Biotin Deficiency: Impaired Heme Synthesis, Loss of Mitochondrial Complex IV , and Oxidative Stress

HEALTH/NUTRITIONCHRONIC ILLNESS
Written By Michael Kreder

*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.

Biotin Deficiency

Biotin Deficiency can drive a significant amount of symptomology, and more importantly dysfunction in mitochondrial function and heme synthesis. Several factors are commonly in play, genetic mutations on SLC5a6, BTD, sympathetic over activation, and candida overgrowth being common. Biotin is more than just be an important structural factor to create nice hair and nails:).

“I commonly see an overlap in cases of candida overgrowth and biotin deficiency.”

Heme is fundamental in many of the body's basic systems. (See earlier blog articles on the Heme Pathway / Porphyria):

·         Hemoglobin

·         Glutathione Peroxidase Enzymes GPX1-8

·         Catalase

·         CYP 450 Enzymes

·         Synthesis of Tryptophan and thus NAD

·         Processing of sulfur

·         and many more

It is common place that i see low biotin status in cases where candida levels are elevated. Its common in typical american diets, common in immune compromise and common in folks on ketogenic diets (candida can use ketones for fuel). In fact the most severe cases of candida i have seen have been with folks who have been on ketogenic diets for some significant time. Candida will deplete both biotin and b5 (pantothenic acid). But before i go into details with how candida effects the body overall, some details on biotin and heme:

Biotin's Connection To Heme:

"Four of the 5 biotin-dependent carboxylases (BDC) are in the mitochondria. BDC replace intermediates in the Krebs [tricarboxylic acid (TCA)] cycle that are regularly removed for the synthesis of key metabolites such as heme or amino acids. Heme, unlike amino acids, is not recycled to regenerate these intermediates, is not utilized from the diet, and must be synthesized in situ. We studied whether biotin deficiency (BD) lowers heme synthesis and whether mitochondria would be disrupted. Biotin-deficient medium was prepared by using bovine serum stripped of biotin with charcoal/dextran or avidin. Biotin-deficient primary human lung fibroblasts (IMR90) lost their BDC and senesced before biotin-sufficient cells. BD caused heme deficiency; there was a decrease in heme content and heme synthesis, and biotin-deficient cells selectively lost mitochondrial complex IV, which contains heme-a. Loss of complex IV, which is part of the electron transport chain, triggered oxidant release and oxidative damage, hallmarks of heme deficiency. Restoring biotin to the biotin-deficient medium prevented the above changes. Old cells were more susceptible to biotin shortage than young cells. These findings highlight the biochemical connection among biotin, heme, and iron metabolism, and the mitochondria, due to the role of biotin in maintaining the biochemical integrity of the TCA cycle. The findings are discussed in relation to aging and birth defects in humans."[1]

Biotin Deficiency Symptoms

Signs of overt biotin deficiency include hair loss (alopecia) and a scaly red rash around the eyes, nose, mouth, and genital area. Neurologic symptoms in adults have included depression, lethargy, hallucinations, numbness and tingling of the extremities, ataxia, and seizures. The characteristic facial rash, together with unusual facial fat distribution, has been termed the "biotin deficient facies" by some investigators [9].

COMMON IN WOMEN - BIOTIN DEFICIENCY

Current research indicates that at least one-third of women develop marginal biotin deficiency during pregnancy [17]. Small observational studies in pregnant women have reported an abnormally high urinary excretion of 3-hydroxyisovaleric acid in both early and late pregnancy, suggesting decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase [36,37]. In a randomized, single-blinded intervention study in 26 pregnant women, supplementation with 300 μg/day of biotin for two weeks limited the excretion of 3-hydroxyisovaleric acid compared to placebo, confirming that increased 3-hydroxyisovaleric acid excretion indeed reflected marginal biotin deficiency in pregnancy [38]. A small cross-sectional study in 22 pregnant women reported an incidence of low lymphocyte propionyl-CoA carboxylase activity greater than 80% [22]. Although these levels of biotin deficiency are not associated with overt signs of deficiency in pregnant women, such observations are sources of concern because subclinical biotin deficiency has been shown to cause cleft palate and limb hypoplasia in several animal species [22]. In addition, biotin depletion has been found to suppress the expression of biotin-dependent carboxylases, remove biotin marks from histones, and decrease the proliferation in human embryonic palatal mesenchymal cells in culture [39]. Impaired carboxylase activity may result in alterations in lipid metabolism, which have been linked to cleft palate and skeletal abnormalities in animals. Further, biotin deficiency leading to reduced histone biotinylation at specific genomic loci may increase genomic instability and result in chromosome anomalies and fetal malformations [22].

