Biotin Deficiency 

Updated: Oct 22, 2018
Author: Gratias Tom Mundakel, MBBS, DCH; Chief Editor: Jatinder Bhatia, MBBS, FAAP 

Overview

Practice Essentials

Deficiency of biotin, a water-soluble B vitamin, may occur from nutritional causes, but more commonly results from deficiencies of enzymes involved in biotin homeostasis (e.g. biotinidase deficiency). Affected patients can present with abnormal skin and hair changes, metabolic and neurologic abnormalities. In severe cases, without treatment, coma and death may ensue. Early detection and treatment with pharmacologic doses of biotin are important to prevent the development of irreversible complications. Marginal biotin deficiency has been demonstrated in pregnancy and lactation, but the clinical significance is uncertain. Biotin supplements have been promoted to improve skin, hair and nail health; however robust evidence for their efficacy is lacking. It is important to be aware that intake of biotin supplements may lead to interference with certain laboratory tests leading to false positive or false negative results. High-dose biotin has been found to be helpful in certain neurological conditions (e.g. multiple sclerosis); however, the mechanism of action is uncertain

Background

Biotin or B7, one of the B vitamins, is an essential nutrient that plays key roles in the metabolism of glucose, amino acids, and fatty acids. Recent studies support a role for biotin in cell proliferation, DNA repair, epigenetic gene regulation as well as normal immune function.[1, 2, 3]

Biotin is available from various food sources, and is also synthesized by intestinal bacteria; hence dietary deficiency is uncommon. Chronic alcoholics and those on long-term anticonvulsants could develop biotin deficiency because of impaired intestinal uptake of the vitamin. Avidin, a protein found in egg whites, binds strongly to biotin, impairing the absorption of the vitamin, leading to severe biotin deficiency in those who consume excessive amounts of raw eggs. Patients affected by certain genetic defects affecting biotin metabolism present with a clinical picture of biotin deficiency. 

The clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails and the central nervous system. Seizures, hypotonia, ataxia, optic atrophy, visual deficits, sensorineural deafness and developmental delay (in children) are some of the neurological manifestations. Metabolic abnormalities may include organic aciduria, lactic acidosis and hyperammonemia. Supplementation with biotin leads to clinical improvement in most cases. 

 

Pathophysiology

History

In the early 1900s, researchers found that the inclusion of large amounts of raw egg whites in diets in rats produced symptoms of toxicity.  In 1926, Boas referred to these symptoms of toxicity as egg-white injury syndrome.[4] 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. A search for this protective factor led to the discovery in 1936 of biotin.

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. The biotin-avidin bond is essentially irreversible; 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.

Structure

Biotin is a bicyclic molecule composed of a ureido ring fused with a tetrahydrothiophene ring.

The ureido ring is involved in the high affinity binding of biotin to avidin, a glycoprotein found in egg-white. 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 5 carboxylases that play critical roles in intermediary metabolism.

FUNCTIONS OF BIOTIN

In addition to biotin's well-known role as a cofactor in carboxylation reactions, recent studies have shown that biotin plays important roles in the regulation of gene expression and immune function.[5, 2, 1, 6]  

Biotin-dependent carboxylation reactions

Biotin functions as a coenzyme in carboxylation reactions involving lipid, glucose and amino acid metabolism. There are 5 biotin-dependent carboxylases each of which exists as an inactive apoform.[3] The enzyme holocarboxylase synthetase (HCLS) catalyzes the addition of biotin (biotinylation) to the inactive apoform, which leads to the formation of the active carboxylase.  In all 5 carboxylases, biotin functions as a coenzyme or prosthetic group that serves as a carrier for CO2 in a multistep reaction.

The five biotin-dependent carboxylases[1]  and their functions[2] are described briefly below: 

Pyruvate carboxylase (PC) catalyzes the formation of oxaloacetate from pyruvate, a step important in the TCA cycle, gluconeogenesis and lipogenesis; lack of this function can lead to hypoglycemia, ketosis, and lactic acidosis. 

Propionyl-CoA carboxylase (PCC) catalyzes the conversion of propionyl CoA to methylmalonyl CoA, which in turn isomerizes to succinyl CoA, and enters the TCA (Kreb's) cycle. PCC is important in the metabolism of odd-chain fatty acids, and the amino acids isoleucine, valine, methionine, and threonine. Lack of this enzyme function can lead to propionic acidemia. Levels of PCC in lymphocytes is a sensitive indicator of biotin status.

