|
|
|
Excerpt from Biotin DeficiencySynonyms, Key Words, and Related Terms: biotin deficiency, carboxylase, carboxylase deficiency, egg-white injury, egg-white syndrome, egg-white injury syndrome, biotinidase deficiency, inherited biotinidase deficiency, nutritional disorder, severe dermatitis, loss of hair, lack of muscular coordination, avidin, propionyl coenzyme A carboxylase, propionyl CoA carboxylase, PCC, pyruvate carboxylase, PC, β-methylcrotonyl CoA carboxylase, β-MCC, acetyl coenzyme A carboxylase, acetyl CoA carboxylase, ACC, acidosis, hypoglycemia, hyperammonemia, coma, seborrheic dermatitis, fungal infections, erythematous periorofacial macular rash alopecia, mild depression, somnolence, myalgias, hyperesthesias, paresthesias, profound lassitude, prolonged total parenteral nutrition therapy, TPN therapy, phenytoin, primidone, carbamazepine, prolonged oral antibiotic therapy, biotin deficiency, anticonvulsant use, broad-spectrum antibiotic use, acidosis, hypoglycemia, hyperammonemia Please click here to view the full topic text: Biotin DeficiencyBackgroundBiotin deficiency is a rare nutritional disorder caused by a deficiency of the water-soluble B vitamin termed biotin. This article discusses biotin deficiency caused by deficiency of the enzyme biotinidase (see also Biotinidase Deficiency). At least 25 countries have included biotinidase deficiency in their screening programs for neonatal disease. Biotin deficiency rarely, if ever, occurs in healthy individuals who consume a regular diet unless they are being treated either with certain anticonvulsants or with broad-spectrum antibiotics. The extremely low prevalence of biotin deficiency is probably the result of a combination of factors. First, the daily requirement for biotin is low (approximately 150-300 µg/d). Second, almost all foods contain significant quantities of biotin, and many widely consumed foods are relatively rich in biotin. Third, the intestinal flora synthesizes significant quantities of biotin, and at least a portion of that biotin is believed to be absorbed into the bloodstream. Fourth, a significant fraction of the body's biotin is recycled; that is, a given molecule of biotin may be repeatedly used before it is eventually lost from the body in the feces or urine. PathophysiologyHistory Biotin was first recognized as an essential nutrient factor in mammals in 1936. Ten years earlier, the inclusion of large amounts of raw egg whites in experimental diets in rats had produced symptoms of toxicity within a few weeks of the diet being initiated. In 1926, Boas referred to these symptoms of toxicity as egg-white injury syndrome.1 The major findings included severe dermatitis, loss of hair, and lack of muscular coordination. Boas also noted that yeast, liver, and several other foodstuffs contained a substance that protected rats from egg-white injury syndrome. Later, the protective compound in the foodstuffs was identified as biotin. Biotinidase deficiency was discovered in 1982. The biochemical basis for egg-white injury syndrome was quickly elucidated when raw egg whites were found to contain the glycoprotein avidin, which has a remarkable affinity for biotin. Once a biotin-avidin complex forms, the bond is essentially irreversible; the biotin-avidin complex is not broken during passage of the food bolus through the stomach and intestines. As a result, biotin is not liberated from food, and the biotin-avidin complex is lost in the feces. The final step in solving the mystery of egg-white injury syndrome was the demonstration that the syndrome could be prevented by heating the egg whites, a process that denatures avidin and destroys its affinity for biotin. Biochemistry Biotin is a bicyclic molecule composed of a ureido ring fused with a tetrahydrothiophene ring (see Medial file 1). A valeric acid substituent is attached to one of the 2 carbon atoms of the tetrahydrothiophene ring. Through this carboxyl group, biotin is linked covalently to the β-amino group of lysine in 4 carboxylases that play critical roles in intermediary metabolism.The 4 enzymes are propionyl coenzyme A (CoA) carboxylase (PCC), pyruvate carboxylase (PC), β-methylcrotonyl CoA carboxylase (β-MCC), and acetyl CoA carboxylase (ACC). PCC is required for the complete catabolism of several branched-chain amino acids and all odd-chain fatty acids. In the absence of PCC, a severe clinical disease (characterized by acidosis, hypoglycemia, hyperammonemia, coma, and death) develops. β-MCC is required for the complete catabolism of the amino acid leucine. In absence of β-MCC, a severe clinical illness (similar to that of PCC deficiency) develops. ACC is required for the catalysis of the first step in fatty acid synthesis. PC is an essential enzyme of gluconeogenesis. In the absence of PC, severe fasting hypoglycemia develops. In all 4 carboxylases, biotin functions as a coenzyme or prosthetic group that serves as a carrier for CO2 in a multistep reaction. In the first reaction, the biotin moiety of a carboxylase is carboxylated at the nitrogen atom diagonally across from the valeric acid substituent (see Media file 2). In the second reaction, the CO2 moiety is transferred to the substrate (causing it to be carboxylated in the process), and the original carboxylase is liberated intact, ready to perform another carboxylation. Given the critical roles of biotin-containing carboxylases in