Biotinidase deficiency: Novel mutations and their biochemical and clinical correlates

Abstract

Biotinidase deficiency is a defect in the recycling of the vitamin biotin. Biotin supplementation can markedly improve the neurological and cutaneous symptoms of affected children and prevent symptoms in children identified by newborn screening or treated since birth. We have determined thirteen novel mutations in children with the disorder. Two nonsense mutations, eight single missense mutations, three allelic double missense mutations, and two are polymorphisms were identified in the biotinidase gene (BTD). One of the missense mutations, c.734G>A (p. C245Y), is the first to be reported that alters the cysteine in the putative location crucial for ester formation and binding of the biotinyl-moiety in the active site of the enzyme. These mutations add to the growing list of mutations that are helping to delineate structure/function relationships of the enzyme.

High Incidence of Biotinidase Deficiency from a Pilot Newborn Screening Study in Minas Gerais, Brazil

“…Thus, the incidence found in the current study was higher than that observed worldwide and in many countries. Nevertheless, pilot newborn screening Wolf et al (2005) studies in isolated regions or selected groups have disclosed higher incidences (1:4,500 to 1:14,000) than that reported in the present research (Thodi et al 2013;Dunkel et al 1989;Lawler et al 1992;Sarafoglou et al 2009). In Brazil, the available prevalence rates are divergent.…”

Differenzialdiagnose des atopischen Ekzems in der Kindheit

“…Bis 2001 wurden über 61 Mutationen in 3 von 4 Exons des Biotinidasegens beschrieben [18]. Bis heute sind noch viele weitere neue Mutationen hinzugekommen [43]. Biotin ist ein wichtiges Koenzym, das in der Glukoneogenese, im Stoffwechsel von verzweigtkettigen Aminosäuren und bei der Fettsäuresynthese eine wichtige Rolle einnimmt.…”

Impaired Biotinidase Activity Disrupts Holocarboxylase Synthetase Expression in Late Onset Multiple Carboxylase Deficiency

“…Although biotinidase mRNA and protein are expressed throughout the brain, they are most abundant in centers of the auditory and visual activity, including dorsal and ventral cochlear nuclei, superior olivary complex, and vestibular nucleus (34). Because these areas also seem to contain more biotin than other regions of the brain, it is possible that regulation of the biotin cycle may be of particular relevance for these cells (26,35). We suggest that biotinidase deficiency in combination with limited amounts of biotin may lead to the development of a secondary HCS deficiency that may compromise the survival of cells with a higher metabolic demand such as neurons.…”

“…Biotinidase exons were amplified from genomic DNA as previously described (26,27) and subcloned also in pGEM. Both cDNA and exons were sequenced at Laragen (Los Angeles, CA).…”

“…2A). These mutations have been previously reported (26) and are considered a common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States (28). Because these mutations were originally described as a double mutation allele (28), we sequenced all four biotinidase exons from genomic DNA to search for another mutation.…”