3-Methylcrotonoyl-CoA carboxylase (MCC) is involved in the catabolism of the branched-chain amino acid, leucine. Lack of biotin can lead to shunting of leucine catabolism products into an alternative catabolic pathway leading to the production of 3-hydoxyisovaleric acid which is then excreted in the urine. 

Acetyl-CoA carboxylase I (ACC I) catalyzes the conversion of acetyl CoA to malonyl CoA, in the cytosol, a step important in lipid synthesis.

Acetyl-CoA carboxylase II (ACC II), catalyzes an identical reaction in the mitochondria; the resultant malonyl CoA plays a regulatory role in fatty acid oxidation. 

ACC I is a cytosolic enzyme; the remaining carboxylases are found in the mitochondria.

Clinical manifestations of biotin deficiency can also occur as a result of genetic disorders causing a deficiency of the enzyme holocarboxylase synthetase or deficiencies of the individual carboxylase enzymes.

Gene expression

Studies have shown that biotinylation of histones may play a role in gene expression. Multiple sites that bind to biotin have been identified in human histones.  Biotin may also affect gene expression by other mechanisms. A few thousand biotin-dependent genes are known in human cells. Some of the genes influenced by biotin include those encoding for enzymes involved in glucose metabolism (e.g. glucokinase), cytokines like interleukin-2 and the insulin receptor.[7, 1, 2, 3]

Immune function

Studies suggest a role for biotin in antibody production, macrophage function, differentiation of T and B lymphocytes, as well the normal function of natural killer cells.[6] Recurrent infections, especially fungal are common in patients with biotin deficiency.

Role of biotin in high-dose biotin-responsive neurologic conditions

Biotin-thiamin-responsive basal ganglia disease (BTBGD) is a rare neurological condition which can present with seizures and encephalopathy progressing to coma and death. High-dose biotin ( 5-10 mg/kg/day) has been used to successfully treat this condition, but the mechanism of action is unknown.[1]  

Recently, high-dose biotin treatment (100-300 mg/day) has been found to improve symptoms in a subset of patients with multiple sclerosis. It is thought that improvement of neurological symptoms may involve improved myelin production secondary to the effect of high-dose biotin on the synthesis of long-chain fatty acids.[1]  [8, 9]

Role of biotin in individuals with hair, skin and nail disorders

Biotin supplements are widely used by those hoping to achieve healthier hair, skin, and nails. However, there is limited evidence of the efficacy of biotin for this use. Biotin in high doses has been found to be helpful in two rare conditions: familial uncombable hair syndrome and brittle nail syndrome.[10]  In a study of 541 females presenting with hair loss, serum biotin levels were found to be low in 38% of patients. The author concluded that the etiology of hair loss is multifactorial and biotin supplements may be considered if biotin deficiency has been demonstrated and other causes have been ruled out.[11]  

Sources of Biotin

Biotin is present in a wide variety of foods (meats, dairy, vegetables, seeds, and nuts) and is also produced by intestinal bacteria. In addition, a substantial proportion of individuals may consume biotin containing dietary supplements.[12]

Biotin Physiology

Ingested biotin is present in free and protein-bound forms. Protein-bound forms are digested by gastrointestinal proteases and peptidases to form biocytin and biotin-oligopeptides. Free biotin is released from biocytin and biotin-oligopeptides by the action of intestinal biotinidase. Free biotin is then absorbed in the small intestine via a Na+ dependent, carrier-mediated mechanism, which also transports two other nutrients, pantothenic acid and lipoate and hence is known as the sodium-dependent multivitamin transporter (SMVT). The human SMVT gene is located on chromosome 2p23. SMVT activity is regulated by biotin levels; with it being up-regulated in biotin deficiency and down-regulated with biotin over-supplementation.  Bacterially synthesized biotin is present in the unbound form and is absorbed in the large intestine by a similar carrier-mediated mechanism.[2]  The combined daily output of biotin in the urine and stool exceeds the dietary intake of biotin, suggesting the important role played by intestinal flora as a source of biotin. 

