SEARCH · PubMed Health

Results for “Biotinidase Deficiency”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2003

Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency.

Biotinidase deficiency is an autosomal recessive disorder of biotin metabolism caused by defects in the biotinidase gene. Symptoms of biotinidase deficiency are resolved or prevented with oral biotin supplementation and as such newborn screening is performed to prospectively identify affected individuals prior to the onset of symptoms. Biotinidase deficiency is detected by determining the activity of the biotinidase enzyme utilizing the newborn dried blood spot and colorimetric end point analysis. While newborn screening by enzyme analysis is effective, external factors may compromise results of the enzyme analysis and difficulty is encountered in distinguishing between complete and partial enzyme deficiencies. In the United States, the four mutations most commonly associated with complete biotinidase deficiency are c98:d7i3, Q456H, R538C, and the double mutation D444H:A171T. Partial biotinidase deficiency is almost universally attributed to the D444H mutation. To more effectively distinguish between profound and partial biotinidase deficiency, a panel of assays utilizing real time PCR and melting curve analysis using Light Cycler technology was developed. Employing DNA extracted from the original dried blood specimens from newborns identified through prospective newborn screening as presumptive positive for biotinidase deficiency, the specimens were analyzed for the presence of the five common mutations. Using this approach it was possible to separate newborns with partial and complete deficiency from each other as well as from many of those with false positive results. In most cases it was also possible to correlate the genotype with the degree of residual enzyme activity present. In newborn screening for biotinidase deficiency, we have shown that the analysis of common mutations is useful in distinguishing between partial and complete enzyme deficiency as well as improving specificity. Combining biotinidase enzyme analysis with genotypic data also increases the sensitivity of screening for biotinidase deficiency and provides information useful to clinicians earlier than would otherwise be possible.

Amidohydrolases↗

PubMed1995

Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency.

Biotinidase deficiency is an autosomal recessive inherited disorder that is characterized by neurological and cutaneous symptoms. Biotinidase-deficient children cannot recycle endogenous biotin, an essential water-soluble B vitamin. Biotin is covalently attached to epsilon-amino groups of lysyl residues of four carboxylases. These carboxylases are subsequently degraded to biocytin (biotin-epsilon-lysine). Biotinidase cleaves biocytin to biotin and lysine, thereby completing the biotin cycle. The symptoms of biotinidase deficiency can be resolved or prevented by treatment with biotin. Therefore, it is important that biotinidase deficiency is diagnosed early so that permanent neurological damage can be prevented. Many states and countries currently perform newborn screening for biotinidase deficiency. We have recently isolated and characterized the cDNA for normal human biotinidase and localized the gene to chromosome 3p25 (ref. 9). We have now identified the first mutation that causes profound biotinidase deficiency. It occurs in a distinct region of the gene that encodes the putative signal peptide. Fifty percent of symptomatic children studied have a 7-bp deletion coupled with a 3-bp insertion in at least one of their alleles of the biotinidase gene. This mutation appears to be a common cause of biotinidase deficiency in symptomatic children.

Alleles↗

PubMed1983

Phenotypic variation in biotinidase deficiency.

Biotinidase deficiency is the usual biochemical defect in biotin-responsive late-onset multiple carboxylase deficiency. We reviewed the clinical features of six patients with the enzyme deficiency and compared them with features described in the literature in children with late-onset MCD. In all of the reported probands, MCD was diagnosed because they had metabolic ketoacidosis and organic aciduria in addition to various neurologic and cutaneous symptoms, such as seizures, ataxia, skin rash, and alopecia. Although in several of our patients biotinidase deficiency was also diagnosed because they manifested a similar spectrum of findings, others never had ketoacidosis or organic aciduria. Thus the initial features of biotinidase deficiency usually include neurologic or cutaneous symptoms, whereas organic aciduria and MCD are delayed, secondary manifestations of the disease. These findings suggest that biotinidase deficiency should be considered in any infant or child with any of these neurologic or cutaneous findings, with or without ketoacidosis or organic aciduria. If the diagnosis cannot be excluded, such individuals should be given a therapeutic trial of pharmacologic doses of biotin.

Amidohydrolases↗

PubMed1986

[Results of a pilot study of neonatal screening for congenital biotinidase deficiency].

