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Biotinidase Deficiency Clinical Presentation

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
Updated: May 06, 2016


Partial biotinidase deficiency (10%-30% mean normal serum biotinidase activity) is associated with an increased risk of developing clinical symptoms that are similar to those seen in children who have a profound deficiency. However, symptom presentation appears to be correlated with metabolic stressors (eg, illness, fever, fasting), and these children may not be symptomatic or only mildly symptomatic until then.

Metabolic deterioration during stress can be a useful clue in diagnosing a partial deficiency, although this type of clinical decline does occur with other inborn errors of metabolism. If there is concern, laboratory studies that specifically measure biotinidase activity should be obtained. In addition, diagnostic clarification is further made with symptom response to biotin treatment.

Sudden death is reported in association with presumed biotinidase deficiency, possibly due to seizures and/or brain stem dysfunction. Therefore, the diagnosis of biotinidase deficiency should be considered when evaluating an infant who died from sudden infant death syndrome (SIDS),[19] especially if there are family members who have possible clinical signs of partial biotinidase deficiency or are known to be heterozygous for a BTD gene mutation.

Clinical signs and symptoms of biotinidase deficiency vary. Consider biotinidase deficiency in patients who present with symptoms such as intractable seizures, hypotonia, spastic paraparesis, acidosis, unexplained visual loss or visual field loss, unexplained sensorineural hearing loss, alopecia, persistent rash, or failure to thrive.[20]

Neurologic sequelae

In a retrospective study published in 1993, 38% of patients with biotinidase deficiency presented with seizures, often in combination with other clinical features indicative of biotinidase deficiency. Approximately 55% of these patients had seizures at some point during the clinical review period. Seizures were described as generalized, tonic-clonic, clonic or myoclonic. Infantile spasms were also reported.[21]

Among patients with biotinidase deficiency, seizures or other neurologic manifestations (typically unresponsive to conventional therapies) quickly respond to pharmacologic doses of biotin. Most neurologic symptoms respond well to treatment with biotin; however, severe permanent neurologic sequelae can result from untreated biotinidase deficiency.

Other neurologic sequelae may include the following:

  • Developmental delay
  • Ataxia
  • Neuropathy
  • Auditory nerve dysfunction (sensorineural hearing loss)
  • Optic nerve atrophy and scotomata
  • Spastic paraparesis (an uncommon presentation)

Respiratory abnormalities

Respiratory difficulties are common. Apnea, hyperventilation, and laryngeal stridor are observed. Stridor and breathing pattern abnormalities possibly result from dysfunction of medullary breathing centers affected by metabolic imbalance. Progression to other bulbar symptoms, such as swallowing difficulties, can occur.


Clinical manifestations, such as loss of hair color (achromotrichia), loss of hair (alopecia), and an eczematous, scaly perioral/facial rash, can be quite striking. The rash distribution is described as periorificial and can be mistaken for eczema, seborrheic dermatitis, or the dermatoses of zinc deficiency.

Immunologic dysfunction

Abnormalities in cellular immunity can result from biotin deficiency. Chronic, potentially lethal fungal infections and recurrent viral infections characterize immunologic dysfunction. Immunologic dysfunction is ameliorated with proper biotin treatment.

Metabolic abnormalities

Profound biotinidase deficiency can cause metabolic ketoacidosis or organic acidosis.




Conjunctivitis and/or sudden vision loss may be presenting signs. Comprehensive ophthalmologic examination by a trained ophthalmologist may reveal optic atrophy and scotomata (alteration in visual fields).

Hair and skin

Clinical findings such as achromotrichia, alopecia, and an eczematous scaly perioral/facial rash can be striking. The rash distribution is described as periorificial, indicating a propensity for the rash to affect areas surrounding body orifices. Rashes may be mistaken for eczema, seborrheic dermatitis, or the dermatoses observed in zinc deficiency. Recalcitrance to conventional treatments for these dermatoses should lead the medical provider to diagnostically consider an inborn error of metabolism, including biotinidase deficiency. Initiation of biotin treatment leads to clinical improvement of alopecia and the periorificial rash within days to months.

