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Biotinidase deficiency is an autosomal recessive disorder of biotin metabolism that can lead to varying degrees of neurologic and cutaneous symptoms when untreated. Because this disorder meets the criteria for newborn screening, many states and countries perform this testing. Because newborn screening should result in complete ascertainment of mutations causing profound biotinidase deficiency (less than 10% of mean normal serum activity), we compared the mutations in a group of 59 children with profound biotinidase deficiency who were identified by newborn screening in the United States with 33 children ascertained by exhibiting symptoms. Of the 40 total mutations identified among the two populations, four mutations comprise 59% of the disease alleles studied. Two of these mutations occur in both populations, but in the symptomatic group at a significantly greater frequency. The other two common mutations occur only in the newborn screening group. Because two common mutations do not occur in the symptomatic population, it is possible that individuals with these mutations either develop mild or no symptoms if left untreated. However, inasmuch as biotin treatment is inexpensive and innocuous, it is still recommended that all children with profound biotinidase deficiency be treated.

Biotinidase deficiency is inherited as an autosomal recessive trait that, unless treated with pharmacologic doses of biotin, can result in neurologic and cutaneous symptoms. We have identified two new mutations in exon D of the biotinidase gene of children with profound biotinidase deficiency ascertained by newborn screening. Transition 511G -> A near the 5' end of exon D results in a substitution of threonine for alanine171 (A171T) and transversion 1330G -> C occurs close to the 3' end of exon D causing a substitution of histidine for aspartic acid444 (D444H). The D444H mutation was detected in four individuals from our normal population whose mean serum biotinidase activity is 5.25 nmol/min/ml, which is significantly lower than the mean normal activity (7.1 nmol/min/ml). We calculated that this mutation causes a 52% loss of activity in the aberrant enzyme. Twenty-three individuals with the D444H mutation were found by allele specific oligonucleotide analysis of DNA from 296 randomly-selected, anonymous dried-blood spots. We estimate the frequency of this allele in the general population to be 0.039. In contrast, no individuals in 376 have the A171T mutation. Fourteen children (eleven probands and three siblings) out of 31 enzyme-deficient children have both the A171T and D444H mutations. Both mutations are inherited from a single parent as a double mutation allele. The eleven families in which this allele was identified are of mostly European ancestry, although the mutation cannot be attributed to a specific nationality or ethnic group. The serum of a child who is homozygous for the double mutation allele has very little CRM and the aberrant enzyme has very low biotinyl-hydrolase activity and no biotinyl-transferase activity. This double mutation allele (A171T and D444H) is a common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States.

Biotinidase deficiency is an autosomal-recessive disorder of biotin recycling. Children with profound biotinidase deficiency usually have neurological and cutaneous symptoms in early childhood, but they may not develop symptoms until adolescence. We now report on a man and a woman with profound biotinidase deficiency who are asymptomatic and who were diagnosed only because their biotinidase-deficient children were identified by newborn screening. These adults have never exhibited symptoms of the disorder and are homozygous for two different mutations resulting in different aberrant enzymes. There is no evidence of an increased dietary intake of biotin to explain why they have remained asymptomatic. Although these adults may still be at risk for developing symptoms, they could represent a small group of individuals with profound biotinidase deficiency who will never develop clinical problems. Their lack of symptoms suggests that there are probably epigenetic factors that protect some enzyme-deficient individuals from developing symptoms. These individuals broaden the spectrum of expression of biotinidase deficiency.

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