Biotinidase activity was determined in a pilot study of 78,000 dried blood samples on filter paper. In the assay the liberation of p-aminobenzoic-acid from biotinyl-p-aminobenzoic-acid by biotinidase is tested. One boy was identified to be with biotinidase deficiency. Transient reduction of biotinidase activity to virtually negative test results was observed in 8 preterm babies (recall: 0,01%). Specificity and sensitivity of the test were nearly 100%. We suggest that screening for biotinidase deficiency should be incorporated into existing neonatal screening programs for inborn errors of metabolism. This suggestion is based on the ease of testing, the necessity for presymptomatic laboratory diagnosis, and on the effectiveness of early treatment of the multiple carboxylase deficiency caused by defective biotinidase.

Amidohydrolases↗

PubMed1988

Basal ganglia calcifications in a case of biotinidase deficiency.

Biotinidase deficiency leads to a biotin-deficient state, with cardinal symptoms of ataxia, alopecia, and skin rash presenting in infancy. Previous reports of head CTs in patients with biotinidase deficiency did not note basal ganglia calcifications. We report the first case of biotinidase deficiency with basal ganglia calcifications. There were no symptoms referable to basal ganglia dysfunction.

Amidohydrolases↗

PubMed1993

Characterization of seizures associated with biotinidase deficiency.

Biotinidase deficiency is an autosomal recessively inherited disorder that is often characterized by neurologic abnormalities. We reviewed the clinical features of 78 symptomatic children, 11 new patients and 67 previously reported cases, to determine the frequency, type, age at onset, and the responsiveness of seizures to antiepileptic drugs and biotin therapy. Forty-three of the 78 (55%) symptomatic children had seizures, and seizures were the presenting symptom in 38% of the enzyme-deficient patients and 70% of those who had had seizures at some time. EEGs were available for 21 of these children. Sixteen were abnormal. The initially abnormal EEGs in eight of 12 infants became normal or improved with biotin therapy, whereas four continued to be abnormal. In 21 (49%) patients, the seizures were not well controlled with antiepileptic drugs. Biotin therapy stopped the seizures within 24 hours in 12 of 16 (75%) of those whose seizures were uncontrolled by anticonvulsants (five children died prior to diagnosis). Although the metabolic and cutaneous abnormalities were corrected in the remaining four children, they continued to have neurologic abnormalities. Biotinidase deficiency and a trial of biotin (5 to 10 mg) should be considered in infants less than 1 year of age with poorly controlled seizures, and biotinidase deficiency should be included in the differential diagnosis of an infant or child with unexplained seizures.

Amidohydrolases↗

PubMed2002

Localization of biotinidase in the brain: implications for its role in hearing loss in biotinidase deficiency.

Biotinidase deficiency is an autosomal recessively inherited disorder characterized by neurological and cutaneous features, including sensorineural hearing loss. Although many of the features of the disorder are reversible following treatment with biotin, the hearing loss appears to be irreversible. To better characterize the nature of the hearing loss in this disorder, location of the expression and presence of biotinidase within the brain was examined using Northern blot analysis, in vitro hybridization of a cDNA panel, and immunohistochemical staining. Results indicate low, but detectable expression of biotinidase throughout the brain, but increased concentrations of biotinidase within the dorsal cochlear nucleus, ventral cochlear nucleus, and superior olivary complex of the brainstem, as well as, in the hair cells and spiral ganglion of the cochlea. These findings suggest that biotinidase and possibly biotin plays an important role in hearing.

Amidohydrolases↗

PubMed1991

Rat as a potential model for hearing loss in biotinidase deficiency.

Biotinidase deficiency is an inborn error of metabolism that is transmitted as an autosomal recessive disorder. Symptoms include hearing loss, ataxia, blindness, mental retardation, and seizures. The metabolic defect is an inability to recycle the vitamin biotin, which is an important cofactor in key enzymes. We therefore sought to develop an animal model for this disorder by inducing biotin deficiency. Rat pups were divided into control and experimental groups. Control rats were fed a normal diet whereas experimental animals were given a diet deficient in biotin. Animals from both groups underwent brain stem auditory evoked potential testing at various ages. Wave I thresholds at various ages were similar in both groups. Latencies for wave I, however, and interpeak latencies (I-IV) were prolonged in the biotin-deficient groups compared to controls. Scanning electron microscopy of the organ of Corti in biotin-deficient animals showed no significant hair cell loss. The biotin-deficient developing rat appears to acquire functional changes in the auditory brain stem. These effects may be caused by defective myelination, since biotin is important in fatty acid metabolism.

Amidohydrolases↗

PubMed1993

Ophthalmologic findings in biotinidase deficiency.