Causative explanations for the dermatologic findings may be abnormal fatty acid synthesis and metabolism, possibly secondary to carboxylase dysfunction. Chronic candidiasis may also develop (as part of immunologic dysfunction).

Neurodevelopmental abnormalities

Infants may present with hypotonia and delay in developmental milestones. Older children may present with developmental delay and ataxia.

Twenty to 30% of symptomatic patients have sensorineural hearing loss. Of these patients, 76% of untreated children with profound biotinidase deficiency have sensorineural hearing loss that will not resolve or improve, but instead remains static, despite initiation of biotin treatment.[22]

Visual loss with progressive optic neuropathy can develop in isolation or in association with spastic paraparesis. Treatment with biotin therapy has demonstrated resolution of ocular findings and improvement of spastic paraparesis.[23, 24]  



Biotinidase deficiency is a genetic disorder that results from an autosomal-recessive Mendelian inheritance pattern. Both biological parents must contribute the biotinidase gene mutation for this deficiency to occur in offspring, as two altered gene copies are required. Biotinidase deficiency heterozygous carriers can be identified via mutation assay.

The gene that encodes biotinidase, called BTD, is cytogenetically located on the short arm (p) of chromosome 3, band 25.1 (3p25.1). The most common BTD mutation, 98_104del7ins3, is present in about 50% of symptomatic children. A less common BTD mutation, Arg538 R→C, has also been described. The BTD mutation known to cause partial deficiency is p.D444H.[13]

As of 2012, Wolf has described 150 novel mutations of BTD.[25] His research cites the difficulty of correlating genotypes with phenotypes, indicating that age at onset of clinical signs and the patient's disease path primarily depend on the amount of functioning biotinidase present.

Prenatal testing via BTD gene analysis can identify the causative mutation(s), identify carriers of a mutated gene, and diagnose biotinidase deficiency via mutation assay.[1]

Contributor Information and Disclosures

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.


Ronald G Davis, MD, MPH, FAAP Assistant Clinical Professor, Child Neurology, Florida State University; Owner and Medical Director of Pediatric Neurology, PA and Pediatric Neurology Epilepsy Center of Central Florida; Medical Director of Epileptology, Arnold Palmer Hospital for Women and Children in Orlando, Florida; Medical Director, Central Florida Muscular Dystrophy Association Clinic

Ronald G Davis, MD, MPH, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose. Marc P DiFazio, MD Associate Professor, Department of Neurology, Uniformed Services University of the Health Sciences; Director, Pediatric Subspecialty Services, Shady Grove Adventist Hospital for Children

Marc P DiFazio, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Cerebral Palsy and Developmental Medicine, American Academy of Neurology, Child Neurology Society, and Movement Disorders Society

Disclosure: Nothing to disclose.

  1. Quest Diagnostics. Biotinidase Deficiency. Available at

  2. Mardach R, Zempleni J, Wolf B, Cannon MJ, Jennings ML, Cress S, et al. Biotin dependency due to a defect in biotin transport. J Clin Invest. 2002 Jun. 109(12):1617-23. [Medline]. [Full Text].

  3. Gompertz D, Draffan GH, Watts JL, Hull D. Biotin-responsive beta-methylcrotonylglycinuria. Lancet. 1971 Jul 3. 2(7714):22-4. [Medline].

  4. Wolf B, Hsia YE, Sweetman L, et al. Multiple carboxylase deficiency: clinical and biochemical improvement following neonatal biotin treatment. Pediatrics. 1981 Jul. 68(1):113-8. [Medline].

  5. Wolf B, Heard GS, Weissbecker KA, et al. Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann Neurol. 1985 Nov. 18(5):614-7. [Medline].

  6. Tsao CY, Kien CL. Complete biotinidase deficiency presenting as reversible progressive ataxia and sensorineural deafness. J Child Neurol. 2002 Feb. 17(2):146. [Medline].

  7. 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].