Once absorbed, biotin becomes available for various biotinylation processes. Biotin binds to each of the 5 apocarboxylases 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.

Recycling of biotin

After the holocarboxylase enzyme has performed several carboxylations it is captured by cellular lysosomes. In the lysosomes, various proteolytic enzymes degrade the holocarboxylase to form biocytin, which, in turn, is hydrolyzed by the enzyme biotinidase to form biotin and lysine. Free biotin is then available for insertion into an apocarboxylase to form a new holocarboxylase molecule. This recycling process 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, biotin must be supplied to the intestine, to replenish the biotin lost from the body. The steps involved in the recycling of biotin- its entry into the gut, its absorption, its incorporation into holocarboxylases, which in turn are broken down to liberate free biotin constitute the biotin cycle and is depicted in the image below.  

The enzyme biotinidase is essential for biotin recycling and individuals with biotinidase deficiency will therefore present with signs and symptoms of biotin deficiency.

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

CAUSES OF BIOTIN DEFICIENCY

As mentioned earlier, biotin is widely available in foods, is also produced by intestinal flora and is extensively recycled in the body with the help of the enzyme biotinidase; hence biotin deficiency in healthy individuals eating a normal diet is rare. Conditions that can lead to biotin deficiency are described below:

Excessive consumption of raw egg whites: Avidin in raw egg whites has a high affinity for biotin, making it unavailable for absorption. Heat destroys the avidin, so those who eat cooked eggs are not at risk of biotin deficiency. Raw egg whites lead to biotin deficiency only when eaten in excessive amounts (perhaps a dozen or more a day).[13]

Total parenteral nutrition without biotin supplementation: Several cases of biotin deficiency in patients receiving prolonged total parenteral nutrition (TPN) therapy without added biotin have been reported.[14]  Therefore, all patients receiving TPN must also receive biotin at the recommended daily dose, especially if TPN therapy is expected to last more than 1 week. All hospital pharmacies currently include biotin in TPN preparations.[15]

Use of infant formulas with inadequate biotin: Biotin deficiency has been reported in infants receiving hypoallergenic formulas.[16]

Chronic anticonvulsant therapy: Prolonged use of the anticonvulsants, phenobarbital, phenytoin, primidone, and carbamazepine, have been linked to biotin deficiency. Possible mechanisms include inhibition of biotin uptake across the intestinal mucosa, accelerated biotin catabolism and impaired renal reabsorption of biotin. Therefore, supplemental biotin has been suggested for patients who are treated with anticonvulsants that have been linked to biotin deficiency.[2, 17]

Prolonged oral antibiotic therapy: Prolonged use of oral antibiotics has been associated with biotin deficiency. Inhibition of intestinal flora that produces biotin is presumed to be the basis for biotin deficiency. Another possible mechanism could be antibiotic-induced overgrowth of bacteria that consume biotin.[18]

Smoking and Chronic alcoholism: Studies have shown that smoking may accelerate biotin catabolism, especially in women. Chronic alcoholism may cause intestinal malabsorption of biotin.[2, 19]

Short gut syndrome and inflammatory bowel disease: Individuals with short bowel syndrome and inflammatory bowel disease are also at risk of biotin deficiency as a result of intestinal malabsorption of biotin. 

Marginal biotin deficiency during pregnancy and lactation: Recent studies have shown decreased biotin levels in a significant proportion of pregnant and lactating women. There are concerns that marginal biotin deficiency during pregnancy might be teratogenic and some experts have recommended a higher intake of biotin by pregnant women.[1]

Certain inborn errors of biotin metabolism may also lead to the manifestation of biotin deficiency. 