Analogous to pregnant women who are advised to consume supplemental folic acid prior to and during pregnancy to prevent neural tube defects , it would also be prudent to ensure adequate biotin intake throughout pregnancy. The current AI for pregnant women is 30 μg/day of biotin, and no toxicity has ever been reported at this level of intake.

Multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by progressive damage to the myelin sheath surrounding nerve fibers (axons) and neuronal loss in the brain and spinal cord of affected individuals in anatomic locations that vary widely among affected individuals producing variable signs and symptoms. The progression of neurologic disabilities in MS patients is often assessed by the Expanded Disability Status Scale (EDSS) with scores from 1 to 10, from minimal signs of motor dysfunction (score of 1) to death by MS (score of 10). ATP deficiency due to mitochondrial dysfunction and increased oxidative stress may be partly responsible for the progressive degeneration of neurons in MS [44] . Given its role in energy production by intermediary metabolism and fatty acid oxidation and in fatty acid synthesis (required for myelin formation), high-dose biotin supplementation it has been hypothesized that to exert beneficial effects that would limit or reverse MS-associated functional impairments [44].

The mechanism of action of high-dose biotin has been investigated in a genetic mouse model of chronic axon injury caused by oxidative damage and bioenergetic failure. High-dose biotin restored redox homeostasis, mitochondria biogenesis, and ATP levels, and reversed axonal death and locomotor impairment. Dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord was also normalized, possibly as the result of hyperactivation of a nutrient/energy/redox sensor that controls protein synthesis restoring lipid homeostasis.

A nonrandomized, uncontrolled pilot study in 23 patients with progressive MS found high doses of biotin (100-600 mg/day) to be associated with sustained clinical improvements in five (out of five) patients with progressive visual loss and 16 (out of 18) patients with partial paralysis of the limbs after a mean three months following treatment onset [45]. Additionally, a multicenter, randomized, placebo-controlled trial in 154 subjects with progressive MS reported that 13 out of 103 patients supplemented with high-dose, pharmaceutical-grade biotin (300 mg/day) for 12 months achieved MS-related disability reversal — assessed by improved EDSS or 25-foot walk time [46]. In comparison, none of the 51 patients randomized to the placebo group showed significant clinical improvements [46]. However, when this regimen of high-dose biotin supplementation was examined in a larger, international cohort of patients with progressive MS (326 patients receiving biotin and 316 patients receiving placebo), no benefits on EDSS or walk time were seen after 12 months [47]. Moreover, a randomized, double-blind, placebo-controlled trial in 93 MS patients with chronic visual loss found that 300 mg/day of pharmaceutical-grade biotin for six months did not improve visual acuity, but an interesting trend favoring the biotin group was observed in the subgroup of patients with progressive optic neuritis [48]. Moreover, a meta-analysis of three randomized controlled trials (2 on disability; 3 on adverse effects), involving 889 individuals diagnosed with MS (the preponderance of participants [830] had progressive MS while only 59 had remitting relapsing MS) was conducted [49]. Pooling results of two trials found no benefit of high-dose biotin on MS-related disability, but there was significant heterogeneity between the trials. When the subgroup progressive MS was analyzed separately, a moderate certainty of evidence suggested a potential benefit in favor of high-dose biotin for the 25-foot minute walk time [49]. On balance, studies remain inconclusive but promising.

Diabetes / Glucose metalbolism / triglycerides / ldl cholesterol

Overt biotin deficiency has been shown to impair glucose utilization in mice [50] and cause fatal hypoglycemia in chickens. Biotin deficiency likely also causes abnormalities in glucose regulation in humans. A human study reported lower serum biotin concentrations in 43 patients with type 2 diabetes mellitus compared to 64 control subjects without the disease; an inverse relationship between fasting blood glucose and biotin concentrations was observed as well [51]. In a small, intervention study in 28 patients with type 2 diabetes, daily supplementation with 9 milligrams (mg) of biotin for one month resulted in a 45% decrease in mean fasting blood glucose concentrations [51]. Yet, another small study in 10 patients with type 2 diabetes and 7 controls without diabetes found no effect of biotin supplementation (15 mg/day) for 28 days on fasting blood glucose concentrations in either group [52]. A more recent controlled study by the same research group showed that the same biotin regimen lowered plasma triglyceride concentrations in patients with hypertriglyceridemia — independent of whether they had type 2 diabetes [53]. In this study, biotin administration did not affect blood glucose concentrations in either patient group. Additionally, a few studies have shown that co-supplementation with biotin and chromium picolinate may be a beneficial adjunct therapy in patients with type 2 diabetes [54-57]. For information on chromium supplementation as a monotherapy for type 2 diabetes, explore research on Chromium.

