Biotin Deficiency Clinical Presentation
- Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Jatinder Bhatia, MBBS, FAAP more...
Profound biotinidase deficiency can be detected with newborn screening. The first symptoms of biotin deficiency are associated with the skin and hair.
Symptoms develop within 3-5 weeks of the onset of deficient biotin intake. The most common cutaneous findings include the following:
- Dry skin
- Seborrheic dermatitis
- Fungal infections
- Rashes, including erythematous periorofacial macular rash
- Fine and brittle hair
- Hair loss or total alopecia
Approximately 1-2 weeks later, neurologic symptoms begin to develop. The most common neurologic findings include the following:
- Mild depression, which may progress to profound lassitude and, eventually, to somnolence
- Changes in mental status
- Generalized muscular pains (myalgias)
- Hyperesthesias and paresthesias
Intestinal tract symptoms also develop and most commonly include the following:
- Nausea, occasionally severe
Spastic tetraparesis in a young woman associated with deficiency of biotinidase has been reported.
Individuals with biotin deficiency are typically healthy before the onset of the biotin-deficient state. Growth and stature are normal. Regardless of the etiology of biotin deficiency, clinical manifestations are essentially the same in all patients; however, the rate of symptom development and the sequence in which symptoms appear greatly vary. Physical manifestations are confined to 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. The hair quickly becomes fine and brittle, and total alopecia often develops.
Genc et al performed subjective and objective audiologic tests on 20 children with profound biotinidase deficiency and found that approximately 55% of children with biotinidase deficiency develop sensorineural hearing loss. The hearing loss varies in severity from mild to profound.
Central and peripheral nervous systems
The neurologic signs are multiple and nonspecific. They include mild depression, which may progress to profound lassitude, and, eventually, somnolence. Occasionally, changes in mental status are observed. 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. Biotinidase deficiency with hypertonia was noted by Rathi and Rathi. Biotin-responsive seizures and encephalopathy due to biotinidase deficiency have been noted.
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.
Biotin responsive seizures and encephalopathy due to biotinidase deficiency has been reported.
Causes of biotin deficiency include the following:
Eating raw egg whites
Some mistakenly believe that raw egg-white consumption is the only cause of biotin deficiency. Nonetheless, a diet that contains raw egg whites quickly and almost invariably leads to biotin deficiency.
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. 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.
Prolonged use of certain drugs, especially phenytoin, primidone, and carbamazepine, may lead to biotin deficiency; however, valproic acid therapy does not cause this condition. Some anticonvulsants inhibit biotin transport across the intestinal mucosa. Evidence suggests that these anticonvulsants accelerate biotin catabolism. Therefore, supplemental biotin, in addition to the usual minimum daily requirements, has been suggested for patients who are treated with anticonvulsants that have been linked to biotin deficiency.
Prolonged oral antibiotic therapy
Prolonged use of oral antibiotics has been associated with biotin deficiency. Alterations in the intestinal flora caused by the prolonged administration of antibiotics are presumed to be the basis for biotin deficiency.
Mikati et al reported a case of partial biotinidase deficiency (plasma biotinidase level of 1.3 nm/min/mL) in a 7-month-old boy. The boy presented with perinatal distress followed by developmental delay, hypotonia, seizures, and infantile spasms without alopecia or dermatitis. The child's neurologic symptoms abated following biotin supplementation and antiepileptic drug therapy. DNA mutational analysis revealed that the child was homozygous for a novel E64K mutation and that his mother and father were heterozygous for the novel E64K mutation. We now report 140 known mutations in the biotinidase gene (BTD) that cause biotinidase deficiency.
Ketogenic diet (high-protein, low-fat)
In a mouse model, a ketogenic diet exaggerated biotin deficiency.
Pindolia K, Jordan M, Wolf B. Analysis of mutations causing biotinidase deficiency. Hum Mutat. 2010 Jun 15. [Medline].
Pindolia K, Jordan M, Guo C, et al. Development and characterization of a mouse with profound biotinidase deficiency: a biotin-responsive neurocutaneous disorder. Mol Genet Metab. 2011 Feb. 102(2):161-9. [Medline]. [Full Text].
Boas MA. The Effect of Desiccation upon the Nutritive Properties of Egg-white. Biochem J. 1927. 21(3):712-724.1. [Medline].
Adhisivam B, Mahto D, Mahadevan S. Biotin responsive limb weakness. Indian Pediatr. 2007 Mar. 44(3):228-30. [Medline].
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 Apr. 23(4):392-9. [Medline].
Yuasa M, Matsui T, Ando S, Ishii Y, Sawamura H, Ebara S, et al. Consumption of a low-carbohydrate and high-fat diet (the ketogenic diet) exaggerates biotin deficiency in mice. Nutrition. 29(10). 2013 Oct:1266-70. [Medline].
Hernández-Vázquez A, Wolf B, Pindolia K, Ortega-Cuellar D, Hernández-González R, Heredia-Antúnez A, et al. Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. Mol Genet Metab. 110(3). 2013 Nov:248-54. [Medline].
Tsuji A, Nakamura T, Shibata K. Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes. Biosci Biotechnol Biochem. 2014 Oct. 10:1-8. [Medline].
Hayashi H, Tokuriki S, Okuno T, Shigematsu Y, Yasushi A, Matsuyama G, et al. Biotin and carnitine deficiency due to hypoallergenic formula nutrition in infants with milk allergy. Pediatr Int. 2014 Apr. 56(2):286-8. [Medline].
