Abstract
This child likely has biotin holocarboxylase synthetase deficiency rather than biotinidase deficiency
I would like to address the diagnosis of the child reported in the recently published paper entitled “Biotinidase deficiency in a newborn” by Dr. Moussaouri and colleagues [1]. As the authors state, biotinidase deficiency presenting in the first week of life is not only uncommon, but essentially doesn’t occur. In fact, this is precisely the reason that the case is being reported. The child had various cutaneous findings and seizures, which can be clinical features of biotinidase deficiency. In addition, the child exhibited acetonuria, mild lactic acidosis and mild hyperammonemia, all of which can be seen in biotinidase deficiency.
However, there is usually a window of time where neonates receive their biotin from their mothers before they must depend on their own biotinidase activity to recycle their biotin [2, 3]. Therefore, it is unlikely that a newborn with biotinidase deficiency will exhibit symptoms in the first week of life unless they have sepsis which brings on the symptoms sooner. However, as the authors suggest, the child was not febrile and apparently did not have a concomitant infection. It is not clear from the description of the child if he had the cutaneous findings at birth or developed them during the first week of life. Given this child’s findings, the authors correctly considered that the infant could have biotinidase deficiency. However, they did not report that they considered that the child could also have another similar disorder, such as biotin holocarboxylase synthetase deficiency [4]. Granted, it is easier to test for biotinidase deficiency than holocarboxylase synthetase deficiency, but finding the adequate degree of biotinidase activity in this child should have prompted the authors to consider looking for another diagnosis. Untreated neonates with biotin holocarboxylase deficiency can present with such cutaneous findings and seizures at birth [4]. In fact, the disorder was originally called neonatal or infantile multiple carboxylase deficiency because of the time when symptoms usually presented.
This child’s biotinidase activity is in the range of partial biotinidase deficiency (10– 30% of mean normal serum activity) or about 28 % of the mean activity (if one uses the mean of the reported normal range or 177 nkat/l) and not consistent with that of profound biotinidase deficiency with less than 10% mean normal biotinidase activity [4]. In fact, it is not unusual for a newborn to have lower than normal adult activity at birth or shortly after birth [5]. Although preterm infants frequently have sufficiently low biotinidase activity resulting in a false positive on newborn screening [5], term infants can have activities of between 25– 50 % of adult normal activity at birth. Within weeks to months, their activities reach adult activities. This child had at least partial biotinidase deficiency, but could have been a carrier for profound biotinidase deficiency or even ultimately had normal biotinidase activity. Nevertheless, based on the activity reported, the child had adequate biotinidase activity to prevent the development of symptoms. In addition, the biotin provided by the mother (unless she was depleted in dietary biotin, which seems unlikely) would have been adequate to prevent symptoms after birth or shortly after birth.
Untreated children with partial biotinidase deficiency usually exhibit only mild clinical problems during their life [6]. In fact, it is still controversial whether children with partial biotinidase deficiency should even be treated [7]. I personally believe they should.
Unfortunately, we do not have confirmation that this child had biotinidase deficiency. We only have the single enzyme activity that is in the partially deficient range. Unfortunately, there were no urinary organic acid analysis, repeat of serum enzymatic activity, serum biotinidase activities of the parents, molecular analysis of the BTD gene or demonstration of a positive response to biotin therapy performed which would have helped to confirm or exclude the diagnosis. A definitive diagnosis can be made by performing molecular analysis of the genes for biotinidase and holocarboxylase synthetase in the parents.
As I have said previously, infants with profound biotinidase deficiency, with little or no biotinidase activity, aggravated by an intervening infection or sepsis, can exhibit symptoms in the neonatal period, but not an infant with apparently adequate biotinidase activity, as in this child. Therefore, given the entire clinical and biochemical scenario of this child, I think it is far more likely that the infant had a recessively inherited, metabolic disorder which can present in the newborn period with the reported symptoms. I think that this child more likely had biotin holocarboxylase synthetase deficiency [4], than biotinidase deficiency, based on the single, non-profoundly deficient biotinidase activity.