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Objective: The aims of this study were to investigate biochemical and genetic tests and treatment plans of newborns referred to our center with inherited metabolic disorders screened in Türkiye National Newborn Screening Program (NNSP). Material and Methods: The medical records of babies referred by the NNSP between January 2019 and November 2023 were scanned retrospectively. Plasma biotinidase activity and the biotinidase gene (BTD) analysis results for suspected biotinidase deficiency (BD), the plasma phenylalanine and phenylalanine hydroxylase gene (PAH) analysis for a suspicion of phenylketonuria (PKU) were documented with treatment information. Results: A total of 143 babies, 78 (54.5%) with suspected BD and 65 (45.5%) with suspected PKU were included. A PAH gene analysis was performed on 23 (35.4%) of those had high plasma phenylalanine levels, among which 86.9% were identified with the biallelic variant. Five patients were started on sapropterin-diet combined therapy, three on diet therapy and one on sapropterin therapy. In the first serum biotinidase activity measurement of babies referred with suspected BD, a heterozygous deficiency was detected in 48.7%, partial deficiency in 39.7% and profound deficiency in 10.3%. A BTD gene analysis was performed on 79.5% of those with suspected BD, and biallelic variants were detected in 50%. Forty-six patients (59.0%) underwent biotin treatment. Conclusion: In our study, approximately one-third of the babies referred from NNSP over the five-year course of the study had biallelic variants of the relevant disease. Our research is one of the few studies on NNSP in our country and presents the diagnosis and treatment process of PKU and BD. [ABSTRACT FROM AUTHOR]

Background: Biotinidase deficiency (BD) is a rare, autosomal recessive metabolic disorder characterized by neurocutaneous symptoms. This study investigates a case of profound BD in an Indian infant and the underlying genetic basis. Methods: A 10-month-old male presenting with seizures, hypotonia, ataxia, visual impairments, and developmental delay underwent biochemical and genetic analysis. Biotinidase activity was measured using an ELISA kit. Sanger sequencing of the biotinidase (BTD) gene was performed to identify genetic variations. In silico analysis was employed to assess the potential impact of the identified variants. Results: The infant biotinidase activity was undetectable and its suggest profound biotinidase deficiency. Novel biallelic loss-of-function variations (c.903G > A and c.946 C > T) in the BTD gene were identified, leading to premature stop codons and truncated, non-functional protein fragments. Conclusion: This case expands our knowledge of BD genetic diversity and underscores the critical role of early diagnosis and newborn screening programs in managing this treatable condition. [ABSTRACT FROM AUTHOR]

This article presents a case study of a 23-year-old male with a rare genetic condition called biotinidase deficiency, which manifested as parkinsonism. The patient experienced symptoms such as stiffness, tremors, and delayed motor and language development. Genetic testing revealed specific variants in the BTD gene, which are considered pathogenic. Treatment with biotin supplementation and dopaminergic therapy showed some improvement in motor symptoms but not in cognitive functions. The article emphasizes the importance of early diagnosis and treatment for better outcomes in biotinidase deficiency cases. It also suggests considering this condition when evaluating juvenile parkinsonism, especially if there are other clinical features present. [Extracted from the article]

Biotin (vitamin B7, or vitamin H) is a water-soluble B-vitamin that functions as a cofactor for carboxylases, i.e., enzymes involved in the cellular metabolism of fatty acids and amino acids and in gluconeogenesis; moreover, as reported, biotin may be involved in gene regulation. Biotin is not synthesized by human cells, but it is found in food and is also produced by intestinal bacteria. Biotin status/homeostasis in human individuals depends on several factors, including efficiency/deficiency of the enzymes involved in biotin recycling within the human organism (biotinidase, holocarboxylase synthetase), and/or effectiveness of intestinal uptake, which is mainly accomplished through the sodium-dependent multivitamin transporter. In the last years, administration of biotin at high/"pharmacological" doses has been proposed to treat specific defects/deficiencies and human disorders, exhibiting mainly neurological and/or dermatological symptoms and including biotinidase deficiency, holocarboxylase synthetase deficiency, and biotin–thiamine-responsive basal ganglia disease. On the other hand, according to warnings of the Food and Drug Administration, USA, high biotin levels can affect clinical biotin-(strept)avidin assays and thus lead to false results during quantification of critical biomarkers. In this review article, recent findings/advancements that may offer new insight in the abovementioned research fields concerning biotin will be presented and briefly discussed. [ABSTRACT FROM AUTHOR]