As a cofactor of carboxylases required for fatty acid synthesis, biotin may increase the utilization of glucose for fat synthesis. Also, biotin stimulates glucokinase, a liver enzyme that increases synthesis of glycogen, the storage form of glucose. Biotin also triggers the secretion of insulin in the pancreas of rats and improves glucose homeostasis [59]. Yet, reduced activity of MCC1 and MCC2 would be expected to reduce fatty acid synthesis and increase fatty acid oxidation, respectively. Hence, whether pharmacologic doses of biotin benefits the management of hyperglycemia in patients with impaired glucose tolerance remains unclear. Moreover, whether supplemental biotin lowers the risk of cardiovascular complications in patients with diabetes by reducing serum triglycerides and LDL-cholesterol remains to be proven [53-55].

Brittle fingernails (onychorrhexis)

The finding that biotin supplements were effective in treating hoof abnormalities in hoofed animals suggested that biotin might also be helpful in strengthening brittle fingernails in humans [59-61]. Three uncontrolled trials examining the effects of biotin supplementation (2.5 mg/day for several months) in women with brittle fingernails have been published [62-64]. In two of the trials, subjective evidence of clinical improvement was reported in 67%-91% of the participants available for follow-up at the end of the treatment period [62,63]. One trial that used scanning electron microscopy to assess fingernail brittleness reported less fingernail splitting and a 25% increase in the thickness of the nail plate in patients supplemented with biotin for 6 to 15 months [64]. Preliminary evidence suggests that supplemental biotin may help strengthen fragile nails [66].

Hair loss (alopecia)

Biotin administration has been associated with alopecia reversal in children treated with the anticonvulsant valproic acid , as well as with hair regrowth or normal hair growth in some children with inborn errors of biotin metabolism or other genetic disorders (i.e., uncombable hair syndrome)[67]. Yet, while hair loss is a symptom of severe biotin deficiency, there are no published scientific studies that support the claim that high-dose biotin supplements are effective in preventing or treating hair loss in men or women [68,69].

Biotin Aids SLC19A3 (a B1 Transporter) In Biotin Responsive Basal Ganglial Disease

Biotin acts as a supportive supplement for thiamine in the treatment of biotin-thiamine-responsive basal ganglia disease (BTBGD), a condition caused by mutations in the SLC19A3 gene, which impairs the body's ability to transport thiamine into cells. The exact mechanism by which biotin helps is unclear, but it may increase the production or stability of the defective thiamine transporter protein, thus improving overall thiamine uptake and utilization.  [2,4,5]

Biotin thiamine responsive basal ganglia disease (BTRBGD) is an inherited autosomal recessive disorder that results from the inability of thiamine to cross the blood-brain barrier. It is considered a treatable condition if vitamin supplementation, most commonly with thiamine and biotin, is initiated early. BTRBGD can present as an infantile form, classical childhood form, or adult Wernicke-like encephalopathy. The infantile form is often the most severe and portends a worse prognosis with high mortality despite vitamin supplementation. [2,4,5]

A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises. Often associated with poor outcomes, acute crises were not observed after thiamin supplementation started (300-400 mg/day) and during a five-year follow-up period, early diagnosis and immediate treatment with biotin and thiamin led to positive outcomes. Although the specific mechanism for therapeutic effects of biotin in biotin-thiamin-responsive basal ganglia disease remains unknown, lifelong high-dose supplementation with a combination of biotin and thiamin is the recommended treatment . Early diagnosis and treatment is important to ensure a better prognosis. [39-42]

MORE Candida Connections

Candida interferes with the MTHFR, NAD, catecholamine, and aldehyde pathways.  Aldehydes produced by candida slow down MTHFR-related pathways like glutathione and methionine synthase. The processing of aldehydes deplete NAD, consume B2 (needed for so many things like recycling glutathione, clearing histamine, etc), and consume molybdenum (needed to process sulfur).   As NAD levels drop we lose tryptophan to make serotonin and melatonin because the body tries to make more NAD from tryptophan.  Depression can result from low serotonin.  Low NAD will cause significant fatigue. Sulfur sensitivity, high oxidative stress (low glutathione), and impaired methylation (build up of histamine) can all result.

Have you ever wondered why getting really stressed out leaves you feeling drained, foggy and out of touch like you have been drinking?  Excess stress can raise catecholamines (dopamine) by-products that turn into alcohol in our brains. If this is not cleared (and they require vitamins like B3 and others to properly detoxify) then the neurons become damaged.  This leads to neural degeneration effects.

