, Melissa Yssel, MB ChB, FC Path(SA) Chem 139, and Wendy M. Zakowicz, BS 79 Purpose: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. Methods: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25-30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration.

Late-onset multiple carboxylase deficiency is characterized clinically by skin rash, alopecia, seizures and ataxia and occasionally by candidiasis and developmental delay. Biochemically, these individuals exhibit findings consistent with a combined deficiency of the biotin-dependent carboxylases. We have found that the activity of the enzyme biotinidase is also deficient in the sera of five affected children (0 to 3% of mean control activity, 5.80 +/- 0.89 nmol X min-1 X ml-1 serum), and believe that it represents the primary biochemical defect in this disease. Biotinidase catalyzes the removal of biotin from the epsilon-amino group of lysine, through which biotin is covalently bound to the four known human carboxylases, thereby regenerating biotin for reutilization. The deficient activity in our patients was not due to an inhibitor, particularly biotin. It is also not a consequence of feedback control in affected individuals under treatment with pharmacologic doses of biotin. The biotinidase activities of the parents of those children who were available for study were intermediate between deficient and normal values (46% to 65% of mean normal activity). Children lacking biotinidase activity are unable to recycle biotin, and are thus entirely dependent upon exogenous biotin to prevent deficiency. Our findings indicate that the primary biochemical defect in late-onset multiple carboxylase deficiency is in biotinidase activity which is inherited as an autosomal recessive trait.

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Biotinidase deficiency is the primary defect in most individuals with late-onset multiple carboxylase deficiency. We have reviewed the presenting clinical features of 31 children with the disorder. Seizures, either alone or with other neurological or cutaneous findings, are the most frequent initial symptom observed. Other neurological symptoms, such as hypotonia, ataxia, hearing loss, optic atrophy, and developmental delay, are seen, in addition to skin rash and alopecia. The disorder is also characterized by ketolactic acidosis and organic aciduria. Biotinidase activity may be diagnosed using a simple, rapid, semiquantitative colorimetric procedure. Samples of whole blood spotted on the same filter paper used by most states to screen for phenylketonuria and other inborn errors of metabolism may be sent to an appropriate reference laboratory. None of the common anticonvulsants or sedatives used to treat newborns and children interfere with the test. Because biotinidase deficiency can be treated readily with biotin, this disorder should be considered in children with infantile seizures, especially in the presence of other characteristic neurological or cutaneous features.

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