Kuroishi T. Biotin is involved in the regulation of immunne and inflammatory regulation. Can J Physiol Pharmacol. 2015 Dec. 93(12):1091-6. [Medline].
Dakshinamurti K, Bagchi RA, Abrenica B, Czubryt MP. Microarray analysis of pancreatic gene expression during biotin repletion in biotin-deficient rats. Can J Physiol Pharmacol. 2015 Dec. 93(12):1103-10. [Medline].
Neto EC, Schulte J, Rubim R, et al. Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. Braz J Med Biol Res. 2004 Mar. 37(3):295-9. [Medline].
Laszlo A, Schuler EA, Sallay E, et al. Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. J Inherit Metab Dis. 2003. 26(7):693-8. [Medline].
Yetgin S, Aytac S, Kalkanoglu S, Coskun T, Ortmann C, Kratz C, et al. Biotinidase deficiency and juvenile myelomonocytic leukemia in a Turkish infant of consanguineous parents. Pediatr Hematol Oncol. 2007 Sep. 24(6):453-5. [Medline].
Baykal T, Gokcay G, Gokdemir Y, et al. Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. J Inherit Metab Dis. 2005. 28(6):903-12. [Medline].
Komur M, Okuyaz C, Ezgu F, Atici A. A girl with spastic tetraparesis associated with biotinidase deficiency. Eur J Paediatr Neurol. 2011 Nov. 15(6):551-3. [Medline].
Genc GA, Sivri-Kalkanoglu HS, Dursun A, et al. Audiologic findings in children with biotinidase deficiency in Turkey. Int J Pediatr Otorhinolaryngol. 2007 Feb. 71(2):333-9. [Medline].
Chedrawi AK, Ali A, Al Hassnan ZN, Faiyaz-Ul-Haque M, Wolf B. Profound biotinidase deficiency in a child with predominantly spinal cord disease. J Child Neurol. 2008 Sep. 23(9):1043-8. [Medline].
Rathi N, Rathi M. Biotinidase deficiency with hypertonia as unusual feature. Indian Pediatr. 2009 Jan. 46(1):65-7. [Medline].
Joshi SN, Fathalla M, Koul R, Maney MA, Bayoumi R. Biotin responsive seizures and encephalopathy due to biotinidase deficiency. Neurol India. 2010 Mar-Apr. 58(2):323-4. [Medline].
Mikati MA, Zalloua P, Karam P, Habbal MZ, Rahi AC. Novel mutation causing partial biotinidase deficiency in a Syrian boy with infantile spasms and retardation. J Child Neurol. 2006 Nov. 21(11):978-81. [Medline].
Moslinger D, Muhl A, Suormala T, Baumgartner R, Stockler-Ipsiroglu S. Molecular characterisation and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies. Eur J Pediatr. 2003 Dec. 162 Suppl 1:S46-9. [Medline].
Schulpis KH, Gavrili S, Tjamouranis J, et al. The effect of neonatal jaundice on biotinidase activity. Early Hum Dev. 2003 May. 72(1):15-24. [Medline].
Dobrowolski SF, Angeletti J, Banas RA, Naylor EW. Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency. Mol Genet Metab. 2003 Feb. 78(2):100-7. [Medline].
Tokuriki S, Hayashi H, Okuno T, et al. Biotin and carnitine profiles in preterm infants in Japan. Pediatr Int. 2013 Jan 14. [Medline].
Bogusiewicz A, Horvath TD, Stratton SL, Mock DM, Boysen G. Measurement of acylcarnitine substrate to product ratios specific to biotin-dependent carboxylases offers a combination of indicators of biotin status in humans. J Nutr. 2012 Sep. 142(9):1621-5. [Medline]. [Full Text].
Bunch M, Singh A. Peculiar neuroimaging and electrophysiological findings in a patient with biotinidasedeficiency. Jan 2011. 1:83-86. [Medline].
Desai S, Ganesan K, Hegde A. Biotinidase deficiency: a reversible metabolic encephalopathy. Neuroimaging and MR spectroscopic findings in a series of four patients. Pediatr Radiol. 2008 Aug. 38(8):848-56. [Medline].
Gonzalez EC, Marrero N, Frometa A, et al. Qualitative colorimetric ultramicroassay for the detection of biotinidase deficiency in newborns. Clin Chim Acta. 2006 Jul 15. 369(1):35-9. [Medline].
Hassan YI, Zempleni J. Epigenetic regulation of chromatin structure and gene function by biotin. J Nutr. 2006 Jul. 136(7):1763-5. [Medline].
Perez-Monjaras A, Cervantes-Roldan R, Meneses-Morales I, et al. Impaired biotinidase activity disrupts holocarboxylase synthetase expression in late onset multiple carboxylase deficiency. J Biol Chem. 20008. 283:34150-8. [Medline].
Pindolia K, Jordan M, Wolf B. Analysis of mutations causing biotinidase deficiency. Hum Mutat. 2010 Sep. 31(9):983-91. [Medline].
Weber P, Scholl S, Baumgartner ER. Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. Dev Med Child Neurol. 2004 Jul. 46(7):481-4. [Medline].
Welling DB. Long-term follow-up of hearing loss in biotinidase deficiency. J Child Neurol. 2007 Aug. 22(8):1055. [Medline].
Wolf B. Disorders of biotin metabolism. Scriver CR, Beaudet AL, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001. 3935-62.