/31) significantly (Z-test, p < 0.005) lower than without supplementation (23/104). The data suggested that although the usual dose of vitamin supplementation in medical inpatients is beneficial thiamin depletion can still be present in catabolic patients.

Vitamin status of eating disorder patients: relationship to clinical indices and effect of treatment.

Vitamin abnormalities in eating disorder patients may contribute to altered neuropsychological status and the development of sequelae such as cognitive dysfunction. We examined the relationship between vitamin status and clinical indices in 13 low-weight patients with anorexia or bulimia nervosa at admission to a treatment program. Vitamin status was evaluated again at discharge (2-6 weeks later) in nine of these patients. Four patients (31%) initially had erythrocyte enzyme activity indices suggesting deficiency for riboflavin and for vitamin B-6. Patients with biochemical evidence for riboflavin deficiency had lower relative body weight than those with normal riboflavin status (p < .02). Three patients (23%) had elevated plasma cholesterol concentrations (> 5.69 mmol/L). Plasma retinol concentrations were within the normal range. Plasma alpha-tocopherol concentrations were positively associated with serum albumin (p < .04), cholesterol (p < .0003), and total lipids (p < .0003), and were inversely associated with body mass index (p < .04). At discharge, thiamin, riboflavin and vitamin B-6 status indicators were normal in all cases examined. Suboptimal vitamin status is common in eating disorder patients but is normalized with dietary intervention and nutritional rehabilitation.