Biotin Deficiency

Updated: Jan 31, 2016
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Jatinder Bhatia, MBBS, FAAP  more...
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Overview

Background

Biotin 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). Over 140 different genetic defects have been noted with biotinase. [1]

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.

A new mouse model of this disease has been noted and could help research on this disease. [2]

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Pathophysiology

History

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. [3] 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 the image below).

Biotin is a bicyclic (more precisely, heterocyclic Biotin is a bicyclic (more precisely, heterocyclic) compound composed of an ureido ring (A) fused with a tetrahydrothiophene ring (B). A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring.

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 the image below).

Carboxybiotin carboxylase is the activated form of Carboxybiotin carboxylase is the activated form of a carboxylase that conducts the actual carboxylation of a substrate. The CO2 residue attached to the nitrogen atom diagonally across from the valeric acid substituent is transferred to the substrate to be carboxylated, and the original carboxylase is liberated intact.

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 the image below.

Depiction of the flow of biotin in the biotin cycl Depiction of the flow of biotin in the biotin cycle.

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 the image below).

Biocytin is the product of the complete proteolysi Biocytin is the product of the complete proteolysis of biotin-containing proteins and peptides. The enzyme biotinidase cleaves biocytin into free biotin and the amino acid lysine. The free biotin is then available for intestinal absorption or intracellular coupling to an apocarboxylase to form a holocarboxylase.

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 free lysine, 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 the image below) via the action of the enzyme holocarboxylase synthetase.

The biotin molecule is bound to the protein by a p The biotin molecule is bound to the protein by a peptide bond to an e-amino group of an apocarboxylase to form a holocarboxylase.

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 reported acute-onset quadriplegia in a 10-year-old boy associated with basal ganglia lesions due to biotin deficiency. [4] The history included prolonged raw egg consumption as the basis for the biotin deficiency. Biotin treatment resulted in remarkable recovery.

Given the critical biochemical pathways affected by biotin deficiency, the involvement of many organs could reasonably be expected; however, this is not the case, and few organs are involved. Based on observations in patients with this inborn error of metabolism, biotin deficiency can have a very serious, even fatal, outcome if it is allowed to progress without treatment. However, to the author's knowledge, no deaths due to biotin deficiency have been reported. That being said, the role of biotin in DNA repair [5] and insulin metabolism [6] has been recently defined in 2012 and is significant. Biotinidase could possess an important regulatory function in chromatin/DNA function. Biotin responsive seizures and encephalopathy due to biotinidase deficiency has been reported.

In a mouse model, ketogenic diet exaggerated biotin deficiency. [7] In biotinase knockout mice, a low-biotin diet triggered severe ATP deficit, activation of the energy sensor AMP-activated protein kinase, inhibition of the signaling protein mTOR, and up-regulation of central-carbon metabolism cellular genes. Insulin sensitivity was also augmented. [8]

Tsuji et al investigated the effect of biotin deficiency on oocyte quality. The study results indicate that steady, sufficient biotin intake is required for the production of high-quality oocytes in mice. [9]

Hayashi et al assessed biotin and carnitine insufficiency in six infants with milk allergy who were fed amino acid formulas and/or hydrolyzed formulas, by measuring urine 3-hydroxyisovaleric acid (3-HIA) and serum free carnitine (C0), respectively. The authors concluded that supplementation with biotin and L-carnitine immediately improved the insufficiency. They also recommend that care should be taken to avoid biotin and carnitine deficiency in allergic infants fed amino acid or hydrolyzed formulas. [10]

Biotin is involved in the regulation of immune and inflammatory regulation. [11]

Even after lengthy deficiency, biotin replacement induces rapid pancreatic repair. [12]  

 

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Epidemiology

Frequency

International

Neto et al noted that the estimated incidence of biotinidase deficiency in Brazil is about 1 case per 9,000 population; this rate is higher than in most other countries, in which the incidence of profound and partial biotinidase deficiency is estimated to be approximately 1 case per 60,000 population. [13]

Laszlo et al reported a series in Hungary from 1989-2001 in which 1,336,145 newborns were screened for biotinidase deficiency in Hungary; 58 children with the disorder were noted to be enzyme deficient. [14]

Yetgin et al noted biotinidase deficiency and juvenile myelomonocytic leukemia in a Turkish infant of consanguineous parents. [15]

Thus, the true incidence of biotin deficiency, although not known, appears to be very low.

Mortality/Morbidity

Baykal et al reported a series of 32 biotinidase-deficient men and women found by family studies in the index patients. [16] 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.

Race

Biotin deficiency can occur in individuals of any race.

Sex

Biotin deficiency occurs with equal frequency in both sexes.

Age

Signs and symptoms of biotin deficiency can develop in persons of any age.

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