The ALR (aldehyde reductase), ALDH (aldehyde dehydrogenase) and ADH (alcohol dehydrogenase) enzymes are all necessary to detoxify and get rid of excessive stress chemicals like dopamine, norepinephrine and epinephrine. High levels of candida can overload these detoxification genes trying to deal with the alcohol and aldehydes from the gut and result in a buildup of toxic stress chemicals from catecholamines in the brain. This will amplify the effects of stress and can lead to – anxiety, insomnia, chronic pain, brain fog, memory issues, depression, etc. Histamine is also detoxified through the aldehyde system as well as the MTHFR related pathways. As MTHFR pathways get overloaded you can see why these folks have histamine intolerance issues, energy deficits, and other GI related issues. It is common in folks with candida issues, to have high dopamine (high stress), food / histamine intolerance symptoms. The presence of Yeast in the GI tract diverts pyruvate away from its preferred metabolic pathway (Krebs cycle), which can also lead to fatigue.

High aldehydes can also deplete B5 (pantethene - preferred form), B5 is needed for the NAT2 gene - which supports acetylation of fatty acids, and detoxification. B5 is also needed for the production of cortisol which helps manage PLA2/ Arachadonic Acid (into the ALOX12 pathway / ALOX5 pathway), and also is involved in gut motility. Further - mutations in SLC5A6 [3] - the multivitamin sodium dependent transporter for (ALA, B7, B5) can further compromise both B7 status (candida consumes B7), as well as B5 status. So, here we see that high levels of candida deplete b5, which is needed to process fats (think keto diets) and to produce cortisol which is needed inhibit platelet activation (PLA2) also known as micro clotting. Micro clotting results in low blood oxygen levels = fatigue, and cognitive impairment.

Biotin Can Accelerate Candida Proliferation

“Bacterial and fungal catheter-related bloodstream infections (CRBSI) cause high fever and blindness due to fungal endophthalmitis. Candidal CRBSI have a particularly high mortality rate and needs attention. In this study, we examined the effect of biotin on the colonization and growth of Candida albicans in the lumen of the catheter used for nutrient infusions…….We demonstrated that nutrient infusion with biotin promoted colonization and proliferation in the catheter lumen, whereas those without biotin had no effect. These results suggest that biotin may accelerate the colonization and growth of Candida albicans in catheter lumen and using biotin-containing nutrient infusions may increase the risk of CRBSI.”[9] . Further, starving candida of biotin, inhibited its growth in this study [91].

More Biotin Related Genes : BTD, PICCA, HLCS, and MCC1

The BTD gene [6], Biotinidase, encoded by BTD, catalyzes the release of free biotin (B7) from protein-bound biotin, as found in a typical diet. Mutations in this gene can also lead to insufficient biotin status. Further, the HLCS gene, is responsible for transporting biotin into several important genes (PICCA, and MCC1). PCCA is used in the the metabolism of propionic acid in the krebs cycle, while MCC1 is used in the leucine metabolism pathway in the production of acetyl co-a. Our good friend resveratrol is a potent inhibitor of HLCS, so if you have mutations here, your dosing and frequency of resveratrol intake may be something to closely inspect.

What Is This Fallacy That Biotin Helps Control Candida ? [17,18,7]

Well, lets dive in. In some BTD (Biotinidase) deficiency cases with vaginal candidasis, have been responsive to biotin therapy [7]. Individuals with hereditary disorders of biotin metabolism that result in functional biotin deficiency often have similar physical findings, impaired immune system function, and increased susceptibility to bacterial and fungal infections. [17,18,19]. This is different than biotin being used to directly kill candida. The effect is through impaired immune functioning in biotin deficiency, so that resolution of biotin deficiency results in improved immune functioning, and better control of fungus and candida. I always prefer to understand the mechanisms of action in play, instead of relying the old good vs bad paradigm, when assessing when something may be appropriate as an intervention.

B5 Considerations - Diet and Genetics (PANK genes)

B5 can also get depleted in high phenol diets (think berries, coffees/teas, and herbs) - so folks who enjoy significant amounts of fruit, teas, coffees may want to consider testing as well. Mutations in the series of PANK genes, specifically PANK2, can make it difficult for some to convert panthenic acid, into pantethine. When this is the case, Pantethenic Acid is often elevated on Organic Acids tests.

Summary

And finally, for those who have read my earlier Heme / Porphyria blog articles, you may recall how anti fungals inhibit the heme cycle - its how they are designed to work - to stop the heme cycle in fungus. Well, for those of you who are eating lots of non organic fruits - you are exposed to another level of heme cycle inhibition through the anti fungal herbicides on these fruits - which are generously loaded on fruits like Strawberries.

The cascade of symptoms and issues from candida overgrowth can be significant as shown above. The simplest markers to monitor candida are on Organic Acids Tests, which are urine based and can be ordered consumer direct from places like MyMedLab or MyLabsForLife. Functional B5, B2 and B7 status markers are also on the Organic Acids test, although these are far from perfect.

