J Pediatr Genet 2023; 12(01): 001-015
DOI: 10.1055/s-0042-1757887
Review Article

A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype–Phenotype Analysis

Balachander Kannan
1   Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
Hepzibah Kirubamani Navamani
2   Department of Obstetrics and Gynaecology, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Saveetha Medical College and Hospitals, Chennai, Tamil Nadu, India
Vijayashree Priyadharsini Jayaseelan
1   Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
Paramasivam Arumugam
1   Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
› Author Affiliations
Funding The Science and Engineering Research Board (SERB), Government of India (EMEQ/2019/000411) supported this work.


Biotinidase (BTD) deficiency is a rare autosomal recessive metabolic disorder caused by insufficient biotin metabolism, where it cannot recycle the vitamin biotin. When this deficiency is not treated with supplements, it can lead to severe neurological conditions. Approximately 1 in 60,000 newborns are affected by BTD deficiency. The BTD deficiency causes late-onset biotin-responsive multiple carboxylase deficiency, which leads to acidosis or lactic acidosis, hypoglycemia, and abnormal catabolism. BTD deficiency is of two types based on the amount of BTD Enzyme present in the serum. A wide range of pathogenic mutations in the BTD gene are reported worldwide. Mutations in the BTD gene lead to profound and partial BTD deficiency. Profound BTD deficiency results in a severe pathogenic condition. A high frequency of newborns are affected with the partial deficiency worldwide. They are mostly asymptomatic, but symptoms may appear during stressful conditions such as fasting or viral infections. Several pathogenic mutations are significantly associated with neurological, ophthalmological, and skin problems along with several other clinical features. This review discusses the BTD gene mutation in multiple populations detected with phenotypic features. The molecular-based biomarker screening is necessary for the disease during pregnancy, as it could be helpful for the early identification of BTD deficiency, providing a better treatment strategy. Moreover, implementing newborn screening for the BTD deficiency helps patients prevent several diseases.

Authors' Contribution

B.K. undertook literature mining from various reputed databases, drafted the manuscript, and prepared illustrations. P.A. gave the concept for this article and is responsible for manuscript proof reading and validated the entire manuscript. H.K.N. and V.P.J. corrected the final manuscript draft.

Publication History

Received: 24 January 2022

Accepted: 06 September 2022

Article published online:
01 November 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Hymes J, Wolf B. Biotinidase and its roles in biotin metabolism. Clin Chim Acta 1996; 255 (01) 1-11
  • 2 Wolf B, Grier RE, Allen RJ, Goodman SI, Kien CL. Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. Clin Chim Acta 1983; 131 (03) 273-281
  • 3 Pispa J. Animal biotinidase. Ann Med Exp Biol Fenn 1965; 43: 5 , 1–39
  • 4 Hymes J, Fleischhauer K, Wolf B. Biotinylation of histones by human serum biotinidase: assessment of biotinyl-transferase activity in sera from normal individuals and children with biotinidase deficiency. Biochem Mol Med 1995; 56 (01) 76-83
  • 5 Li H, Spencer L, Nahhas F. et al. Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene. Mol Genet Metab 2014; 112 (03) 242-246
  • 6 Wiltink RC, Kruijshaar ME, van Minkelen R. et al. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations. Eur J Hum Genet 2016; 24 (10) 1424-1429
  • 7 Wolf B, Jensen K, Hüner G. et al. Seventeen novel mutations that cause profound biotinidase deficiency. Mol Genet Metab 2002; 77 (1-2): 108-111
  • 8 Wolf B, Grier RE, Secor McVoy JR, Heard GS. Biotinidase deficiency: a novel vitamin recycling defect. J Inherit Metab Dis 1985; 8 (Suppl. 01) 53-58
  • 9 Wolf B, Heard GS, Weissbecker KA, McVoy JR, Grier RE, Leshner RT. Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann Neurol 1985; 18 (05) 614-617
  • 10 Wolf B, Grier RE, Allen RJ. et al. Phenotypic variation in biotinidase deficiency. J Pediatr 1983; 103 (02) 233-237
  • 11 Wolf B. Biotinidase deficiency: “if you have to have an inherited metabolic disease, this is the one to have”. Genet Med 2012; 14 (06) 565-575
  • 12 McVoy JR, Levy HL, Lawler M. et al. Partial biotinidase deficiency: clinical and biochemical features. J Pediatr 1990; 116 (01) 78-83
  • 13 Burlina AB, Dermikol M, Mantau A. et al. Increased plasma biotinidase activity in patients with glycogen storage disease type Ia: effect of biotin supplementation. J Inherit Metab Dis 1996; 19 (02) 209-212
  • 14 Hymes J, Wolf B. Human biotinidase isn't just for recycling biotin. J Nutr 1999; 129 (suppl 2S): 485S-489S
  • 15 Wolf B. The neurology of biotinidase deficiency. Mol Genet Metab 2011; 104 (1-2): 27-34
  • 16 Rybak LP, Whitworth C, Scott V, Weberg AD, Bhardwaj B. Rat as a potential model for hearing loss in biotinidase deficiency. Ann Otol Rhinol Laryngol 1991; 100 (4 Pt 1): 294-300
  • 17 Micó SI, Jiménez RD, Salcedo EM, Martínez HA, Mira AP, Fernández CC. Epilepsy in biotinidase deficiency after biotin treatment. JIMD Rep 2012; 4: 75-78
  • 18 Thodi G, Molou E, Georgiou V. et al. Mutational analysis for biotinidase deficiency of a Greek patients' cohort ascertained through expanded newborn screening. J Hum Genet 2011; 56 (12) 861-865
  • 19 Heard GS, Secor McVoy JR, Wolf B. A screening method for biotinidase deficiency in newborns. Clin Chem 1984; 30 (01) 125-127
  • 20 Broda E, Baumgartner ER, Scholl S. et al. Biotinidase determination in serum and dried blood spots--high sensitivity fluorimetric ultramicro-assay. Clin Chim Acta 2001; 314 (1-2): 175-185
  • 21 Cole H, Reynolds TR, Lockyer JM. et al. Human serum biotinidase. cDNA cloning, sequence, and characterization. J Biol Chem 1994; 269 (09) 6566-6570
  • 22 Knight HC, Reynolds TR, Meyers GA, Pomponio RJ, Buck GA, Wolf B. Structure of the human biotinidase gene. Mamm Genome 1998; 9 (04) 327-330
  • 23 Swango KL, Hymes J, Brown P, Wolf B. Amino acid homologies between human biotinidase and bacterial aliphatic amidases: putative identification of the active site of biotinidase. Mol Genet Metab 2000; 69 (02) 111-115
  • 24 Carvalho NO, Del Castillo DM, Januário JN. et al. Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil. Am J Med Genet A 2019; 179 (06) 978-982
  • 25 Iqbal F, Item CB, Vilaseca MA. et al. The identification of novel mutations in the biotinidase gene using denaturing high pressure liquid chromatography (dHPLC). Mol Genet Metab 2010; 100 (01) 42-45
  • 26 Mühl A, Möslinger D, Item CB, Stöckler-Ipsiroglu S. Molecular characterisation of 34 patients with biotinidase deficiency ascertained by newborn screening and family investigation. Eur J Hum Genet 2001; 9 (04) 237-243
  • 27 Ye J, Wang T, Han LS. et al. Diagnosis, treatment, follow-up and gene mutation analysis in four Chinese children with biotinidase deficiency. J Inherit Metab Dis 2009; 32 (Suppl. 01) S295-S302