Biotinidase deficiency (BTD) is inherited in an autosomal recessive fashion and occurs at a frequency of approximately 1 in 60,000 live births.; an estimated 1 in 120 individuals are heterozygous for the condition.  In individuals homozygous for the disorder, biotinidase levels are < 30% normal leading to biotin deficiency from insufficient free biotin release due to diminished biotin recycling. Symptoms of BTD typically develop between 1 week and 1 year of age. The severity of the enzyme deficiency may vary. Those with profound biotinidase deficiency have BTD levels less than 10% normal, while those with partial biotinidase deficiency have enzyme levels between 10-30% normal. In the US and many other countries, newborn screening includes tests for BTD deficiency. Approximately 150 mutations in the BTD gene have been reported to cause biotinidase deficiency. The BTD gene is located on chromosome 3p25. A mouse model of biotinidase deficiency has been developed to study various aspects of the disorder.[20, 21]

Holocarboxylase Synthetase (HCLS) Deficiency is also an autosomal recessive disorder and can be diagnosed prenatally. As discussed earlier, the enzyme HCLS is required for the biotinylation of the apocarboxylase enzymes into the active holocarboxylase forms; therefore deficiency leads to multiple carboxylase deficiency. Infants with this disorder present in the first few months of life with acidosis, hyperammonemia, hypotonia, seizures and developmental delay. Mutations in the HCLS gene cause HCLS deficiency. 

Because both biotinidase and HCLS deficiency leads to decreased levels of the biotin-dependent carboxylases, the two conditions have also been classified as multiple carboxylase deficiency. Profound biotinidase deficiency was previously known as early-onset multiple carboxylase deficiency, partial biotinidase deficiency as late-onset or juvenile-onset multiple carboxylase deficiency and HCLS deficiency as neonatal or early-onset multiple carboxylase deficiency.[22, 23, 24]

Rarely, isolated deficiencies of each of the five individual biotin-dependent carboxylases may also occur.

Biotin deficiency due to a defect in biotin transport has also been described.[25]

Regardless of the etiology of biotin deficiency, clinical manifestations are similar. However, the age of onset, rates of symptom development and the sequence in which symptoms appear can greatly differ.  All of the mechanisms responsible for the development of the manifestations have not been established.

 

 

Epidemiology

Incidence

As mentioned previously, dietary deficiency of biotin is uncommon. 

Worldwide the incidence of profound biotinidase deficiency is estimated to be 1 in 137,401; the incidence of partial biotinidase deficiency, 1 in 109,921 and the overall incidence, 1 in 61,067.[24]  In populations with high rates of consanguinity (e.g., Saudi Arabia, Turkey) the incidence is higher. Neto et al noted that the estimated incidence of biotinidase deficiency in Brazil is about 1 case per 9,000 population.[26] In the US the incidence is reported to be higher in Hispanics and lower in African Americans. In the general population, 1 in 120  is a carrier.   

The incidence of holocarboxylase synthetase deficiency is estimated to be 1 in 87,000. 

Race

Biotin deficiency can occur in individuals of any race; however, as mentioned above genetic disorders affecting biotin metabolism may affect certain races and ethnic groups disproportionately. 

Sex

Biotin deficiency occurs with equal frequency in both sexes.

Age

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

Prognosis

With early detection and biotin therapy, many of the symptoms and signs of biotin deficiency are reversible. However, if left untreated, vision problems, hearing loss, and developmental delay can occur and these are usually irreversible.[27]  Dietary biotin deficiency, biotinidase deficiency, and holocarboxylase synthetase deficiency all respond to biotin treatment; however isolated carboxylase deficiencies are not biotin-responsive.[24]

Patient Education

Patients at risk of dietary deficiency of biotin (chronic alcoholics, those who are pregnant or lactating, those consuming excessive egg whites, those on chronic antibiotics or anticonvulsants) should be appropriately counseled and biotin supplements offered if appropriate. 

Genetic counseling should be offered when the cause is a genetic disorder, such as biotinidase deficiency or holocarboxylase synthetase deficiency, both of which are inherited in an autosomal recessive manner. Genetic testing of asymptomatic siblings should be offered to ensure early detection and treatment.[28]  At-risk relatives may also be tested to determine carrier status. Prenatal testing and preimplantation genetic diagnosis may be offered if appropriate. 

Intake of biotin supplements may lead to interference with certain laboratory tests; it is advisable for patients to inform their health care providers if they are taking any supplements that contain biotin.[12]

Resources

Biotinidase Deficiency Family Support Group: biotinidasedeficiency.20m.com

National Library of Medicine Reference: Biotinidase deficiency

 

 

Presentation

History

Presentation depends on the etiology and severity of the deficiency. 

Biotinidase deficiency is the most common etiology; in most developed countries including the US, newborn screening includes tests for biotinidase deficiency and the condition, therefore, is identified in a majority of individuals even before symptoms develop. 