Biotinidase deficiency is an autosomal recessively inherited metabolic disorder characterized by neurological and cutaneous manifestations and metabolic abnormalities. We studied 78 symptomatic children and found that 51% had ophthalmologic abnormalities. These include infections (30%), optic neuropathies and visual disturbances (13%), motility disturbances (13%), retinal pigment changes (4%) and pupillary findings (1%). The most commonly reported findings are optic atrophy and keratoconjunctivities. Although the disorder can be effectively treated with biotin therapy, untreated children are at risk of developing permanent neuro-ophthalmic damage.

Amidohydrolases↗

PubMed2001

Mutations in BTD causing biotinidase deficiency.

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 disorder 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.

Alleles↗

PubMed1992

Biochemical and immunologic characterization of serum biotinidase in partial biotinidase deficiency.

Newborn screening for biotinidase deficiency has identified children with profound biotinidase deficiency (less than 10% of mean normal activity) and about an equal number of children with partial biotinidase deficiency (10 to 30% of mean normal activity). Partial biotinidase deficiency was initially considered a variant without clinical consequences until one child, during an episode of gastroenteritis, developed symptoms of biotinidase deficiency that resolved with biotin therapy. Biochemical and immunologic characterization of biotinidase was performed in sera from 23 children with partial biotinidase deficiency from 19 families and 18 of their parents. As expected, all patients had cross-reacting material in their serum. Patients with partial biotinidase deficiency can be classified into six distinct biochemical phenotypes on the basis of the number of isoforms and the distribution frequency of the isoforms. Kinetic studies were performed on samples from 17 of the patients and were found to be normal in all cases. The patient with partial deficiency who became symptomatic has an isoform profile that is not different from 10 other asymptomatic, partially deficient children. The parents had normal isoform patterns. The isoform patterns observed in the patients with partial biotinidase deficiency were not different from those of the profoundly deficient patients who had cross-reacting material.

Adult↗

PubMed1995

Biotinylation of histones by human serum biotinidase: assessment of biotinyl-transferase activity in sera from normal individuals and children with biotinidase deficiency.

Serum biotinidase has biotinyl-transferase activity in addition to biocytin hydrolase activity. A sensitive assay for biotinyl-transferase activity was developed based on the transfer of biotin from biocytin to histones. Biotinidase biotinyl-transferase occurs at physiological and alkaline pHs, whereas hydrolysis of biocytin occurs optimally at pH 4.5 to 6.0. Measurement of hydrolysis requires micromolar concentrations of biocytin, whereas biotinylation of histones can be detected readily at 1.5 nM biocytin. Because polylysine is readily biotinylated by biotinidase in the presence of biocytin, whereas polyarginine is not, the enzyme likely transfers biotin to the epsilon-amino group of lysyl residues. To determine if patients who are deficient in biocytin hydrolase activity are also deficient in biotinyl-transferase activity, serum from 103 children (25 identified by exhibiting clinical symptoms and 78 detected by newborn screening) with profound biotinidase deficiency (less than 10% of mean normal biotinyl-p-aminobenzoate hydrolyzing activity) were assessed for biotinyl-transferase activity and for the presence of cross-reacting material (CRM) to antibodies prepared against purified serum biotinidase. Sera from all symptomatic patients, both CRM-negative and CRM-positive, had no biotinyl-transferase activity. Sera that was CRM-negative from children ascertained by newborn screening also had no biotinyl-transferase activity, whereas sera from 67% of the CRM-positive children identified by newborn screening had varying degrees of biotinyl-transferase activity. These results indicate that there is a large group of enzyme-deficient children detected by newborn screening who are different biochemically from those who are symptomatic. The clinical relevance of having some degree of biotinyl-transferase activity for individuals with biotinidase deficiency remains to be determined. In addition, it is important to determine if biotinyl-transferase activity, especially biotinylation of histones, is a physiological function of biotinidase.

Amidohydrolases↗

PubMed2006

Audiologic findings in children with biotinidase deficiency in Turkey.

OBJECTIVE: Biotinidase deficiency is an autosomal recessively inherited disorder characterized by neurological and cutaneous features, including sensorineural hearing loss. Although many features of the disorder are reversible following treatment with biotin, the hearing loss appears to be irreversible. In the present study, hearing status of patients with biotinidase deficiency is characterized in a Turkish population. METHODS: Subjective and objective audiologic tests were performed on 20 children with profound biotinidase deficiency. RESULTS: Sensorineural hearing loss occurs in approximately 55% of the children with biotinidase deficiency. The hearing loss varies in severity from mild to profound hearing loss. In children diagnosed immediately after birth because they had an older sibling with the disorder, statistically significant differences were found between ABR results and age of diagnosis (p<0.05). Greater prolongation in ABR latencies were observed in the late-diagnosed children compared to that in the early-diagnosed children (p<0.05). CONCLUSION: Early diagnosis is important to prevent peripheral and central hearing loss. Children with biotinidase deficiency who have hearing loss are likely at increased risk for having speech and language problems. If hearing aids do not provide sufficient amplification, cochlear implantation may be indicated in these children. Therefore, it is important to test the hearing thresholds of these children with hearing aids and evaluate their language development.

