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Role of biotinidase activity testing in the investigation of children with global developmental delay (Prevalence, role of newborn screening and efficacy of early treatment in biotinidase deficiency)

Three Part Question

In a [pre-school children with global developmental delay] (patient) is [the test of biotinidase activity level] (intervention) in such children [cost-effective based on the prevalence and treatment of biotinidase deficiency] (outcome)?

Clinical Scenario

A 2.5 year old boy has presented in clinic with mild to moderate general delay in all areas. There is no other relevant history, no family history and clinical examination is normal. The paediatric registrar decided to order some investigations for identifying the possible aetiology of the global developmental delay including the biotinidase activity level. His consultant asked him to justify the test for biotinidase deficiency based on the prevalence of biotinidase deficiency in the population of pre-school children with developmental delay and the possible efficacy of treatment.

Search Strategy

Primary search sources:
EMBASE- 1996- Aug 2010.
Medline 1950- Aug 2010.
Secondary search sources:
The Cochrane library and Online Mendelian Inheritance in Man [OMIM]

In Medline different combinations of Mesh terms including ‘global developmental delay’, ‘severe learning disabilities’, ‘moderate learning disabilities’, ‘developmental disability’, ‘developmental delay disorder’ ‘mental retardation‘ were used in various combinations with keywords ‘biotin’, ‘biotinidase activity’ or ‘biotinidase deficiency’ (Table 1).
In EMBASE similar keywords combinations were searched. The search was carried out on 29th Aug 2010.

Search Outcome

The search yielded 42 relevant articles. The search of a secondary database in the Cochrane library showed no results. After reviewing all the abstracts 9 relevant studies were reviewed (Table 2).

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Sutherland SJ, Olsen RD, Michels V, Schmidt MA, O'Brien JF.
Children with low IQ, seizures, hearing loss, ataxia or motor disorder attending a large outpatient clinic over a four-year period.Incidence of biotinidase deficiencyNone of 274 children had biotinidase deficiencyThere is a low frequency of consanguineous marriages in this population and the sample size is too small to detect even a 10-fold increase in frequency of biotinidase deficiency.
7. Marrero-Gonzalez N., Portuondo-Sao M., Lardoeyt-Ferrer R., Tasse-Vila D., Lantigua-Cruz A.
September 2002
A cohort of 55 patients with Mental Retardaton of unspecific origin born within the period 1977-1997Incidence of biotinidase deficiencyNoneSample size is too small to detect even a 10-fold increase in frequency of biotinidase deficiency in this cohort compared to general population.
24. Zhang JM, Gu XF, Shao XH, Song XQ, Han LS, Ye J, Qiu WJ, Gao XL, Wang Y, Wang MX.
A cohort of 158 children with cerebral developmental retardationPrevalence of biotinidase deficiency in patients with brain heteroplasia had inborn metabolic errors.11/158 (7%) Prevalence of biotinidase deficiency was high in this group of children (1/158). Prevalence of consanguineous marriages in the population was not stated.
Marrero-Gonzalez N., Frometa-Suarez A., Gonzalez-Reyes E. et al.
neonatal screening of 1038 newbornsNewborn screening for congenital hypothyroidism, phenylketonuria, galatosemia and biotinidase deficiency.None of 1038 neonatesSample size was too small to detect any case of biotinidase deficiency in general population (estimated 1:60000).
Tanzer F, Sancaktar M, Buyukkayhan D.
34,378 neonates born in four cities in central Anatolia Neonatal screening for biotidinidase deficiency (BD)The estimated incidence of BD was 1:34,378This is an area where consanguineous marriages are very common (26%) and a high rate of inborn errors of metabolism is expected.
Möslinger D, Stöckler-Ipsiroglu S, Scheibenreiter S, Tiefenthaler M, Mühl A, Seidl R, Strobl W,
Newborn screening and family studies of index patients with biotinidase deficiency (BD)Incidence of profound BD was 1:59,800 and incidence of partial BD was 1:89,700)Many patients with Partial BD were asymptomatic and could have been missed by clinical screening.
Overall incidence of BD estimated to be approximately 1:35 000


Biotinidase deficiency is an autosomal recessively inherited disorder that manifests during childhood with various cutaneous and neurological symptoms particularly seizures, hypotonia, developmental delay, ataxia, dermatitis, hair loss, mental retardation, lactic acidosis, hearing and visual loss, organic aciduria and foetal malformations. BTD is also known to present as cerebral palsy (Livne 1994), and other developmental disorders such as autism (Manzi et al, 2008). Patients with residual BTD activities >1% may remain asymptomatic even without treatment (Möslinger et al, 2001). Biotin is a water-soluble vitamin that is used as a co-factor by enzymes involved in carboxylation reactions. It functions as the carboxyl carrier for five biotin-dependent carboxylases in mammals. These enzymes catalyze gluconeogenesis, fatty acid metabolism and amino acid catabolism, thus biotin plays an essential role in maintaining metabolic homeostasis. Biotin is also covalently attached to histones; biotinylated histones are enriched in repeat regions in the human genome and appear to play a role in transcriptional repression of genes and genome stability. Dietary biotin exists in free and protein-bound forms (Said et al, 1993). Gastrointestinal proteases and peptidases digest biotin-containing proteins to release biocytin (biotinyl-ε-lysine) and biotin-containing peptides (Wolf et al, 1985). Biotinidase (BTD) is secreted in pancreatic fluids and plays a critical role in releasing free biotin from dietary biotin (biocytin and biotinylated peptides) prior to absorption. Intestinal BTD may also be derived from the intestinal flora, intestinal secretions and brush-border membranes (Zempleni et al, 2008) More than 110 BTD mutations have been reported that decrease BTD activity (OMIM accession #609019), leading to multiple carboxylase deficiency. It has been speculated that the early-onset forms of BTD deficiency (multiple carboxylase deficiency) might be caused by mutations in the BTD gene, whereas the late-onset forms might be caused by decreased secretion of BTD into the intestinal lumen (Thoene & Wolf, 1983). Profound BTD deficiency is characterized by less than 10% of normal serum BTD activity, whereas patients with partial deficiency possess 10–30% of normal BTD activity (Wolf, 1991). Learning disability (LD) /global developmental delay (GDD) is a common problem affecting 1-3% of the population. Moderate mental retardation is a recognised manifestation of cerebral dysfunction in patients with profound biotinidase deficiency (Möslinger et al, 2001). Screening children with LD /GDD for BTD deficiency has yielded mixed results. A study of 274 children over a four-year period in the USA identified no index case (Sutherland et al, 1991). Another smaller study involving 55 patients in Cuba was also negative (Marrero-Gonzalez et al, 2003). However a study of 158 children with clinical presentation of LD from cerebral heteroplasia yielded a high incidence of 0.01% for BTD deficiency, which is at least 3 to 6 times higher than the general population (Zhang et al, 2007). The highest estimated incidence of BTD deficiency in the general population is 1:35000 (Möslinger et al, 2001). Even if the incidence of BTD deficiency is assumed to be ten times higher in the patients with LD /GDD, a minimum of 3500 patients would need to be screened to identify one index case. Hence larger, multicentre, multinational studies would be needed to clarify the true estimate of the incidence of BTD deficiency in pre-school children with LD /GDD. Given the low yield of about 1%, conflicting recommendations have been given for the role of routine metabolic screening for inborn errors of metabolism, including BTD-deficiency, in the evaluation of children with GDD or LD. Some authors have emphasised the need for universal newborn screening of BTD activity, rather than clinical-based screening (Shevell et al, 2003). A pre-selection of cases using a stepwise or checklist approach (including the presence of dysmorphologic symptoms, hepato-splenomegaly, and ophthalmologic and neurologic findings etc), which could increase the yield to 13.6% have also been advocated (vanKarnebeek et al, 2005). In the absence of any historical or physical examination findings, a stepwise sequential investigation of children with global developmental delay should take into account the diagnostic yield and potential treatability of the conditions (Shevell et al, 2003). Some evidence-based clinical guidelines have recommended that biotinidase should be measured early in the investigation pathway for global developmental delay (McDonald et al, 2006). BTD deficiency is one of the inborn metabolic diseases amenable to neonatal or simple postnatal screening. Newborn screening is cost effective because delay in diagnosis results in irreversible morbidity, and early therapy prevents the neurologic sequelae. BTD-deficiency is easily treated with biotin supplementation with reversal of most symptoms if commenced early (Grunewald et al, 2004). Treatment typically consist of lifelong daily doses of biotin 5–20 mg to compensate for decreased bioavailability from food sources and increased urinary losses (Wolf, 1991). There are reported symptomatic cases of biotinidase deficiency diagnosed after neonatal period which did not respond to biotin treatment such as autism (Zaffanello et al, 2003), residual hearing impairments, optic atrophy or both and developmental delay (Weber et al, 2004, Hoffman et al, 2005), persistent spastic paraparesis (Chedrawi et al, 2008). Early treatment within the first week after newborn screening usually lead to normal neuropsychological outcome (Möslinger et al, 2001). Delayed diagnosis also leads to increased parental stress and greater burden on healthcare services (Waisbren et al, 2002). Although the number of children to investigate for possible Learning disability/ global developmental delay in order to diagnose one case of BTD-deficiency may seem high, this investigation seems to be cost-effective, considering the life-time potentially very serious disabilities that may result and the treatment (oral biotin) is cheap, safe, simple and effective in preventing or reversing severe long-term sequelae (especially if commenced early).

Clinical Bottom Line

1. Biotinidase deficiency is easily amenable to neonatal or simple postnatal screening (strength of recommendation C) 2. Biotinidase should be measured early in the investigation pathway for children with global developmental delay (strength of recommendation C) 3. Biotinidase deficiency is easily treated with biotin supplementation with reversal of most symptoms if commenced early (strength of recommendation C)


  1. Sutherland et al Screening for biotinidase deficiency in children with unexplained neurologic or developmental abnormalities. Clin Pediatr (Phila) 1991;30(2):81-4.
  2. Marrero-Gonzalez et al Screening for congenital hypothyroidism, phenylketonuria, galactosemia and biotinidase deficiency in a sample of mentally retarded patients in the City of Havana [Article in Spanish] Revista de Neurologia 2003, 36(10):913-916
  3. Zhang et al Values of tandem mass spectrometry in etiologic diagnosis of cerebral developmental retardation. [Article in Chinese] Zhonghua Er Ke Za Zhi 2007;45(12):932-6
  4. Marrero-Gonzalez et al Neonatal pilot screening for congenital hypothyroidism, phenylketonuria, galatosemia and biotinidase deficiency [Article in Spanish] Revista Espanola de Pediatria 2002, 58(347):356-362
  5. Tanzer eat al Neonatal screening for biotidinidase deficiency: results of a 1-year pilot study in four cities in central Anatolia. J Pediatr Endocrinol Metab 2009;22(12):1113-6
  6. Möslinger 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;160(5):277-82