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PloS One 2017The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent....
INTRODUCTION
The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity.
METHODS
All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed.
RESULTS
Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients.
CONCLUSIONS
The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.
Topics: Adolescent; Biotinidase; Biotinidase Deficiency; Brazil; Child; Child, Preschool; Computational Biology; Cross-Sectional Studies; Female; Genetic Association Studies; Genotype; Humans; Infant; Male
PubMed: 28498829
DOI: 10.1371/journal.pone.0177503 -
Journal of Inherited Metabolic Disease May 2022Deficiency of the biotinidase (BTD) enzyme is an inborn error of biotin metabolism caused by biallelic pathogenic variants in the BTD gene. There are two forms, partial...
Deficiency of the biotinidase (BTD) enzyme is an inborn error of biotin metabolism caused by biallelic pathogenic variants in the BTD gene. There are two forms, partial and profound BTD deficiency, which both can be successfully treated with pharmacological doses of biotin, justifying the inclusion of this disorder in the newborn screening in numerous countries. We investigated the BTD deficiency cohort (N = 87) in our metabolic center, as it was detected upon newborn screening since 2005, and aimed to better understand the long-term course of BTD enzyme activity and how it may relate to the patients' genetic background. We observed that individuals with partial BTD deficiency display an elevation of BTD enzyme activity with increasing age in 48% of cases-a recovery which allowed adjustment or stop of biotin supplementation in 20% of all individuals. In addition, we were able to recruit 56 patients (64%) for genetic testing, revealing 19 different variants (2 novel), and constituting 22 different genotypes. Genotype-phenotype correlations revealed that the most abundant allele in our cohort p.(Asp444His) was also the most common variant in patients displaying recovery of BTD enzyme activity. Based on our results, we recommend to retest all patients with partial BTD deficiency at the age of 5 years, as this may result in an impact on therapy. Moreover, genetic testing of BTD deficient individuals can allow prediction of the severity of BTD deficiency and of the likelihood of BTD enzyme activity recovery with age.
Topics: Biotin; Biotinidase; Biotinidase Deficiency; Child, Preschool; Genetic Testing; Humans; Infant, Newborn; Mutation; Neonatal Screening
PubMed: 35195902
DOI: 10.1002/jimd.12490 -
Bioinformation 2022The process of testing newborn infants for hormonal, genetic, metabolic, and other disorders is known as newborn screening (NSB). Newborn screening is essential for...
The process of testing newborn infants for hormonal, genetic, metabolic, and other disorders is known as newborn screening (NSB). Newborn screening is essential for detecting, diagnosing, and treating disorders that could save serious consequences for a newborn's health. Congenital Hypothyroidism (CH), Cystic Fibrosis (CF), Glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Profound Biotinidase deficiency (BD) are common disorders in India. A retrospective analysis of the results of NBS by Cord blood spots was performed at the department of Obstetrics and Gynecology, 7 Airforce Hospital, Kanpur, Uttar Pradesh, from June 2022 to September 2022. During this period, 26 newborns were screened for four disorders, including CH, CF, G6PD deficiency, and BD. In this investigation, no cases of CH, CF, G6PD deficiency, or BD were found to be positive. The results of the current data provide a distinct opportunity to investigate the birth prevalence of inborn metabolic disorders in the area close to the city of Kanpur.
PubMed: 37701517
DOI: 10.6026/973206300181122 -
Journal of Medical Biochemistry Apr 2016Biotin, a water-soluble vitamin, is used as a co-factor by enzymes involved in carboxylation reactions. Biotinidase (BTD) catalyzes the recycling of biotin from...
BACKGROUND
Biotin, a water-soluble vitamin, is used as a co-factor by enzymes involved in carboxylation reactions. Biotinidase (BTD) catalyzes the recycling of biotin from endogenous and dietary sources. Biotinidase deficiency (BD) is an autosomal recessively inherited disorder of biotin recycling that is associated with neurologic and cutaneous consequences when untreated. The aim of the study was to compare the results of spectrophotometric and fluorimetric methods, as well as to evaluate the advantages and disadvantages of both methods in current research practices.
METHODS
Study group was chosen among the BD suspected newborn, children and parents (n = 52) who applied to Hacettepe University Pediatric Metabolism Unit.
RESULTS
BTD activity is stable for 2 hours at room temperature and at 4 °C, and for 4 months at -20 °C and -80 °C. Genetic and clinical results showed that 25% of the total number of patients had complete BD which was treated with 10 mg/day biotin, while 15.38% of the patients had partial BD, and they were prescribed biotin 5 mg/day. The area under the ROC curve was 0.960±0.25 and 0.927± 0.41 for the fluorimetric and spectrophotometric method, respectively. Fluorimetric method showed 100% sensitivity and 97% specificity, whereas spectrophotometric method showed 90.5% sensitivity and 93.7% specificity.