Impaired growth, skin, and hair changes and neurological problems are common in individuals with profound biotinidase deficiency (< 10% normal serum biotinidase activity) who are diagnosed late or are untreated. Individuals with partial biotinidase deficiency (10-30% of normal serum biotinidase activity) usually become symptomatic only during periods of stress, such as an infection. 

Most individuals with untreated profound biotinidase deficiency develop symptoms in early infancy (mean age 3.5 months); however some may develop it as early as one week of life, and others may remain asymptomatic until adolescence. Some individuals present with a single finding and others present with multiple findings.  

The first symptoms are usually associated with the skin and hair[29]  and may include:

  • Dry skin

  • conjunctivitis

  • Seborrheic dermatitis

  • Fungal infections, especially candidiasis. 

  • scaly, red rash, around eyes, nose, mouth, and perineum 

  • Fine and brittle hair

  • brittle nails

  • Hair loss or total alopecia

If undiagnosed and left untreated neurologic symptoms begin to develop.[13, 30, 31, 32, 33, 34, 35, 36]  The most common neurologic findings include the following:

  • hypotonia, motor, weakness, and lethargy 

  • ataxia and developmental delay 

  • Mild depression, which may progress to profound lassitude and, eventually, to somnolence and coma

  • Changes in mental status

  • Generalized muscular pains (myalgias)

  • hallucinations

  • Hyperesthesias and paresthesias

  • seizures (commonly myoclonic, grand mal and focal seizures as well as infantile spasms)

  • progressive spastic paresis and myelopathy

  • Optic atrophy

  • Sensorineural hearing loss may develop in 75% of untreated infants with profound biotinidase deficiency.[24]  

Intestinal tract symptoms also develop and most commonly include the following:

  • Nausea, occasionally severe

  • Vomiting

  • Anorexia

Respiratory symptoms include stridor, apnea and hyperventilation. 

Metabolic problems include organic aciduria, ketolactic acidosis, and mild hyperammonemia.[37]   In severe cases, especially with profound untreated biotinidase deficiency, coma and death may ensue. 

Holocarboxylase synthetase deficiency may present as early as during fetal life with intrauterine growth retardation and abnormal CNS findings.[38]

 

 

Physical

Physical manifestations usually involve the skin and hair, central and peripheral nervous systems, and intestinal tract.

Skin and hair

The first signs that develop in biotin deficiency are associated with the skin and hair. Dry skin is a consistent finding and is often associated with seborrheic dermatitis, which can be severe. The skin lesions provide an ideal environment for fungal infections that may be resistant to treatment until the biotin-deficient state is reversed. An erythematous periorofacial macular rash is a common finding and may be confused with the rash seen with zinc deficiency. The hair quickly becomes fine and brittle, and total alopecia often develops.[29]

Hearing

Individuals with untreated biotinidase deficiency develop sensorineural hearing loss.[31]  [24]  The hearing loss varies in severity from mild to profound.

Central and peripheral nervous systems

The neurologic signs are multiple[30, 31]  and nonspecific. With untreated, profound biotinidase deficiency seizures[34]  and hypotonia are common.[24] Progressive spastic paresis, myelopathy, encephalopathy, ataxia, and developmental delay may also occur. Occasionally, changes in mental status are observed. They include mild depression, which may progress to profound lassitude, and, eventually, somnolence. Generalized muscular pains (myalgias), hyperesthesias, and paresthesias are common findings that occasionally become disabling. Profound biotinidase deficiency in a 3-year-old boy with progressive spastic paraparesis and ascending weakness but not the typical neurological symptoms was noted by Chedrawi et al.[32] Biotinidase deficiency with hypertonia was noted by Rathi and Rathi.[33]

Intestinal tract

Nausea, occasionally severe, is an occasional finding, as is anorexia. These problems are rarely severe enough to significantly interfere with the adequate oral intake of food.

 

Causes

Causes of biotin deficiency are discussed under Overview/Pathophysiology

Physical Examination

Once biotin deficiency has been confirmed, physical exam should be focused on evaluating the extent and severity of the disease and should include a detailed neurological exam, developmental assessment (if appropriate), visual and hearing assessment.  