 

References:

  1. Biotin Deficiency Inhibits Heme Synthesis and Impairs Mitochondria in Human Lung Fibroblasts. By Atamna Hani, Newberry Justin, et. al. The Journal of Nutrition 
 Volume 137, Issue 1, January 2007, Pages 25-30. https://doi.org/10.1093/jn/137.1.25
  2. Child Neurology: Infantile Biotin Thiamine Responsive Basal Ganglia Disease: Case Report and Brief Review.  Kayli Maney, et. al. Neurology.  . 2023 Apr 25;100(17):836-839.  doi: 10.1212/WNL.0000000000206832. Epub 2023 Jan 19.   PMID: 36657988, PMCID: PMC10136005, DOI: 10.1212/WNL.0000000000206832
  3. Genome-wide association studies of metabolites in Finnish men identify disease-relevant lociNat Communication.   By Yin. et. al.   2022 Mar 28;13(1):1644.  doi: 10.1038/s41467-022-29143-5.  PMID: 35347128 PMCID: PMC8960770 DOI: 10.1038/s41467-022-29143-5
  4. Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy.  Satoshi Kono, et. al. N Engl J Med . 2009 Apr 23;360(17):1792-4.  doi: 10.1056/NEJMc0809100. PMID: 19387023.  DOI: 10.1056/NEJMc0809100
  5. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases.  Majid Alfadhel.  By Orphanet J, et. al.  Rare Disease. . 2013 Jun 6;8:83. doi: 10.1186/1750-1172-8-83
  6. Profound biotinidase deficiency in two asymptomatic adults. B Wolf , et.Am J Med Genetics.  . 1997 Nov 28;73(1):5-9. doi: 10.1002/(sici)1096-8628(19971128)73:1<5::aid-ajmg2>3.0.co;2-u.  al. PMID: 9375914.  DOI: 10.1002/(sici)1096-8628(19971128)73:1<5::aid-ajmg2>3.0.co;2-u
  7. Chronic vaginal candidiasis responsive to biotin therapy in a carrier of biotinidase deficiency. C M Strom , et. al. Obstet Gynecol. 1998 Oct;92(4 Pt 2):644-6. doi: 10.1016/s0029-7844(98)00293-2. PMID: 9764646.  DOI: 10.1016/s0029-7844(98)00293-2.  
  8. Biotin Regulates Colonization and Growth of Candida albicans in the Catheter Lumen During Nutrient Infusions.  Hiroshi Ohara, et. al.  Int J Pharm Compd.  . 2020 Sep-Oct;24(5):420-425. PMID: 32886641
  9. Food and Nutrition Board, Institute of Medicine. Biotin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:374-389.  (National Academy Press)
  10. Mock DM. Biotin. Handbook of vitamins. 4th ed. Boca Raton, FL: CRC Press; 2007:361-383.
  11. Zempleni J, Teixeira DC, Kuroishi T, Cordonier EL, Baier S. Biotin requirements for DNA damage prevention. Mutat Res. 2012;733(1-2):58-60.  (PubMed)
  12. Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr. 2008;28:253-272.  (PubMed)
  13. Zempleni J, Wijeratne SSK, Kuroishi T. Biotin. In: Erdman JWJ, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed: John Wiley & Sons, Inc.; 2012:359-374.  
  14. Zempleni J, Li Y, Xue J, Cordonier EL. The role of holocarboxylase synthetase in genome stability is mediated partly by epigenomic synergies between methylation and biotinylation events. Epigenetics. 2011;6(7):892-894.  (PubMed)
  15. Zempleni J, Gralla M, Camporeale G, Hassan YI. Sodium-dependent multivitamin transporter gene is regulated at the chromatin level by histone biotinylation in human Jurkat lymphoblastoma cells. J Nutr. 2009;139(1):163-166.  (PubMed)
  16. Mock DM. Biotin. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed: Lippincott Williams & Wilkins; 2014:390-398.
  17. Baumgartner ER, Suormala T. Inherited defects of biotin metabolism. Biofactors. 1999;10(2-3):287-290.  (PubMed)
  18. Elrefai S, Wolf B. Disorders of biotin metabolism. In: Rosenberg RN, Pascual JM, eds. Rosenberg's Molecular and Genetic basis of Neurological and Psychiatric Disease. 5th ed. United States of America: Elsevier; 2015:531-539.  
  19. Sealey WM, Teague AM, Stratton SL, Mock DM. Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004;80(4):932-935.  (PubMed)
  20. Perry CA, West AA, Gayle A, et al. Pregnancy and lactation alter biomarkers of biotin metabolism in women consuming a controlled diet. J Nutr. 2014;144(12):1977-1984.  (PubMed)
  21. Mock DM. Marginal biotin deficiency is common in normal human pregnancy and is highly teratogenic in mice. J Nutr. 2009;139(1):154-157.  (PubMed)
  22. Pabuccuoglu A, Aydogdu S, Bas M. Serum biotinidase activity in children with chronic liver disease and its clinical significance. J Pediatr Gastroenterol Nutr. 2002;34(1):59-62.  (PubMed)