CONCLUSIONS
Fluorimetric method is superior to the spectrophotometric method due to higher sensitivity and specificity.
PubMed: 28356871
DOI: 10.1515/jomb-2016-0004 -
Genetics in Medicine : Official Journal... Apr 2017We began screening newborns for biotinidase deficiency disorder in 1984, and now all states in the United States and many countries perform this screening. The purpose...
PURPOSE
We began screening newborns for biotinidase deficiency disorder in 1984, and now all states in the United States and many countries perform this screening. The purpose of this study was to determine the outcomes of older adolescent and adult individuals with the disorder identified by newborn screening.
SUBJECTS AND METHODS
We located and surveyed, by questionnaire and telephone interviews, 44 individuals with profound biotinidase deficiency identified by newborn screening with a mean age of 23.1 years.
RESULTS
All individuals had successfully completed high school, and many were attending or had completed college or graduate school. Compliance in using biotin has been excellent. Several individuals developed a variety of symptoms when they discontinued biotin for days or weeks. These features readily resolved when biotin was resumed. In addition, five treated women had nine uneventful pregnancies and deliveries.
CONCLUSIONS
Newborn screening for profound biotinidase deficiency and early treatment with biotin result in excellent outcomes for older adolescents and adults with the disorder. In addition, mothers with profound biotinidase deficiency who were treated with biotin had pregnancies with good outcomes. These outcome results indicate that newborn screening for biotinidase deficiency is one of the most successful newborn screening programs.Genet Med 19 4, 396-402.
Topics: Adolescent; Adult; Biotin; Biotinidase Deficiency; Female; Humans; Infant, Newborn; Male; Neonatal Screening; Surveys and Questionnaires; Treatment Outcome; Young Adult
PubMed: 27657684
DOI: 10.1038/gim.2016.135 -
Molecular Genetics and Metabolism... Dec 2017We reviewed the outcome of newborn screening for biotinidase deficiency performed at our department since 1987. Among 1,097,894 newborns screened, 461 were recalled, and...
We reviewed the outcome of newborn screening for biotinidase deficiency performed at our department since 1987. Among 1,097,894 newborns screened, 461 were recalled, and 18 were identified as affected by complete or partial biotinidase deficiency (incidence 1:61,000, false positive rate 0.04%). The common missense mutation Q456H was found in 80% of patients with profound biotinidase deficiency. Of them, one patient harbored the novel mutation M399I in compound heterozygosity (M399I/Q456H). The complex allele A171T/D444H was found in two patients with profound biotinidase deficiency (in homozygosity and in compound heterozygosity with the R211H mutation, respectively) and in one patient with partial biotinidase deficiency (in compound heterozygosity with the protective allele D444H ). All detected patients were treated and followed up at our Center until present. Biotin therapy (10-20 mg/day) allowed the full prevention of clinical symptoms in all patients with no adverse effects. These excellent outcomes confirm that newborn screening for biotinidase deficiency is a very effective secondary prevention program.
PubMed: 28971021
DOI: 10.1016/j.ymgmr.2017.08.005 -
International Journal of Environmental... Jul 2022Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not...
Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not recycled. BD meets the major criteria for a population screening program. Newborn bloodspot screening (NBS) allows early diagnosis of BD, thus preventing the high morbidity and mortality associated with untreated disease. Both profound and partial BD variant can be detected by NBS test, and serum enzyme activity and/or mutational analysis are required for definitive diagnosis. In Italy, BD is included in the screening panel for inborn errors of metabolism (IEMs) that has been declared mandatory in 2016. We analyzed the data of the first 3 years of the NBS for BD in our region (Abruzzo, Italy), with the aim to describe the outcomes of this recently introduced screening program. In over 26,393 newborns screened, we found 2 carriers and 16 cases with genotype associated with partial BD. Since the serum biotinidase assay has been recently introduced in our algorithm, only three of our newborns met the criteria of genetic and biochemical confirmation, with an incidence of 1:8797, which is in the high range of what has been reported in the literature. All affected infants carried the 1330G>C (D444H) variant in compound heterozygosis, with variants known to be associated with profound BD. A variant previously not described and likely pathogenic was found in one newborn. None of the infants had signs or symptoms. The study of the distribution of the enzyme activity in our population allowed us to validate the adopted cutoff with which the program has a positive predictive value of 18% and to analyze some preanalytical factors influencing biotinidase activity: A correlation of the enzyme activity with gestational age and time at specimen collection was found. Lower mean values of enzyme activity were found in infants born in the summer.