 

Complications

Irreversible complications that may develop if treatment is delayed or inadequate include vision problems, sensory-neural hearing loss, ataxia, cognitive impairment, and developmental delay. [39, 40, 41, 27]

 

DDx

Diagnostic Considerations

The differential diagnosis includes inborn errors of metabolism that present with organic aciduria, metabolic acidosis or hyperammonemia. Skin manifestations of biotin deficiency may mimic those seen with zinc deficiency or essential fatty acid deficiency. Seizures, developmental delay, optic atrophy, sensorineural deafness, ataxia, and paresis may present secondary to various disorders affecting the nervous system. Fungal infections may occur with other conditions causing immunodeficiency. 

Differential Diagnoses

 

Workup

Approach Considerations

Work up for biotin deficiency should be considered if the clinical presentation raises a suspicion of biotin deficiency or the patient is at risk for biotin deficiency (e.g. chronic alcoholism)

Profound and partial biotinidase deficiency are identified by newborn screening; however, newborn screening became available in developed countries only in the eighties, and is not routinely available in many developing nations.[42]  

Nutritional biotin deficiency, biotinidase deficiency as well as HCLS deficiency all respond to biotin treatment. However, isolated carboxylase deficiencies do not respond to biotin.  

Once biotin deficiency has been established, further evaluation is recommended to determine the extent and severity of disease, and may include:

  1. detailed neurologic exam, to look for hypotonia, ataxia, evaluate seizure activity, evaluation of psychomotor deficits
  2. vision and hearing tests to evaluate for optic atrophy and sensorineural deafness.

 

 

Laboratory Studies

In healthy individuals, serum biotin ranges from 133-329 pmol/L and urinary excretion of biotin is 18-127 nmol/24 hours.

Decreased urinary excretion of biotin and its catabolites is an early indicator of biotin deficiency.[3]

Biotin deficiency leads to decreased activity of biotin-dependent carboxylases. Reduced activity of pyruvate carboxylase leads to lactic acidosis. Reduced levels of the carboxylases may also affect levels of various intermediary metabolites and provide additional diagnostic clues. Organic aciduria may occur. For example, reduced activity of β-methylcrotonyl-CoA carboxylase leads to shunting of β-methylcrotonyl-CoA (MCC) to alternative pathways, leading to increased production of 3-hydroxyisovaleric acid and its excretion into urine. However, urinary organic acids may be not be elevated in all cases. 

Adults who consume raw egg whites for 14-21 days demonstrate decreased biotin levels in serum and urine and excrete large amounts of β-hydroxyisovalerate in the urine.

The levels of biotinylated MCC and propionyl-CoA carboxylase in white blood cells are considered to be one of the most reliable indicators of biotin status and are decreased in even those with marginal biotin deficiency. In contrast, serum biotin levels do not reliably indicate individuals with marginal biotin deficiency.

In individuals with suspected biotinidase deficiency, enzyme activity can be measured. Testing for biotinidase deficiency is included as part of newborn screening in all US States and in many developed countries. [26, 43, 44, 42]

Individuals with profound biotinidase deficiency have serum enzyme activity of less than 10% of mean normal activity.[26] Children with biotinidase deficiency commonly become symptomatic if caregivers do not administer biotin. Children who have partial biotinidase deficiency have 10-30% of mean normal serum biotinidase activity and usually develop clinical manifestations of biotinidase deficiency only during times of stress, such as infection or a systemic illness. False positive newborn screening tests for biotinidase deficiency may occur in premature infants[45]  as well as neonates with jaundice.   [46]

When biotinidase deficiency has been identified, testing for the responsible mutation may be helpful. [47] Dobrowolski et al noted that, in the United States, the 4 mutations most commonly associated with complete biotinidase deficiency are c98:d7i3, Q456H, R538C, and the double mutation D444H:A171T.[48]  Partial biotinidase deficiency is almost universally attributed to the D444H mutation.

Prenatal testing and preimplantation genetic diagnosis are possible for biotinidase deficiency as well as holocarboxylase synthetase deficiency.[24, 38]

 

Imaging Studies

MRI changes have been described in individuals with biotinidase deficiency.[49, 50]

A 3-year-old male with biotinidase deficiency presented with skin eruption, ataxia, paraparesis, and MRI findings of myelopathy; all of which resolved with treatment.