  23. Yang Y, Yang JY, Chen XJ. Biotinidase deficiency characterized by skin and hair findings. Clin Dermatol. 2020;38(4):477-483.  (PubMed)
  24. Mohite K, Nair KV, Sapare A, et al. Late onset subacute profound biotinidase deficiency caused by a novel homozygous variant c.466-3T>G in the BTD gene. Indian J Pediatr. 2022;89(6):594-596.  (PubMed)
  25. Radelfahr F, Riedhammer KM, Keidel LF, et al. Biotinidase deficiency: A treatable cause of hereditary spastic paraparesis. Neurol Genet. 2020;6(6):e525.  (PubMed)
  26. Zempleni J, Hassan YI, Wijeratne SS. Biotin and biotinidase deficiency. Expert Rev Endocrinol Metab. 2008;3(6):715-724.  (PubMed)
  27. Saleem H, Simpson B. Biotinidase deficiency. StatPearls. Treasure Island (FL); 2022.  (PubMed)
  28. Canda E, Kalkan Ucar S, Coker M. Biotinidase deficiency: prevalence, impact and management strategies. Pediatric Health Med Ther. 2020;11:127-133.  (PubMed)
  29. Wolf B. Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". Genet Med. 2012;14(6):565-575.  (PubMed)
  30. Bandaralage SP, Farnaghi S, Dulhunty JM, Kothari A. Antenatal and postnatal radiologic diagnosis of holocarboxylase synthetase deficiency: a systematic review. Pediatr Radiol. 2016;46(3):357-364.  (PubMed)
  31. Mardach R, Zempleni J, Wolf B, et al. Biotin dependency due to a defect in biotin transport. J Clin Invest. 2002;109(12):1617-1623.  (PubMed)
  32. Eng WK, Giraud D, Schlegel VL, Wang D, Lee BH, Zempleni J. Identification and assessment of markers of biotin status in healthy adults. Br J Nutr. 2013;110(2):321-329.  (PubMed)
  33. Bogusiewicz A, Boysen G, Mock DM. In HepG2 cells, coexisting carnitine deficiency masks important indicators of marginal biotin deficiency. J Nutr. 2015;145(1):32-40.  (PubMed)
  34. Mock DM. Adequate intake of biotin in pregnancy: why bother? J Nutr. 2014;144(12):1885-1886.  (PubMed)
  35. Mock DM, Stadler DD. Conflicting indicators of biotin status from a cross-sectional study of normal pregnancy. J Am Coll Nutr. 1997;16(3):252-257.  (PubMed)
  36. Mock DM, Stadler DD, Stratton SL, Mock NI. Biotin status assessed longitudinally in pregnant women. J Nutr. 1997;127(5):710-716.  (PubMed)
  37. Mock DM, Quirk JG, Mock NI. Marginal biotin deficiency during normal pregnancy. Am J Clin Nutr. 2002;75(2):295-299.  (PubMed)
  38. Takechi R, Taniguchi A, Ebara S, Fukui T, Watanabe T. Biotin deficiency affects the proliferation of human embryonic palatal mesenchymal cells in culture. J Nutr. 2008;138(4):680-684.  (PubMed)
  39. Tabarki B, Al-Hashem A, Alfadhel M. Biotin-thiamine-responsive basal ganglia disease. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA); 1993-2022.  (PubMed)
  40. Kilic B, Topcu Y, Dursun S, et al. Single gene, two diseases, and multiple clinical presentations: Biotin-thiamine-responsive basal ganglia disease. Brain Dev. 2020;42(8):572-580.  (PubMed)
  41. Alfadhel M, Almuntashri M, Jadah RH, et al. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis. 2013;8:83.  (PubMed)
  42. Algahtani H, Ghamdi S, Shirah B, Alharbi B, Algahtani R, Bazaid A. Biotin-thiamine-responsive basal ganglia disease: catastrophic consequences of delay in diagnosis and treatment. Neurol Res. 2017;39(2):117-125.  (PubMed)
  43. Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016;110(Pt B):644-653.  (PubMed)
  44. Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015;4(2):159-169.  (PubMed)
  45. Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016;22(13):1719-1731.  (PubMed)
  46. Cree BAC, Cutter G, Wolinsky JS, et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2020;19(12):988-997.  (PubMed)
  47. Tourbah A, Gout O, Vighetto A, et al. MD1003 (high-dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, placebo-controlled study. CNS Drugs. 2018;32(7):661-672.  (PubMed)
  48. Espiritu AI, Remalante-Rayco PPM. High-dose biotin for multiple sclerosis: A systematic review and meta-analyses of randomized controlled trials. Mult Scler Relat Disord. 2021;55:103159.  (PubMed)
  49. Larrieta E, Vega-Monroy ML, Vital P, et al. Effects of biotin deficiency on pancreatic islet morphology, insulin sensitivity and glucose homeostasis. J Nutr Biochem. 2012;23(4):392-399.  (PubMed)
  50. Maebashi M, Makino Y, Furukawa Y, Ohinata K, Kimura S, Sato T. Therapeutic evaluation of the effect of biotin on hyperglycemia in pateints with non-insulin dependent diabetes mellitus. J Clin Biochem Nutr.1993;14:211-218. 
  51. Baez-Saldana A, Zendejas-Ruiz I, Revilla-Monsalve C, et al. Effects of biotin on pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and markers for glucose and lipid homeostasis in type 2 diabetic patients and nondiabetic subjects. Am J Clin Nutr. 2004;79(2):238-243.  (PubMed)
  52. Revilla-Monsalve C, Zendejas-Ruiz I, Islas-Andrade S, et al. Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in nondiabetic subjects with hypertriglyceridemia. Biomed Pharmacother. 2006;60(4):182-185.  (PubMed)
  53. Geohas J, Daly A, Juturu V, Finch M, Komorowski JR. Chromium picolinate and biotin combination reduces atherogenic index of plasma in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Am J Med Sci. 2007;333(3):145-153.  (PubMed)
  54. Albarracin C, Fuqua B, Geohas J, Juturu V, Finch MR, Komorowski JR. Combination of chromium and biotin improves coronary risk factors in hypercholesterolemic type 2 diabetes mellitus: a placebo-controlled, double-blind randomized clinical trial. J Cardiometab Syndr. 2007;2(2):91-97.  (PubMed)
  55. Singer GM, Geohas J. The effect of chromium picolinate and biotin supplementation on glycemic control in poorly controlled patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized trial. Diabetes Technol Ther. 2006;8(6):636-643.  (PubMed)
  56. Albarracin CA, Fuqua BC, Evans JL, Goldfine ID. Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes. Diabetes Metab Res Rev. 2008;24(1):41-51.  (PubMed)
  57. Lazo de la Vega-Monroy ML, Larrieta E, German MS, Baez-Saldana A, Fernandez-Mejia C. Effects of biotin supplementation in the diet on insulin secretion, islet gene expression, glucose homeostasis and beta-cell proportion. J Nutr Biochem. 2013;24(1):169-177.  (PubMed)
  58. Randhawa SS, Dua K, Randhawa CS, Randhawa SS, Munshi SK. Effect of biotin supplementation on hoof health and ceramide composition in dairy cattle. Vet Res Commun. 2008;32(8):599-608.  (PubMed)
  59. Reilly JD, Cottrell DF, Martin RJ, Cuddeford DJ. Effect of supplementary dietary biotin on hoof growth and hoof growth rate in ponies: a controlled trial. Equine Vet J Suppl.1998(26):51-57.  (PubMed)
  60. Zenker W, Josseck H, Geyer H. Histological and physical assessment of poor hoof horn quality in Lipizzaner horses and a therapeutic trial with biotin and a placebo. Equine Vet J.1995;27(3):183-191.  (PubMed)
  61. Romero-Navarro G, Cabrera-Valladares G, German MS, et al. Biotin regulation of pancreatic glucokinase and insulin in primary cultured rat islets and in biotin-deficient rats. Endocrinology.1999;140(10):4595-4600.  (PubMed)
  62. Floersheim GL. [Treatment of brittle fingernails with biotin]. Z Hautkr.1989;64(1):41-48.  (PubMed)
  63. Hochman LG, Scher RK, Meyerson MS. Brittle nails: response to daily biotin supplementation. Cutis.1993;51(4):303-305.  (PubMed)
  64. Boccaletti V, Zendri E, Giordano G, Gnetti L, De Panfilis G. Familial uncombable hair syndrome: ultrastructural hair sudy and response to biotin. Pediatr Dermatol. 2007;24(3):E14-16.  (PubMed)
  65. Lipner SR, Scher RK. Biotin for the treatment of nail disease: what is the evidence? J Dermatolog Treat. 2018;29(4):411-414.  (PubMed)
  66. Walth CB, Wessman LL, Wipf A, Carina A, Hordinsky MK, Farah RS. Response to: "Rethinking biotin therapy for hair, nail, and skin disorders". J Am Acad Dermatol. 2018;79(6):e121-e124.  (PubMed)
  67. Famenini S, Goh C. Evidence for supplemental treatments in androgenetic alopecia. J Drugs Dermatol. 2014;13(7):809-812.  (PubMed)
  68. Patel DP, Swink SM, Castelo-Soccio L. A review of the use of biotin for hair loss. Skin Appendage Disord. 2017;3(3):166-169.  (PubMed)
  69. Staggs CG, Sealey WM, McCabe BJ, Teague AM, Mock DM. Determination of the biotin content of select foods using accurate and sensitive HPLC/avidin binding. J Food Compost Anal. 2004;17(6):767-776.  (PubMed)
