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Scenario
A 3-year-old girl presents 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 decides to order some investigations, including the biotinidase activity level, to identify the possible aetiology of the global developmental delay (GDD).
Structured clinical question
In preschool children with global developmental delay [patients], is the prevalence of biotinidase deficiency [outcome] higher than in the general population?
Search strategy and outcome
Medline (1950–August 2010) was searched using different combinations of MeSH terms including ‘global developmental delay’, ‘severe learning disabilities’, ‘moderate learning disabilities’, ‘developmental disability’, ‘developmental delay disorder’ and ‘mental retardation’ in various combinations with the keywords ‘biotin’, ‘biotinidase activity’ or ‘biotinidase deficiency’. The search was carried out on 29 August 2010 and yielded 41 articles. A search of Embase (1996–August 2010) using similar keyword combinations yielded 42 relevant articles. The search of a secondary database in the Cochrane Library produced no results. After review of all abstracts, three relevant studies were selected (table 2).
Commentary
Biotinidase deficiency (BTD) is an autosomal recessive inherited disorder that manifests during childhood with various cutaneous and neurological symptoms including dermatitis, hair loss, seizures, hypotonia, developmental delay, ataxia, mental retardation, hearing and visual loss, lactic acidosis, organic aciduria and fetal malformations. BTD is also known to present as cerebral palsy1 and other developmental disorders such as autism.2
Learning disability (LD)/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 BTD. Patients with residual biotinidase activity >1% may remain asymptomatic even without treatment.3 Profound BTD is characterised by less than 10% of normal serum biotinidase activity, while patients with partial deficiency have 10–30% of normal biotinidase activity.4
BTD is easily treated with biotin supplementation with reversal of most symptoms if commenced early.5 Treatment typically consists of lifelong daily doses of biotin 5–20 mg to compensate for decreased bioavailability from food sources and increased urinary losses.4
Screening children with LD/GDD for BTD has yielded mixed results. A study of 274 children over a 4-year period in the USA identified no cases of BTD.6 Another smaller study involving 55 patients in Cuba was also negative.7 However, a study of 158 children with clinical presentation of LD from cerebral heteroplasia yielded a high incidence of BTD of 0.01%, which is at least 3–6 times higher than in the general population.8 The highest estimated incidence of BTD in the general population is 1:35 000.3 Even if the incidence of BTD is assumed to be 10 times higher in patients with LD/GDD, a minimum of 3500 patients would need to be screened to identify one case. Hence, larger, multicentre, multinational studies would be required to clarify the true incidence of BTD deficiency in preschool children with LD/GDD.
Given the low yield of about 1%, conflicting recommendations have been given regarding the role of routine metabolic screening for inborn errors of metabolism, including BTD, in the evaluation of children with GDD or LD. Some authors have promoted universal newborn screening of biotinidase activity rather than clinical-based screening.9 Preselection of cases using a stepwise or checklist approach (assessing the presence of dysmorphology, hepato-splenomegaly, and ophthalmological and neurological findings, etc), which could increase the yield to 13.6%, has also been advocated.10
Some evidence-based clinical guidelines have recommended that biotinidase activity should be measured early in the investigation pathway for GDD.11
Although the number of children with possible LD/GDD who need to be tested in order to diagnose one case of BTD may seem high, this investigation would seem to be cost-effective, considering the potentially very serious life-time disabilities that may result if BTD is not identified.
Clinical bottom line
▶ The prevalence of biotinidase deficiency in children with global developmental delay (GDD) is higher than in the general population. (Grade C)
▶ A minimum of 3500 patients with GDD would need to be tested to identify one case of biotinidase deficiency. (Grade C)
References
Footnotes
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Competing interests None.
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Provenance and peer review Commissioned; internally peer reviewed.