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Three Part Question

In [preschool children with global developmental delay], is [the prevalence of biotinidase deficiency] [higher than in the general population]?

Clinical 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).

Search Strategy

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.

Search Outcome

After review of all abstracts, three relevant studies were selected

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Sutherland et al, 1991	274 Children with low IQ, seizures, hearing loss, ataxia or motor disorder in a large outpatient clinic over a 4-year period	Prospective cohort (level 4)	Prevalence of BTD	None (95% CI 0 to 3.6) of the patients had BTD	Sample size is too small to detect BTD in the general population (95% CI 0 to 6/60 089)
Marrero- Gonzalez et al, 2003	55 patients with MR of unspecific origin born within the period 1977–1997	Prospective cohort (level 4)	Prevalence of BTD	None (95% CI 0 to 3.6) of the patients had evidence of BTD	Sample size is too small to detect BTD in general population (95% CI 0 to 6/60 089)
Zhang et al, 2007	155 children with developmental delay from various brain disorders	Prospective cohort (level 4)	Prevalence of BTD and inborn metabolic errors	11/158 (7%) had inborn metabolic errors, 1/158 had BTD	Prevalence of BTD in children with MR from brain disorders is higher than in the general population

Comment(s)

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 palsy (Livne) and other developmental disorders such as autism (Manzi).

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 (Möslinger). 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 (Wolfe).

BTD is easily treated with biotin supplementation with reversal of most symptoms if commenced early (Grünewald). Treatment typically consists of lifelong daily doses of biotin 5–20 mg to compensate for decreased bioavailability from food sources and increased urinary losses (Wolfe).

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(Sutherland). Another smaller study involving 55 patients in Cuba was also negative (Marrero-González).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 (Zhang). The highest estimated incidence of BTD in the general population is 1:35 000 (Möslinger). 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 (Shevell). 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(van Karnebeek).

Some evidence-based clinical guidelines have recommended that biotinidase activity should be measured early in the investigation pathway for GDD(McDonald).

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.

Editor Comment

BTD, biotinidase deficiency; MR, mental retardation.

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

1. Livne M, Gibson KM, Amir N, et al . Holocarboxylase synthetase deficiency: a treatable metabolic disorder masquerading as cerebral palsy. J Child Neurol 1994;9:170–2.
2. Manzi B, Loizzo AL, Giana G, et al . Autism and metabolic diseases. J Child Neurol 2008;23:307–14.
3. Möslinger D, Stöckler-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;160:277–82.
4. Wolf B . Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis 1991;14:923–7.
5. Grünewald S, Champion MP, Leonard JV, et al . Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics 2004;35:211–16.
6. Sutherland SJ, Olsen RD, Michels V, et al . Screening for biotinidase deficiency in children with unexplained neurologic or developmental abnormalities. Clin Pediatr (Phila) 1991;30:81–4.
7. Marrero-González N, Portuondo-Sao M, Lardoeyt-Ferrer R, et al . [Screening for congenital hypothyroidism, phenylketonuria, galactosemia and biotinidase deficiency in a sample of mentally retarded patients in the city of Havana]. Rev Neurol 2003;36:913–16.
8. Zhang JM, Gu XF, Shao XH, et al . [Values of tandem mass spectrometry in etiologic diagnosis of cerebral developmental retardation]. Zhonghua Er Ke Za Zhi 2007;45:932–6
9. Shevell M, Ashwal S, Donley 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 ..... Neurology 2003;60:367–80.
10. van Karnebeek CD, Jansweijer MC, Leenders AG, et al . Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005;13:6–25.
11. McDonald L, Rennie A, Tolmie J, et al . Investigation of global developmental delay. Arch Dis Child 2006;91:701–5.