intermediary metabolism, the existence of major gaps in knowledge regarding the biochemistry of biotin is remarkable. For example, the source of the sulfur atom is unknown, as is the mechanism by which it is inserted into the biotin ring. Moreover, neither the precise mechanism by which biotin crosses the intestinal border nor the mechanism by which biotin is delivered to peripheral tissues has been established. Although the ability of the intestinal flora to synthesize biotin is known, the absorbability of this biotin has not been demonstrated. The strongest evidence that supports a significant contribution by the intestinal flora to the body's biotin economy is the consistent finding that the combined daily output of biotin in the urine and stool exceeds the dietary intake of biotin. The daily dietary requirement of biotin has not been established in rigorous studies; instead, only recommended ranges for daily intake of this important vitamin are available. The major reason for this gap in knowledge is the fact that the biotin present in some foods is highly bioavailable, whereas a significant portion of the biotin in other foods is in a form that prevents its absorption. Thus, the percentage of absorbable biotin in a given food cannot be easily determined. Biotin cycle The steps in the flow of biotin from its entry into the body (via the mouth or peripheral vein) to its exit in the stool or urine are depicted in Media file 3. Free biotin enters the body via the intestinal mucosa. The biotin present in food is essentially protein bound and must be converted to free biotin in the intestine before it can be absorbed. Protein-bound biotin is subjected to the action of the major proteolytic enzymes of the stomach and pancreas. Proteolysis is completed by the action of the oligopeptidases of the pancreas and jejunal-brush border. The final product is biocytin (see Media file 4). In biocytin, biotin is covalently bound to the β-amino moiety of lysine, the amino acid to which it was bound in the food that was consumed. The enzyme biotinidase cleaves biocytin into biotin and freelysine, and these molecules are rapidly absorbed. The proteolytic reaction sequence in the intestine has an efficiency of 60-80%. As a result, significant quantities of biotin-containing peptides are lost in the feces. Once absorbed, biotin is covalently bound to one of the 4 apocarboxylases (apo-PCC, apo-PC, apo-β-MCC, apo-ACC) to form the corresponding holocarboxylase (see Media file 5) via the action of the enzyme holocarboxylase synthetase. A single holocarboxylase molecule can perform many carboxylations before it is captured by cellular lysosomes. In the lysosomes, various proteolytic enzymes degrade the holocarboxylase to form biocytin, which, in turn, is hydrolyzed by biotinidase to form biotin and lysine. Free biotin is then available for insertion into an apocarboxylase to form a new holocarboxylase molecule. The biotin cycle is not 100% efficient. As a result, small amounts of free biotin (and some biocytin) escape the cycle and are lost in the feces and urine. For this reason, mammals must consume some biotin to replenish the biotin lost from the body.Biotin deficiency Regardless of the etiology of biotin deficiency (see Causes), clinical manifestations are essentially the same. However, the rates of symptom development and the sequence in which symptoms appear can greatly differ. Clinical manifestations are confined to the intestinal tract, skin, hair, CNS, and peripheral nervous system. The mechanism responsible for the development of the manifestations has not been established; however, altered fatty acid synthesis (due to deficient activity of the biotin-containing enzyme ACC) may play an important role. Adhisivam et al (2007) reported acute-onset quadriplegia in a 10-year-old boy associated with basal ganglia lesions due to biotin deficiency.2 The history included prolonged raw egg consumption as the basis for the biotin deficiency. Biotin treatment resulted in remarkable recovery. FrequencyInternationalNeto et al noted that the estimated incidence of biotinidase deficiency in Laszlo et al reported a series in Mortality/MorbidityBaykal et al reported a series of 32 biotinidase-deficient men and women found by family studies in the index patients.6 The series included 10 mothers, 4 fathers, and 18 siblings. Seventeen individuals (3 mothers, 4 fathers, and 10 brothers and sisters) had profound biotinidase deficiency (<10% of mean normal activity), and 15 (7 mothers and 8 brothers and sisters) had partial biotinidase deficiency (10-30% of mean normal activity). In the group with profound biotinidase deficiency, only 3 brothers and sisters had symptoms. The investigators noted skin eruption, microcephaly, developmental delay, and convulsions as symptoms. The patients with partial biotinidase deficiency lacked clinical manifestations, other than one sibling with a borderline intelligence quotient (IQ) score. RaceBiotin deficiency can occur in individuals of any race. SexBiotin deficiency occurs with equal frequency in both sexes. AgeSigns and symptoms of biotin deficiency can develop in persons of any age. Please click here to view the full topic text: Biotin Deficiency |
 |
| About Us | Privacy | Code of Ethics | Terms of Use | Contact Us | Advertising | Institutional Subscribers |
|
|||
|
| Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER |
