Health Research, Vol. 1, Issue 1, Dec  2017, Pages 50-65; DOI: 10.31058/ 10.31058/

Clinical Indications and Outcome of Biotinidase Deficiency Screening among Children and Youths in a Scottish NHS Region Between 2014 and 2016

Health Research, Vol. 1, Issue 1, Dec  2017, Pages 50-65.

DOI: 10.31058/

Michael O. Ogundele 1*

1 Community Paediatric Unit, NHS Fife, Glenwood Health Centre, Glenrothes, Scotland

Received: 6 December 2017; Accepted: 27 December 2017; Published: 23 January 2018

Download PDF | Views 503 | Download 302


Biotinidase deficiency (BTD) is an autosomal recessive metabolic disorder characterized by neurodevelopmental and cutaneous disorders.  Individuals with a biotinidase deficiency have either homozygous or compound heterozygous variants of biotinidase (BT) enzyme.   We aimed to analyze the pattern and outcome of investigations for BTD among for children and young people in a Scottish NHS Board.  We retrospectively analysed the clinical and laboratory data of all children within the Fife area who were screened for BTD between July 2014 and July 2016.   BTA levels ranged between 2.7 and 14.1 nmol/min/mL from a total of 191 patients.  262 tests were requested for 243 children aged between 1 month and 17 years-6 months (Mean 70 months).  75 of the samples (29%) were ordered to be repeated.  59 samples from 53 patients (22%) could not be analysed for reasons including “insufficient sample” (34), “unsuitable bottle” (10), “missed in error” (7), and “samples leaked in transit” (3).   The commonest indications for the BTD screening were developmental delay (63%) and social communication concerns (49%).  The commonest professionals requesting the tests were the either the consultant or specialist Community Paediatricians (93%).   None of the 191 patients analysed had BTD.  However a substantial proportion of the patients (22%) could not be analysed due to various problems with their blood samples.  It is therefore difficult to determine precisely the prevalence of BT deficiency in this small cohort of children and adolescents.  A larger prospective study is required to verify the true prevalence of BTD in the population.  


Biotin, Biotinidase Screening, Biotinidase Deficiency, Enzyme, Developmental Delay, Learning Disability, Metabolic Disorder, Inborn Errors


© 2017 by the authors. Licensee International Technology and Science Press Limited. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


[1] Küry, S.; Ramaekers, V.; Bézieau, S.; Wolf, B. Clinical utility gene card for: Biotinidase deficiency—update 2015. European Journal of Human Genetics 2016; 24(7). doi:10.1038/ejhg.2015.246.
[2] Wolf, B. Biotinidase Deficiency Synonym: Late-Onset Multiple Carboxylase Deficiency. Gene Reviews: 2016.
[3] Zempleni, J.; Hassan, Y.I.; Wijeratne, S.S. Biotin and biotinidase deficiency. Expert Rev Endocrinol Metab. 2008; 3(6):715-724.
[4] Loeber, J.G. Neonatal screening in Europe; the situation in 2004. Journal of inherited metabolic disease 2007; 30: 430–438.
[5] Wolf, B. Why screen newborns for profound and partial biotinidase deficiency? 2015; 114(3):382–387. doi:
[6] Demirci, A.;Kartal, M. The prevalence of developmental delay among children aged 3-60 months in Izmir, Turkey. Child Care Health Dev. 2015; doi: 10.1111/cch.12289. [Epub ahead of print]
[7] Valla, L.; Wentzel-Larsen, T.; Hofoss, D.; Slinning, K. Prevalence of suspected developmental delays in early infancy: results from a regional population-based longitudinal study. BMC Pediatr 2015; 15:215. doi: 10.1186/s12887-015-0528-z.
[8] Eun, S.H.; Hahn, S.H. Metabolic evaluation of children with global developmental delay. Korean Journal of Pediatrics. 2015; 58(4): 117-122. doi: 10.3345/kjp.2015.58.4.117.
[9] van Karnebeek, C.D.; Stockler-Ipsiroglu, S. Early identification of treatable inborn errors of metabolism in children with intellectual disability: The Treatable Intellectual Disability Endeavor protocol in British Columbia. Paediatrics & Child Health. 2014; 19(9): 469-471.
[10] Meerding, W.J.; Bonneux, L.; Polder, J.J.; Koopmanschap, M.A.; van der Maas, P.J. Demographic and epidemiological determinants of healthcare costs in Netherlands: cost of illness study. BMJ 1998; 317(7151):111-5.
[11] Ogundele, M.O. An Audit of biotinidase screening at a tertiary children’s hospital before and after implementation of an evidence-based practice guideline for developmental delay. Int Med Rev 2017; 3(3):1-8. doi: 10.18103/imr.v3i3.383
[12] Zhang, J.M.; Gu, X.F.; Shao, X.H.; Song, X.Q.; Han, L.S.; Ye, J. et al. [Values of tandem mass spectrometry in etiologic diagnosis of cerebral developmental retardation] (Chinese). Zhonghua Er Ke Za Zhi 2007; 45(12):932-6.
[13] Wuu, K.D.; Chiu, P.C.; Li, S.Y.; Chen, J.Y.; Chao, M.C.; Ko, F.J. et al. Chromosomal and biochemical screening on mentally retarded school children in Taiwan. Jinrui Idengaku Zasshi. 1991; 36(3):267-74.
[14] Sutherland, S.J.; Olsen, R.D.; Michels, V.; Schmidt, M.A.; OBrien, J.F. Screening for biotinidase deficiency in children with unexplained neurologic or developmental abnormalities. Clin Pediatr (Phila) 1991; 30(2):81-4.
[15] Ogundele, M.O. What is the incidence of biotin deficiency in preschool children with global developmental delay? Arch Dis Child 2011; 96(9):895-7. doi: 10.1136/archdischild-2011-300411.
[16] Shevell, M.; Ashwal, S.; Donley, D.; Flint, J.; Gingold, M.; Hirtz, D. et al. Practice parameter: Evaluation of the child with global developmental delay: Report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 2003; 60:367-380. doi: 10.1212/01.WNL.0000031431.81555.16
[17] Van Karnebeek, C.D.; Jansweijer, M.C.; Leenders, A.G.; Offringa, M.; Hennekam, R.C. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005; 13(1): 6−25.
[18] Van Karnebeek, C.D.; Shevell, M.; Zschocke, J.; Moeschler, J.B.; Stockler, S. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab 2014b; 111(4):428-38.
[19] McDonald, L.; Rennie, A.; Tolmie, J.; Galloway, P.; McWilliam, R. Investigation of global developmental delay. Arch Dis Child 2006; 91:701-705. doi: 10.1136/adc.2005.078147.
[20] National Metabolic Biochemistry Network. Best Practice Guidelines for the Biochemical Investigation of Global Developmental Delay for Inherited Metabolic Disorders (IMD). Jan 2010. Available online: (Last accessed Jan 2018)
[21] Wolf, B.; Heard, G.S.; Jefferson, L.G.; Proud, V.K.; Nance, W.E.; Weissbecker, K.A. Clinical findings in four children with biotinidase deficiency detected through a statewide neonatal screening program. N Engl J Med 1985; 313(1):16-9.
[22] Wiltink, R.C.; Kruijshaar, M.E.; van Minkelen, R.; Onkenhout, W.; Verheijen, F.W.; Kemper, E.A. et al. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations. Eur J Hum Genet 2016; 24(10):1424-9. doi: 10.1038/ejhg.2016.65. [Epub 2016 Jun 22].
[23] Grünewald, S.; Champion, M.P.; Leonard, J.V.; Schaper, J.; Morris, A.A. Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics 2004; 35(4):211-6.
[24] McSweeney, N.; Grunewald, S.; Bhate, S.; Ganesan, V.; Chong, W.K.; Hemingway, C. Two unusual clinical and radiological presentations of biotinidase deficiency. Eur J Paediatr Neurol 2010; 14(6):535-8. doi: 10.1016/j.ejpn.2010.01.001. [Epub 2010 Feb 12].
[25] UK National Screening Committee (NSC). Newborn screening for biotinidase deficiency: External review against programme appraisal criteria for the UK National Screening Committee. 2012. Available online: (Last accessed Jan 2018)
[26] Scottish Government. SIMD16 Technical Notes. Aug 2016. Available online (Last accessed Jan 2018).
[27] National Records of Scotland (NRS). Population Projections for Local Authority Areas. Mid-Year Population Estimates Scotland, Mid-2016. April 2017. Available online: (Last accessed Jan 2018).
[28] Fife Council Research Team. Fife Strategic Assessment 2017. Report number 10. 2017. Available online: (Last accessed Jan 2018).
[29] Tsai, J.T.; Kuo, H.T.; Chou, I.C.; Tsai, M.Y.;Tsai, C.H. A clinical analysis of children with developmental delay. Acta Paediatr Taiwan. 2005; 46(4):192-5.
[30] Hart, A.R.; Sharma, R.; Atherton, M.; Alabed, S.; Simpson, S.; Barfield, S. et al. Aetiological investigations in early developmental impairment: are they worth it? Arch Dis Child. 2017 Jul 22; doi: 10.1136/archdischild-2017-312843. [Epub ahead of print].
[31] Dunhill, Z. Developing a Community Child Health Service for the 21st Century. A Report for the Children and Young People’s Health Support Group. Edinburgh. Scottish Government. January 2013. Available online: (Last accessed Jan 2018)
[32] Zaffanello, M.; Zamboni, G.; Fontana, E.; Zoccante, L.; Tatò, L. A case of partial biotinidase deficiency associated with autism. Child Neuropsychol. 2003; 9(3):184-8.
[33] Spilioti, M.; Evangeliou, A.E.; Tramma, D.; Theodoridou, Z.; Metaxas, S.; Michailidi, E. et al. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front Hum Neurosci 2013;7:858. doi:10.3389/fnhum.2013.00858.
[34] Kiykim, E.; Zeybek, C.A.; Zubarioglu, T.; Cansever, S.; Yalcinkaya, C.; Soyucen, E.; Aydin, A. Inherited metabolic disorders in Turkish patients with autism spectrum disorders. Autism Res 2016; 9(2):217-23. doi: 10.1002/aur.1507. [Epub 2015 Jun 7].
[35] Rapin, I. Autism. N Engl J Med. 1997; 337:97-104.
[36] Cohen, D.; Pichard, N.; Tordjman, S.; Baumann, C.; Burglen, L.; Excoffier, E. et al. Specific genetic disorders and autism: clinical contribution towards their identification. J. Autism Dev Disord 2005; 35:103–116.
[37] Manzi, B.; Loizzo, A.L.; Giana, G.G.; Curatolo, P. Autism and metabolic diseases. J Child Neurol 2008; 23(3), 307-314.
[38] National Institute for Health and Care Excellence (NICE). Autism spectrum disorder in under 19s: recognition, referral and diagnosis (NICE clinical guideline 128). London. 2011. Available online: uk/guidance/CG128 (Last accessed Jan 2018)
[39] Horridge, K.A. Assessment and investigation of the child with disordered development. Arch Dis Child Educ Pract Ed 2011; 96:9–20.
[40] Lund, A.M.; Hougaard, D.M.; Simonsen, H.; Andresen, B.S.; Christensen, M.; Dunø, M. et al. Biochemical screening of 504,049 newborns in Denmark, the Faroe Islands and Greenland--experience and development of a routine program for expanded newborn screening. Mol Genet Metab. 2012; 107(3):281-93. doi: 10.1016/j.ymgme.2012.06.006. [Epub 2012 Jun 21].
[41] Hoffman, T.L.; Simon, E.M.; Ficicioglu, C. Biotinidase deficiency: the importance of adequate follow-up for an inconclusive newborn screening result. Eur J Pediatr 2005; 164(5):298-301. [Epub 2005 Feb 15].
[42] Waisbren, S.E.; Read, C.Y.; Ampola, M.; Brewster, T.G.; Demmer, L.; Greenstein, R. et al; New England Consortium of Metabolic Programs. Newborn screening compared to clinical identification of biochemical genetic disorders. J Inherit Metab Dis. 2002; 25(7):599-600.
[43] Weber, P.; Scholl, S.; Baumgartner, E.R. Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. Dev Med Child Neurol. 2004; 46(7):481-4.
[44] Landau, Y.E.; Waisbren, S.E.; Chan, L.M.; Levy, H.L. Long-term outcome of expanded newborn screening at Boston childrens hospital: benefits and challenges in defining true disease. J Inherit Metab Dis. 2017; 40(2):209-218. doi: 10.1007/s10545-016-0004-4. [Epub 2017 Jan 4].
[45] Wolf, B. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med 2017; 19(4):396-402. doi: 10.1038/gim.2016.135. [Epub 2016 Sep 22].
[46] Wolf, B. Biotinidase deficiency: “If you have to have an inherited metabolic disease, this is the one to have”.Genet Med 2012; 14:565-575.
[47] Collins, J.E.; Nicholson, N.S.; Dalton, N.; Leonard, J.V. Biotinidase deficiency: early neurological presentation. Dev Med Child Neurol 1994; 36(3):268-70. doi: 10.1111/j.1469-8749.1994.tb11840.x
[48] Lara, M.T.; Gurgel-Giannetti, J.; Aguiar, M.J.; Ladeira, R.V.; Carvalho, N.O.; Del Castillo, D.M. et al. High Incidence of Biotinidase Deficiency from a Pilot Newborn Screening Study in Minas Gerais, Brazil. JIMD Rep 2015; 24:103-7. doi: 10.1007/8904_2015_447. [Epub 2015 May 13].
[49] Karaca, M.; Özgül, R.K.; Ünal, Ö.; Yücel-Yılmaz, D.; Kılıç, M.; Hişmi, B. et al. Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening. Eur J Pediatr 2015; 174(8):1077-84. doi: 10.1007/s00431-015-2509-5. [Epub 2015 Mar 11].
[50] Vallejo-Torres, L.; Castilla, I.; Couce, M.L.; Pérez-Cerdá, C.; Martín-Hernández, E.; Pineda, M. et al. Cost-Effectiveness Analysis of a National Newborn Screening Program for Biotinidase Deficiency. Pediatrics 2015; 136(2):e424-32. doi: 10.1542/peds.2014-3399. [Epub 2015 Jul 13].