Desai et al noted MRI findings in 4 patients and found (1) encephalopathy, low cerebral volume, ventriculomegaly, and widened extracerebral cerebrospinal fluid (CSF) spaces were common; (2) caudate involvement and parieto-occipital cortical abnormalities were uncommon; (3) a single patient had restricted diffusion; (4) 2 patients manifested with subdural effusions, and (5) 1H-magnetic resonance (MR) spectroscopy revealed decreased NAA peaks, elevated lactate levels, and reversal of the choline-to-creatine ratio. With use of biotin, a total reversal of imaging findings occurred in 2 patients.

Both antenatal and postnatal abnormal CNS findings have been described in individuals with holocarboxylase synthetase deficiency and include subependymal cysts, ventriculomegaly and intraventricular hemorrhage.[38]

 

Treatment

Approach Considerations

Lifelong treatment with biotin is required in individuals diagnosed with genetic disorders affecting biotin metabolism (biotinidase deficiency and holocarboxylase synthetase deficiency). 

Medical Care

The management of a patient with biotin deficiency must take the etiology into account.

If the deficiency is from excess consumption of raw eggs, the patient must stop consuming raw eggs and should be started on oral biotin therapy.

Ensure biotin containing vitamins are included in total parental nutrition (TPN) solutions if therapy is expected to last more than one week.

If the cause of biotin deficiency is anticonvulsant therapy, the anticonvulsant may be changed to another drug that does not interfere with biotin absorption. Alternatively, the patient may be started on supplemental biotin.

Similarly, those on prolonged oral antibiotic therapy may benefit from biotin supplementation.

Biotinidase deficiency can be detected with newborn screening. The most important aspects of the medical care in patients with biotin deficiency include the early recognition of the condition and the prompt institution of therapy with 5-10 mg per day of oral biotin. Some experts suggest increasing the dose to 15-20 mg per day at onset of puberty.[37]  Children with partial deficiency are usually treated with 1-5 mg per day.[23, 24]

Those with biotin deficiency secondary to genetic disorders of biotin metabolism (biotinidase deficiency, holocarboxylase synthetase deficiency) will need to be on lifelong biotin therapy. Non-compliance with treatment may be a significant problem and should be thought of especially when symptoms of biotin deficiency recur or the patient fails to show adequate improvement.  

Fungal skin infections should be treated with the appropriate antifungal agents; however, controlling such skin infections may be difficult until the biotin deficiency is corrected.

Antenatal treatment with biotin has been found to be useful when holocarboxylase synthetase deficiency has been detected antenatally.[38]

 

Consultations

The services of experienced dermatologists, neurologists, and biochemical geneticists may be helpful in the evaluation and management of patients with biotin deficiency.  

Diet

The patient should eat a regular, well-balanced diet that contains adequate amounts of biotin. Fortunately, almost all foodstuffs contain significant quantities of biotin, and many widely consumed foods are relatively rich in biotin. No dietary restriction is needed. 

Sources of Biotin

Foods that are rich in biotin, include meats, especially liver, eggs, brewers yeast,  fish, many cereals, especially oats, nuts, such as peanuts and walnuts, many vegetables such as cauliflower and peas, lentils and soybeans. 

Recommended Intakes

Recommendations for adequate intakes (AIs) for biotin have been developed by the Food and Nutrition Board of the National Academy of Sciences, Engineering and Medicine and are as follows: Birth to 6 months, 5 μg/day; 7-12 months, 6 μg/day; 1-3 yrs, 8 μg/day; 4-8 yrs, 12 μg/day; 9-13 yrs, 20 μg/day; 14-18 yrs, 25 μg/day and 30 μg/day in those 19 yrs or older. The AIs during pregnancy and lactation are 30 μg/day and 35 μg/day, respectively.[12]  It has been reported that the diet in developed countries contains 35- 70 μg/day of biotin.[10]  

Biotin supplements

Biotin supplements are popular among those seeking healthy skin, nails and hair. However, they contain up to 10000 mcg per pill which is more than 300 times the AI for biotin. It has been reported that up to 20% of individuals in the US consume biotin containing supplements. Although biotin toxicity with these doses have not been reported, biotin supplements may cause clinically significant interference with laboratory test results in those taking them. Therefore, doctors have been advised to include intake of biotin supplements as part of patient history.[1, 12]

 

 

 

Activity

Activity restrictions are not necessary except in patients with neurologic symptoms (eg, myalgias, hyperesthesias, paresthesias).