  • 28 Wolf B, Spencer R, Gleason T. Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. J Pediatr 2002; 140 (02) 242-246
  • 29 Pindolia K, Jordan M, Wolf B. Analysis of mutations causing biotinidase deficiency. Hum Mutat 2010; 31 (09) 983-991
  • 30 Norrgard KJ, Pomponio RJ, Hymes J, Wolf B. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res 1999; 46 (01) 20-27
  • 31 Procter M, Wolf B, Mao R. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab 2016; 117 (03) 369-372
  • 32 Norrgard KJ, Pomponio RJ, Swango KL. et al. Mutation (Q456H) is the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Biochem Mol Med 1997; 61 (01) 22-27
  • 33 Swango KL, Demirkol M, Hüner G. et al. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet 1998; 102 (05) 571-575
  • 34 Cowan TM, Kazerouni NN, Dharajiya N. et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab 2012; 106 (04) 485-487
  • 35 Karaca M, Özgül RK, Ünal Ö. et al. Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening. Eur J Pediatr 2015; 174 (08) 1077-1084
  • 36 Pindolia K, Jensen K, Wolf B. Three dimensional structure of human biotinidase: computer modeling and functional correlations. Mol Genet Metab 2007; 92 (1-2): 13-22
  • 37 Sivri HS, Genç GA, Tokatli A. et al. Hearing loss in biotinidase deficiency: genotype-phenotype correlation. J Pediatr 2007; 150 (04) 439-442
  • 38 Wolf B, Jensen KP, Barshop B. et al. Biotinidase deficiency: novel mutations and their biochemical and clinical correlates. Hum Mutat 2005; 25 (04) 413
  • 39 Pace HC, Brenner C. The nitrilase superfamily: classification, structure and function. Genome Biol 2001; 2 (01) REVIEWS0001
  • 40 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; 23 (09) 1043-1048
  • 41 Kasapkara ÇS, Akar M, Özbek MN. et al. Mutations in BTD gene causing biotinidase deficiency: a regional report. J Pediatr Endocrinol Metab 2015; 28 (3-4): 421-424
  • 42 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 (06) 903-912
  • 43 Seker Yilmaz B, Mungan NO, Kor D. et al. Twenty-seven mutations with three novel pathogenic variants causing biotinidase deficiency: a report of 203 patients from the southeastern part of Turkey. J Pediatr Endocrinol Metab 2018; 31 (03) 339-343
  • 44 Liu Z, Zhao X, Sheng H. et al. Clinical features, BTD gene mutations, and their functional studies of eight symptomatic patients with biotinidase deficiency from Southern China. Am J Med Genet A 2018; 176 (03) 589-596
  • 45 Wiznitzer M, Bangert BA. Biotinidase deficiency: clinical and MRI findings consistent with myelopathy. Pediatr Neurol 2003; 29 (01) 56-58
  • 46 Yang Y, Li C, Qi Z. et al. Spinal cord demyelination associated with biotinidase deficiency in 3 Chinese patients. J Child Neurol 2007; 22 (02) 156-160
  • 47 Pomponio RJ, Coskun T, Demirkol M. et al. Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis 2000; 23 (02) 120-128
  • 48 Yang Y, Yang JY, Chen XJ. Biotinidase deficiency characterized by skin and hair findings. Clin Dermatol 2020; 38 (04) 477-483
  • 49 Geng J, Sun Y, Zhao Y. et al. Two novel BTD mutations causing profound biotinidase deficiency in a Chinese patient. Mol Genet Genomic Med 2021; 9 (02) e1591
  • 50 Karimzadeh P, Ahmadabadi F, Jafari N. et al. Biotinidase deficiency: a reversible neurometabolic disorder (an Iranian pediatric case series). Iran J Child Neurol 2013; 7 (04) 47-52
  • 51 Singh A, Lomash A, Pandey S, Kapoor S. Clinical, biochemical and outcome profile of biotinidase deficient patients from tertiary centre in Northern India. J Clin Diagn Res 2015; 9 (12) SC08-SC10
  • 52 Sarafoglou K, Bentler K, Gaviglio A. et al. High incidence of profound biotinidase deficiency detected in newborn screening blood spots in the Somalian population in Minnesota. J Inherit Metab Dis 2009; 32 (Suppl. 01) S169-S173
  • 53 Norrgard KJ, Pomponio RJ, Swango KL. et al. Double mutation (A171T and D444H) is a common cause of profound biotinidase deficiency in children ascertained by newborn screening the United States. Mutations in brief no. 128. Online. Hum Mutat 1998; 11 (05) 410
  • 54 Pomponio RJ, Hymes J, Reynolds TR. et al. Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediatr Res 1997; 42 (06) 840-848
  • 55 Milánkovics I, Németh K, Somogyi C, Schuler A, Fekete G. High frequencies of biotinidase (BTD) gene mutations in the Hungarian population. J Inherit Metab Dis 2010; 33 (Suppl. 03) S289-S292
  • 56 Milánkovics I, Kámory E, Csókay B, Fodor F, Somogyi C, Schuler A. Mutations causing biotinidase deficiency in children ascertained by newborn screening in Western Hungary. Mol Genet Metab 2007; 90 (03) 345-348
  • 57 László 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 (07) 693-698
  • 58 Raha S, Udani V. Biotinidase deficiency presenting as recurrent myelopathy in a 7-year-old boy and a review of the literature. Pediatr Neurol 2011; 45 (04) 261-264
  • 59 Szymańska E, Średzińska M, Ługowska A, Pajdowska M, Rokicki D, Tylki-Szymańska A. Outcomes of oral biotin treatment in patients with biotinidase deficiency - twenty years follow-up. Mol Genet Metab Rep 2015; 5: 33-35
  • 60 Tonin R, Caciotti A, Funghini S. et al. Biotinidase deficiency due to a de novo mutation or gonadal mosaicism in a first child. Clin Chim Acta 2015; 445: 70-72
  • 61 Weber P, Scholl S, Baumgartner ER. Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. Dev Med Child Neurol 2004; 46 (07) 481-484
  • 62 Funghini S, Tonin R, Malvagia S. et al. High frequency of biotinidase deficiency in Italian population identified by newborn screening. Mol Genet Metab Rep 2020; 25: 100689
  • 63 Maguolo A, Rodella G, Dianin A. et al. Newborn screening for biotinidase deficiency. The experience of a regional center in Italy. Front Pediatr 2021; 9: 661416
  • 64 Torkamandi S, Rezaei S, Mirfakhraie R, Golmohamadi S, Gholami M. The novel homozygous p.Asn197_Ser201del mutation in BTD gene is associated with profound biotinidase deficiency in an Iranian consanguineous family. Mol Biol Rep 2020; 47 (05) 4021-4027
  • 65 Mardhiah M, Azize NAA, Yakob Y. et al. Clinical, biochemical and mutational findings in biotinidase deficiency among Malaysian population. Mol Genet Metab Rep 2019; 22: 100548
  • 66 Senanayake DN, Jasinge EA, Pindolia K. et al. First contiguous gene deletion causing biotinidase deficiency: the enzyme deficiency in three Sri Lankan children. Mol Genet Metab Rep 2015; 2: 81-84
  • 67 Al-Eitan LN, Alqa'qa' K, Amayreh W. et al. Identification and characterization of BTD gene mutations in Jordanian children with biotinidase deficiency. J Pers Med 2020; 10 (01) 4
  • 68 Ohlsson A, Guthenberg C, Holme E, von Döbeln U. Profound biotinidase deficiency: a rare disease among native Swedes. J Inherit Metab Dis 2010; 33 (Suppl. 03) S175-S180
  • 69 Yanling Y. Biotin and Biotinase Deficiency. Basic and Clinical Diseases of Pediatric Nervous System. 2nd ed. Beijing: People's Health Publishing House; 2009: 634-635
  • 70 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 (04) 680-684
  • 71 Patra S, Senthilnathan G, Bhari N. Acrodermatitis enteropathica-like skin eruption with neonatal seizures in a child with biotinidase deficiency. Clin Exp Dermatol 2020; 45 (02) 266-267
  • 72 Singhi P, Ray M. Ohtahara syndrome with biotinidase deficiency. J Child Neurol 2011; 26 (04) 507-509
  • 73 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; 38 (08) 848-856
  • 74 Honavar M, Janota I, Neville BG, Chalmers RA. Neuropathology of biotinidase deficiency. Acta Neuropathol 1992; 84 (04) 461-464
  • 75 Wolf B. Disorders of biotin metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D. eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001: 3935-3962
  • 76 Mukhopadhyay D, Das MK, Dhar S, Mukhopadhyay M. Multiple carboxylase deficiency (late onset) due to deficiency of biotinidase. Indian J Dermatol 2014; 59 (05) 502-504
  • 77 Möslinger D, Mühl A, Suormala T, Baumgartner R, Stöckler-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; 162 (Suppl. 01) S46-S49
  • 78 Neto EC, Schulte J, Rubim R. et al. Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. Brazilian journal of medical and biological research. Rev Bras Pesqui Med Biol 2004; 37 (03) 295-299
  • 79 Canda E, Yazici H, Er E. et al. Single center experience of biotinidase deficiency: 259 patients and six novel mutations. J Pediatr Endocrinol Metab 2018; 31 (08) 917-926
  • 80 Couce Pico ML, Martinón-Torres F, Castiñeiras DE, Alonso-Fernández JR, Fraga JM. Deficiencia de biotinidasa: importancia de su diagnóstico neonatal y tratamiento precoz. [Biotinidase deficiency: importance of its neonatal diagnosis and early treatment] An Esp Pediatr 1999; 50 (05) 504-506
  • 81 Hsu RH, Chien YH, Hwu WL. et al. Genotypic and phenotypic correlations of biotinidase deficiency in the Chinese population. Orphanet J Rare Dis 2019; 14 (01) 6
  • 82 Murry JB, Machini K, Ceyhan-Birsoy O. et al; BabySeq Project Team. Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report. Cold Spring Harb Mol Case Stud 2018; 4 (04) a002873