Adolescent↗

PubMed1991

Worldwide survey of neonatal screening for biotinidase deficiency.

Neonatal screening for biotinidase deficiency has been conducted in 14 countries since 1984. To 31 December 1990, 8,532,617 newborns were screened. One hundred and forty-two infants with biotinidase deficiency were identified; 76 infants with profound deficiency (less than 10% of mean normal serum activity) and 66 infants with partial deficiency (10-30% of mean normal activity). The estimated incidence of profound biotinidase deficiency is 1:112,271 (1:85,000 to 1:145,000; 95% confidence limits) and the incidence of partial deficiency is 1:129,282 (1:112,700 to 1:177,000). The incidence of combined profound and partial deficiency is 1:60,089 newborns (1:49,500 to 1:73,100). The estimated frequency of the allele for biotinidase deficiency is 0.004 and an estimated 1 in 123 individuals is heterozygous for the disorder.

Amidohydrolases↗

PubMed1998

Delayed-onset profound biotinidase deficiency.

Children with biotinidase deficiency usually exhibit symptoms at several months to years of age. We describe four children who had symptoms later in childhood or during adolescence; they had motor limb weakness, spastic paresis, and eye problems, such as loss of visual acuity and scotomata, rather than the more characteristic symptoms observed in young untreated children with the disorder. These older children each have different mutations, but they are the same as those of children who have exhibited symptoms at an early age. Biotinidase deficiency should be considered in older children who suddenly experience limb weakness and/or spastic paresis and eye symptoms.

Acyltransferases↗

PubMed1997

Profound biotinidase deficiency in two asymptomatic adults.

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.

Adult↗

PubMed1998

Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene.

Newborn screening for biotinidase deficiency has identified children with profound biotinidase deficiency (<10% of mean normal serum activity) and those with partial biotinidase deficiency (10%-30% of mean normal serum activity). Children with partial biotinidase deficiency and who are not treated with biotin do not usually exhibit symptoms unless they are stressed (i.e., prolonged infection). We found that 18 of 19 randomly selected individuals with partial deficiency have the transversion missense mutation G1330>C, which substitutes a histidine for aspartic acid444 (D444H) in one allele of the biotinidase gene. We have previously estimated that the D444H mutation results in 48% of normal enzyme activity for that allele and occurs with an estimated frequency of 0.039 in the general population. The D444H mutation in biotinidase deficiency is similar to the Duarte variant in galactosemia. The D444H mutation in one allele in combination with a mutation for profound deficiency in the other allele is the common cause of partial biotinidase deficiency.

Alleles↗

PubMed1997

Arg538 to Cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of profound biotinidase deficiency in symptomatic children.

Biotinidase deficiency is an autosomal recessively inherited disorder in the recycling of the vitamin biotin. The most common mutation that causes profound biotinidase deficiency in symptomatic individuals is a deletion/insertion (G98:d7i3) that occurs in exon B of the biotinidase gene. We now report the second most common mutation, a C-to-T substitution (position 1612) in a CpG dinucleotide in exon D of the biotinidase gene. This mutation results in the substitution of a cysteine for arginine538 (designated R538C) and was found in 10 of 30 symptomatic children with profound biotinidase deficiency, 5 of whom also have the G98:d7i3 mutation. This mutation was not found in DNA samples from 32 individuals with normal biotinidase activity, but was found in one individual with enzyme activity in the heterozygous range. This mutation was not detected in 371 randomly selected, normal individuals using allele-specific oligonucleotide hybridization analysis. Aberrant biotinidase protein was not detectable in extracts of fibroblasts from a child who is homozygous for the R538C mutation, but was present in less than normal concentration in identical extracts treated with beta-mercaptoethanol. Because there is no detectable biotinidase protein in sera of children who are homozygous for the R538C mutation and in combination with the deletion/insertion mutation, the R538C mutation likely results in inappropriate intra- or intermolecular disulfide bond formation, more rapid degradation of the aberrant enzyme, and failure to secrete the residual aberrant enzyme from the cells into blood.

Acyltransferases↗