  8. Dahiphale R, Jain S, Agrawal M. Biotinidase deficiency. Indian Pediatr. 2008 Sep. 45(9):777-9. [Medline].

  9. National Center for Biotechnology Information. Biotin. Available at http://ttp://

  10. Zempleni J, Wijeratne SS, Hassan YI. Biotin. Biofactors. 2009 Jan-Feb. 35(1):36-46. [Medline].

  11. Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis. 1991. 14 (6):923-7. [Medline].

  12. Cowan TM, Kazerouni NN, Dharajiya N, Lorey F, Roberson M, Hodgkinson C, et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug. 106 (4):485-7. [Medline].

  13. Wolf B. Biotinidase Deficiency. Available at

  14. Heard GS, Annison EF. Gastrointestinal absorption of vitamin B-6 in the chicken (Gallus domesticus). J Nutr. 1986 Jan. 116(1):107-20. [Medline].

  15. National Newborn Screening Status Report. Available at

  16. Medical Home Portal. Biotinidase deficiency. Available at

  17. Venkataraman V, Balaji P, Panigrahi D, Jamal R. Biotinidase deficiency in childhood. Neurol India. 2013 Jul-Aug. 61(4):411-3. [Medline].

  18. Thodi G, Schulpis KH, Molou E, Georgiou V, Loukas YL, Dotsikas Y, et al. High incidence of partial biotinidase deficiency cases in newborns of Greek origin. Gene. 2013 Jul 25. 524(2):361-2. [Medline].

  19. Burton BK, Roach ES, Wolf B, Weissbecker KA. Sudden death associated with biotinidase deficiency. Pediatrics. 1987 Mar. 79(3):482-3. [Medline].

  20. Welling DB. Long-term follow-up of hearing loss in biotinidase deficiency. J Child Neurol. 2007 Aug. 22(8):1055. [Medline].

  21. Salbert BA, Pellock JM, Wolf B. Characterization of seizures associated with biotinidase deficiency. Neurology. 1993 Jul. 43(7):1351-5. [Medline].

  22. Wolf B, Spencer R, Gleason T. Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. J Pediatr. 2002 Feb. 140(2):242-6. [Medline].

  23. Tokatli A, Coşkun T, Ozalp I. Biotinidase deficiency with neurological features resembling multiple sclerosis. J Inherit Metab Dis. 1997 Sep. 20 (5):707-8. [Medline].

  24. Wolf B, Pomponio RJ, Norrgard KJ, et al. Delayed-onset profound biotinidase deficiency. J Pediatr. 1998 Feb. 132(2):362-5. [Medline].

  25. Wolf B. Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". Genet Med. 2012 Jan 5. [Medline].

  26. 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].

  27. Armstrong RW, Steinbok P, Cochrane DD, Kube SD, Fife SE, Farrell K. Intrathecally administered baclofen for treatment of children with spasticity of cerebral origin. J Neurosurg. 1997 Sep. 87(3):409-14. [Medline].

  28. Procter M, Wolf B, Crockett DK, Mao R. The Biotinidase Gene Variants Registry: A Paradigm Public Database. G3 (Bethesda). 2013 Mar 11. [Medline]. [Full Text].

  29. Wolf B, Heard GS, Jefferson LG, Proud VK, Nance WE, Weissbecker KA. Clinical findings in four children with biotinidase deficiency detected through a statewide neonatal screening program. N Engl J Med. 1985 Jul 4. 313(1):16-9. [Medline].

  30. [Guideline] Michigan Quality Improvement Consortium. Routine preventive services for infants and children (birth-24 months). 2007 May. [Full Text].

  31. Wolf B. Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". Genet Med. 2012 Jun. 14(6):565-75. [Medline].

  32. Ataman M, Sozeri B, Ozalp I. Biotinidase deficiency: a rare cause of laryngeal stridor. Int J Pediatr Otorhinolaryngol. 1992 May. 23(3):281-4. [Medline].

  33. Baumgartner ER, Suormala TM, Wick H, et al. Biotinidase deficiency: a cause of subacute necrotizing encephalomyelopathy (Leigh syndrome). Report of a case with lethal outcome. Pediatr Res. 1989 Sep. 26(3):260-6. [Medline].