Long-Term Monitoring

Surveillance of patients with biotin deficiency, especially those with inborn errors of biotin metabolism may include:

  • periodic visual and auditory testing 
  • evaluation by clinical geneticist or metabolic specialist as needed

 

 

Medication

Medication Summary

Biotin is available as 1mg, 3mg, 5 mg and 10 mg oral capsules or tablets. The recommended dosage for biotinidase deficiency is 5-20mg per day. Biotin is also available in supplements containing combinations of other B vitamins or multivitamins. The dosage of biotin in these supplements are often much higher than the recommended adequate intakes. However, toxicity from biotin even when taken in high dosage (up to 200 mg/day) has not been reported. However high intakes of biotin may be associated with clinically important interference with certain lab tests leading to inappropriate medical care.[1, 12]

FDA Biotin Safety Alert November 2017

High intakes of biotin may occur in individuals taking biotin supplements and this may lead to interference with certain diagnostic assays. False negative, as well as false positive results, have been reported for thyroid hormone, TSH, and serum troponin. The FDA is advising health care providers to ask patients if they are on biotin containing supplements and to consider biotin interference as a possible source of error if test results do not correlate with the patient's clinical presentation.  

Drug Interactions: As mentioned elsewhere, chronic therapy with certain anticonvulsants ( phenobarbital, phenytoin, primidone and carbamazepine) may put patients at risk for biotin deficiency. Chronic antibiotic usage may also interfere with biotin production by intestinal flora.

Lipoic acid, often used as a dietary supplement, competes with biotin for the biotin transporter and may lead to decreased levels of some of the carboxylase enzymes.[3]

 

 

 

Follow-up

Further Outpatient Care

Follow-up visits should be scheduled as needed to ensure that all of the signs and symptoms of the condition have resolved with therapy.

Visual and hearing aids will benefit those with visual or hearing deficits. Children with developmental delay will benefit from appropriate interventions. Appropriate rehabilitation will be needed for those with spastic paresis. 

Annual vision and hearing evaluations must be scheduled. In those with genetic defects leading to biotin deficiency, lifelong biotin therapy is needed and lack of compliance may lead to recurrence of symptoms and complications.  Periodic assessment with a metabolic specialist will be useful. 

 

Deterrence/Prevention

Instruct patients to avoid consuming raw eggs.

Ensure biotin is included in total parental nutrition (TPN) solutions.

Monitor patients who are receiving prolonged oral antibiotic treatment or anticonvulsant medications for signs and symptoms suggestive of biotin deficiency. Consider biotin supplementation if appropriate. 

Pregnant and lactating women should be advised regarding adequate intake of biotin.

Monitor biotin status of individuals at risk of biotin deficiency due to intestinal malabsorption (those with inflammatory bowel disease, short bowel syndrome) and offer biotin supplements if appropriate. Infants placed on hypoallergenic formula  containing inadequate biotin should be offered biotin supplements.

Complications

Fungal infections are common at initial presentation and need to be treated with appropriate antifungal medications. In those where the diagnosis has been delayed and irreversible complications have occurred, deficits may persist despite biotin therapy. Complications that may be irreversible include vision and hearing loss, and developmental and cognitive delay. 

Prognosis

The prognosis in most cases is excellent when biotin deficiency is promptly detected and treated. 

Once biotin therapy has been initiated with the proper dosage, most signs and symptoms of biotin deficiency should begin to disappear within 3-5 weeks and completely resolve within 2-3 months.

Children who have developed sensorineural hearing loss secondary to profound biotinidase deficiency usually do not have improved hearing after biotin treatment. Also, optic atrophy and developmental delay are usually irreversible. 

Holocarboxylase synthetase deficiency is biotin-responsive; however, the isolated carboxylase deficiencies are not. 

 

Patient Education

See Overview/Patient Education

Instruct patients regarding the dangers of consuming raw eggs.

Instruct patients who are receiving certain anticonvulsant medications regarding signs and symptoms of biotin deficiency so that they can seek medical attention should signs and symptoms develop.