The importance of developing novel diagnostic tools for congenital metabolic disorders

Abstract

Babies are not little adults. This frequently repeated statement implies that to develop accurate diagnostic methods to identify potentially catastrophic disorders, it is not sufficient to just wait until permanent changes have occurred and are clearly recognized by physicians in clinical practice. This is the position of many organizations that advocate on behalf of children [1]. Moreover, in the United States, the Food and Drug Administration grants approvals for diagnostic tools based on the populations in which they were studied. One of such examples is biotinidase deficiency. This autosomal recessive disorder has an estimated prevalence of 1 in 60,000 cases [2,3]. Most affected infants become symptomatic in the first months of life and are characterized by abnormal respiratory drive, hypotonia, failure to thrive, seborrheic dermatitis like-rash, progressive developmental delay, and myoclonic seizures. If untreated, this leads to a static-encephalopathy picture and significant motor and metal handicaps with subsequent significant morbidity and mortality and the increased costs for health care support [4]. The pathogenesis of this disease is secondary to a profound deficiency (less than 10% of enzyme activity) of biotinidase. This enzyme has ubiquitous distribution and is essential for the recycling of biotin by releasing it from any of the four holo-carboxylases: pyruvate, acetyl-CoA, propionyl-CoA, and 3-methylcrotonyl [5]. Treatment with biotin leads to a significant response and resolution of symptoms. Therefore, early diagnosis and identification of asymptomatic subjects is of the utmost importance in order to establish rapid treatment and prevent the neurological consequences of this disorder. Most laboratories typically rely on a semi-quantitative analysis for screening of this disorder in the newborn period by testing colorimetric changes of biotinidase enzyme activity in dried blood samples (DBS). However, this approach opens the possibility of impaired quality of enzyme activity in the sample, with the caveat that the mutant DNA remains relatively intact [6]. Consequently, there is a growing interest on developing more precise or adjunctive methodologies for more accurate and rapid diagnosis of this and other potentially treatable disorders. Therefore, the Lindau-Shepard et al. [7] study is a welcome addition to our understanding of diagnostic methods in the newborn period using molecular genotyping and illustrates the advantages of developing supplemental screening tools. Historically, the use of real time *Corresponding author: Edgard Andrade, University of Florida, Department of Pediatrics, Division of Neurology, PO Box 100296, Gainesville, FL 32610, USA. Tel.: +1 352 273 5778; Fax: +1 352 392 9802; E-mail: andrade@peds.ufl.edu. Journal of Pediatric Genetics 1 (2012) 149–151 DOI 10.3233/PGE-2012-024 IOS Press 149