  34. Bousounis DP, Camfield PR, Wolf B. Reversal of brain atrophy with biotin treatment in biotinidase deficiency. Neuropediatrics. 1993 Aug. 24(4):214-7. [Medline].

  35. Colamaria V, Burlina AB, Gaburro D, et al. Biotin-responsive infantile encephalopathy: EEG-polygraphic study of a case. Epilepsia. 1989 Sep-Oct. 30(5):573-8. [Medline].

  36. Grapp M, Just IA, Linnankivi T, Wolf P, Lücke T, Häusler M. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012 Jul. 135(Pt 7):2022-31. [Medline].

  37. Honavar M, Janota I, Neville BG, Chalmers RA. Neuropathology of biotinidase deficiency. Acta Neuropathol (Berl). 1992. 84(4):461-4. [Medline].

  38. Kalayci O, Coskun T, Tokatli A, et al. Infantile spasms as the initial symptom of biotinidase deficiency. J Pediatr. 1994 Jan. 124(1):103-4. [Medline].

  39. Kalkanoglu HS, Dursun A, Tokatli A, et al. A boy with spastic paraparesis and dyspnea. J Child Neurol. 2004 May. 19(5):397-8. [Medline].

  40. Kimura M, Fukui T, Tagami Y, et al. Normalization of low biotinidase activity in a child with biotin deficiency after biotin supplementation. J Inherit Metab Dis. 2003. 26(7):715-9. [Medline].

  41. Mardach R, Zempleni J, Wolf B, et al. Biotin dependency due to a defect in biotin transport. J Clin Invest. 2002 Jun. 109(12):1617-23. [Medline].

  42. Mock DM. Skin manifestations of biotin deficiency. Semin Dermatol. 1991 Dec. 10(4):296-302. [Medline].

  43. Moslinger D, Stockler-Ipsiroglu S, Scheibenreiter S, et al. Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr. 2001 May. 160(5):277-82. [Medline].

  44. 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].

  45. Ozand PT, Gascon GG, Al Essa M, et al. Biotin-responsive basal ganglia disease: a novel entity. Brain. 1998 Jul. 121 (Pt 7):1267-79. [Medline].

  46. 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. 2008 Dec 5. 283(49):34150-8. [Medline].

  47. Pidcock FS. Botulinum toxin type A treatment in neurogenetic syndromes. Pediatr Rehabil. 2005 Oct-Dec. 8(4):298-302. [Medline].

  48. Reed JJ, Rupp T. Emergency department presentation of biotinidase deficiency: fulminant sepsis in a 4-year-old Hispanic male. Pediatr Emerg Care. 2004 Jan. 20(1):37-9. [Medline].

  49. Riudor E, Vilaseca MA, Briones P, et al. Requirement of high biotin doses in a case of biotinidase deficiency. J Inherit Metab Dis. 1989. 12(3):338-9. [Medline].

  50. Straussberg R, Saiag E, Harel L, et al. Reversible deafness caused by biotinidase deficiency. Pediatr Neurol. 2000 Sep. 23(3):269-70. [Medline].

  51. 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].

  52. Williams ML, Packman S, Cowan MJ. Alopecia and periorificial dermatitis in biotin-responsive multiple carboxylase deficiency. J Am Acad Dermatol. 1983 Jul. 9(1):97-103. [Medline].

  53. Wiznitzer M, Bangert BA. Biotinidase deficiency: clinical and MRI findings consistent with myelopathy. Pediatr Neurol. 2003 Jul. 29(1):56-8. [Medline].

  54. Wolf B. Biotinidase Deficiency: New Directions and Practical Concerns. Curr Treat Options Neurol. 2003 Jul. 5(4):321-328. [Medline].

  55. Wolf B, Grier RE, Allen RJ, et al. Phenotypic variation in biotinidase deficiency. J Pediatr. 1983 Aug. 103(2):233-7. [Medline].

  56. Zempleni J. Uptake, localization, and noncarboxylase roles of biotin. Annu Rev Nutr. 2005. 25:175-96. [Medline].

Biotin structure.
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