Biotinidase (BTD) is the only enzyme that can cleave biocytin, a product of the proteolytic digestion of holocarboxylases. Profound BTD deficiency (less than 10% mean normal activity in serum) is an autosomal recessive disor
der that can result in neurological and cutaneous abnormalities. Both the cDNA and the genomic DNA of normal BTD gene have been isolated and characterized. The BTD gene is localized to chromosome 3p25. Thus far 61 mutations in three of the four exons of the BTD and one mutation in an intron gene that cause profound BTD deficiency have been reported. Mutations occur at different frequencies in symptomatic children than they do in children ascertained by newborn screening. Two mutations, 98-104del7ins3 and R538C, were present in 52% or 31 of 60 alleles found in symptomatic patients. Three other mutations, A755G, Q456H, and 511 G>A; 1330G>C (double mutation), accounted for 52% of the alleles detected by newborn screening in the United States. Two asymptomatic adults, parents of children with profound BTD deficiency detected by newborn screening, have been described. Additional different mutations have been found in Turkish, Saudi Arabian, and Japanese children with profound BTD deficiency. Partial BTD deficiency (10-30% of mean normal serum activity) is predominantly caused by the single 1330G>C mutation that results in D444H on one allele in combination with one of the mutations causing profound deficiency on the other allele. Four intragenic polymorphisms, three neutral and one amino acid change, have also been found. Although a preponderance of mutations causing the production of truncated BTD protein occurs in symptomatic children with profound deficiency, preliminary studies fail to demonstrate clear genotype-phenotype correlations.
Biotinidase deficiency is an autosomal recessive inborn error of biotin metabolism. Children with biotinidase deficiency cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the bioti
n-dependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms. Biotinidase deficiency is characterized by neurological, cutaneous manifestations and metabolic abnormalities. The worldwide incidence of profound biotinidase deficiency has been estimated at 1:112,271. The human biotinidase gene is located on chromosome 3p25 and consists of four exons with a total length of 1629 base pairs. To date, more than 100 mutations in the biotinidase gene known to cause biotinidase deficiency have been reported. The vast majority of mutations are homozygous or compound heterozygous. Finding known mutations can be correlated with the biochemical enzymatic results. This report summarizes the demographic features of patients identified as biotinidase deficient from August of 2012 through August of 2013 and mutation analysis results for 20 cases in the southeast region of Turkey.
Milankovics I, etal., J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S289-92. doi: 10.1007/s10545-010-9152-0. Epub 2010 Jun 15.
Biotinidase deficiency, an autosomal recessively inherited disorder, is characterized by neurologic and cutaneous symptoms and can be detected by newborn screening. In Hungary the national screening programme was launched in 1989 with two screening centres. Over 1,070,000 neonates from western Hung
ary were screened for biotinidase deficiency in the Budapest Screening Centre between 1989 and December 2008. In this period, 57 patients with profound or partial biotinidase deficiency from 50 families were identified through routine newborn screening. The incidence of the disorder in western Hungary is 1 in 18,700, which is about three times the worldwide incidence. Twenty-four different mutations were identified in patients including the c.406delC novel mutation in exon 3, which is a frameshift mutation. To better understand the background of the unusually high disease incidence, 100 healthy subjects from the Hungarian population were screened by PCR and RFLP for the frequencies of p.D444H, p.Q456H and p.A171T;p.D444H, the three most common BTD mutations. The frequencies were found to be 5.5, 0.5 and 0%, respectively. The results demonstrate that the frequencies of two of the most common biotinidase variant alleles are higher in the Hungarian population than in other Caucasian populations. This and the presence of a unique Hungarian mutation may explain the high incidence of biotinidase deficiency in Hungary.