Topics: Biotinidase; Biotinidase Deficiency; Humans; Incidence; Infant; Infant, Newborn; Mutation; Neonatal Screening
PubMed: 35805799
DOI: 10.3390/ijerph19138141 -
Molecular Genetics and Metabolism Feb 2011Biotinidase deficiency is the primary enzymatic defect in biotin-responsive, late-onset multiple carboxylase deficiency. Untreated children with profound biotinidase...
Biotinidase deficiency is the primary enzymatic defect in biotin-responsive, late-onset multiple carboxylase deficiency. Untreated children with profound biotinidase deficiency usually exhibit neurological symptoms including lethargy, hypotonia, seizures, developmental delay, sensorineural hearing loss and optic atrophy; and cutaneous symptoms including skin rash, conjunctivitis and alopecia. Although the clinical features of the disorder markedly improve or are prevented with biotin supplementation, some symptoms, once they occur, such as developmental delay, hearing loss and optic atrophy, are usually irreversible. To prevent development of symptoms, the disorder is screened for in the newborn period in essentially all states and in many countries. In order to better understand many aspects of the pathophysiology of the disorder, we have developed a transgenic biotinidase-deficient mouse. The mouse has a null mutation that results in no detectable serum biotinidase activity or cross-reacting material to antibody prepared against biotinidase. When fed a biotin-deficient diet these mice develop neurological and cutaneous symptoms, carboxylase deficiency, mild hyperammonemia, and exhibit increased urinary excretion of 3-hydroxyisovaleric acid and biotin and biotin metabolites. The clinical features are reversed with biotin supplementation. This biotinidase-deficient animal can be used to study systematically many aspects of the disorder and the role of biotinidase, biotin and biocytin in normal and in enzyme-deficient states.
Topics: Animals; Behavior, Animal; Biotin; Biotinidase; Biotinidase Deficiency; Body Weight; Diet; Disease Models, Animal; Female; Gene Expression Regulation, Enzymologic; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurocutaneous Syndromes; Vitamin B Complex
PubMed: 21051254
DOI: 10.1016/j.ymgme.2010.10.005 -
ORL; Journal For Oto-rhino-laryngology... 2006Understanding the genetic basis of hearing loss is important because almost 50% of profound hearing loss are caused by genetic factors and more than 120 independent... (Review)
Review
Understanding the genetic basis of hearing loss is important because almost 50% of profound hearing loss are caused by genetic factors and more than 120 independent genes have been identified. In this review, after a brief explanation of some genetic terms (allele, heterozygosis, homozygosis, polymorphism, genotype and phenotype), classification of genetic hearing loss (syndromic versus nonsyndromic, and recessive dominant, X-linked and mitochondrial) was performed. Some of the most common syndromes (Usher, Pendred, Jervell and Lange-Nielsen, Waardenburg, branchio-oto-renal, Stickler, Treacher Collins and Alport syndromes, biotinidase deficiency and Norrie disease) causing genetic hearing loss were also explained briefly. The genes involved in hearing loss and genetic heterogeneity were presented.
Topics: Alleles; DNA, Mitochondrial; Genetic Heterogeneity; Genotype; Hearing Loss; Humans; Inheritance Patterns; Phenotype; Polymorphism, Genetic; Syndrome
PubMed: 16428895
DOI: 10.1159/000091090 -
Neurology India 2013This study reports the clinical, laboratory profile and outcome in seven patients with biotinidase deficiency. The serum biotinidase activity was assayed using...
This study reports the clinical, laboratory profile and outcome in seven patients with biotinidase deficiency. The serum biotinidase activity was assayed using spectrophotometric analysis. The age at presentation varied from day 1 of life to the 5 th month. Seizures were the presenting complaint in six patients and clonic seizures were the predominant seizure type. Sparse hair was seen in four patients, while three did not have any cutaneous manifestation. None of the patients had acidosis or hyperammonemia. The clinical response to biotin was dramatic with seizure control in all patients. One patient had neurological deficit at follow-up, while none had optic atrophy or sensorineural hearing loss. Biotinidase deficiency, a potentially treatable condition, should be thought of in any child presenting with neurological symptoms, especially seizures, even in the absence of cutaneous or laboratory manifestations.
Topics: Biotinidase; Biotinidase Deficiency; Child, Preschool; Epilepsy; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Spectrometry, Fluorescence
PubMed: 24005734
DOI: 10.4103/0028-3886.117614