  70. Briggs DR, Wahlqvist ML. Food facts: the complete no-fads-plain-facts guide to healthy eating. Victoria, Australia: Penguin Books; 1988. 
  71. Magnusdottir S, Ravcheev D, de Crecy-Lagard V, Thiele I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front Genet. 2015;6:148.  (PubMed)
  72. Said HM. Cell and molecular aspects of human intestinal biotin absorption. J Nutr. 2009;139(1):158-162.  (PubMed)
  73. US Department of Health and Human Services, National Institutes of Health, Office of Dietary Supplements. Dietary Supplement Label Database (DSLD). [Internet]. [Accessed 7/5/2022]. Available at: https://dsld.od.nih.gov/. 
  74. Koutsikos D, Agroyannis B, Tzanatos-Exarchou H. Biotin for diabetic peripheral neuropathy. Biomed Pharmacother.1990;44(10):511-514.  (PubMed)
  75. Tourbah A LFC, Edan G, Clanet M, Papeix C, Vukusic S, et al. Effect of MD1003 (high doses of biotin) in progressive multiple sclerosis: results of a pivotal phase III randomized double blind placebo controlled study. Paper presented at: American Association of Neurological Surgeons (AANS) Annual Scientific Meeting 2015; Washington, D.C.  
  76. Debourdeau PM, Djezzar S, Estival JL, Zammit CM, Richard RC, Castot AC. Life-threatening eosinophilic pleuropericardial effusion related to vitamins B5 and H. Ann Pharmacother. 2001;35(4):424-426.  (PubMed)
  77. Chirapu SR, Rotter CJ, Miller EL, Varma MV, Dow RL, Finn MG. High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid. Curr Top Med Chem. 2013;13(7):837-842.  (PubMed)
  78. Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, Rubin S. Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol.1998;275(5 Pt 1):C1365-1371.  (PubMed)
  79. Prasad PD, Wang H, Kekuda R, et al. Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J Biol Chem.1998;273(13):7501-7506.  (PubMed)
  80. Zempleni J, Trusty TA, Mock DM. Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver. J Nutr.1997;127(9):1776-1781.  (PubMed)
  81. Natural-Medicines. Biotin/Drug interactions. www.naturaldatabase.com/. 2014.
  82. Castro-Gago M, Gomez-Lado C, Eiris-Punal J, Diaz-Mayo I, Castineiras-Ramos DE. Serum biotinidase activity in children treated with valproic acid and carbamazepine. J Child Neurol. 2010;25(1):32-35.  (PubMed)
  83. Castro-Gago M, Perez-Gay L, Gomez-Lado C, Castineiras-Ramos DE, Otero-Martinez S, Rodriguez-Segade S. The influence of valproic acid and carbamazepine treatment on serum biotin and zinc levels and on biotinidase activity. J Child Neurol. 2011;26(12):1522-1524.  (PubMed)
  84. Schulpis KH, Karikas GA, Tjamouranis J, Regoutas S, Tsakiris S. Low serum biotinidase activity in children with valproic acid monotherapy. Epilepsia. 2001;42(10):1359-1362.  (PubMed)
  85. Yilmaz Y, Tasdemir HA, Paksu MS. The influence of valproic acid treatment on hair and serum zinc levels and serum biotinidase activity. Eur J Paediatr Neurol. 2009;13(5):439-443.  (PubMed)
  86. Mock DM. Biotin: from nutrition to therapeutics. J Nutr. 2017;147(8):1487-1492.  (PubMed)
  87. Li J, Wagar EA, Meng QH. Comprehensive assessment of biotin interference in immunoassays. Clin Chim Acta. 2018;487:293-298.  (PubMed)
  88. Gifford JL, de Koning L, Sadrzadeh SMH. Strategies for mitigating risk posed by biotin interference on clinical immunoassays. Clin Biochem. 2019;65:61-63.  (PubMed)
  89. Bowen R, Benavides R, Colon-Franco JM, et al. Best practices in mitigating the risk of biotin interference with laboratory testing. Clin Biochem. 2019;74:1-11.  (PubMed)
  90. US Food and Drug Administration. Biotin interference with troponin lab tests — assays subject to biotin interference. Available at: https://www.fda.gov/medical-devices/in-vitro-diagnostics/biotin-interference-troponin-lab-tests-assays-subject-biotin-interference. Accessed 7/5/2022.  
  91. Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence. Marcel Sprenger, et. al.  Cellular microbiology. First published: 21 February 2020.  https://doi.org/10.1111/cmi.13197
Michael Kreder
Next

Herxheimer Reactions - What Exactly Are They ?