Objective: Hypotonia, lethargy, eczema, alopecia, conjunctivitis, ataxia, hearing loss, optic atrophy, cognitive retardation, and seizures can be seen in biotinidase deficiency. This study aimed to compare the hemogram values of infants with biotinidase deficiency and healthy infants. Material and Method: Hemogram data of 35 cases who were found to have biotinidase deficiency with the neonatal screening program and 41 healthy infants were recorded retrospectively. Results: While 51.4% of 35 cases in the patient group were male and the mean age at presentation was 19,02±5,485 days, 51.2% of 41 cases in the control group were male and the mean age at presentation was 15,41±7,269 days. While a statistically significant elevation was found in the total leukocytes, lymphocytes, monocytes, thrombocyte, MPV, PCT and MCHC values in the patient group compared to the control group; a statistically significant decrease was detected in basophil, MCV and RDW values. Conclusion: In the patients with biotinidase deficiency, higher levels of white blood cells, lymphocytes and platelets were detected compared to the control group. These higher rates are thought to be a part of the mechanism leading to immune dysfunction and hair and skin abnormalities in biotinidase deficiency. [ABSTRACT FROM AUTHOR]

Abstract Objective Biotinidase deficiency (BTD) is characterized by a wide range of genetic variants. However, the correlation between these variants and the biochemical phenotypes of BTD is not well-established due to the diversity of the BTD gene, the variable nature of biotinidase, and difficulties in measuring enzyme activity. This study aims to identify BTD gene variants in newborns screened for biotinidase deficiency in Southeastern Anatolia and to examine the correlation between these variants and biochemical phenotypes. Materials and methods BTD variant analysis and biotinidase enzyme (BT) activity measurements were performed on 711 newborns. Enzyme activity was measured using the colorimetric method. Biochemical phenotyping was categorized into three groups based on mean residual enzyme activity: profound (≤ 10%), partial (10.1–30%), and normal (> 30.1%). The pathogenicity of BTD gene variants was determined using BTD databases. Results The biochemical phenotypes were distributed as follows: a) profound: n = 22 (3%), b) partial: n = 95 (13.3%), and c) normal: n = 594 (83.7%). The mean enzyme activities (%) for these groups were 8.79 ± 1.87, 22.67 ± 4.55, and 97.98 ± 17.45, respectively. The most common alleles and their frequencies were p.D444H (n = 526) (37%), p.R157H (n = 172) (12.1%), and p.C33Ffster*36 (n = 73) (9%). The pathogenicity of the variants was as follows: pathogenic: 481 (33.8%), likely pathogenic: 4 (0.2%), and variant of uncertain significance (VUS): 538 (37.8%). Conclusion In this large cohort in Southeastern Anatolia, the most common alleles were p.D444H, p.R157H, and p.C33Ffster*36 in BTD variants. The results indicate a low concordance between the biochemical phenotype and genotype in newborns with BTD. This study highlights the inadequacy of predicting the biochemical phenotype based solely on variant pathogenicity in biotinidase deficiency during the neonatal period.

Biotinidase deficiency (BD) is an inherited autosomal recessive metabolic disorder. BD has been associated with optic nerve atrophy, eye infections, and retinopathy. The most prevalent ophthalmic manifestation of BD is optic atrophy, which might be misdiagnosed as multiple sclerosis or neuromyelitis optica, especially in late-onset BD cases. In this article, we report a 9-year-old boy with gradual vision loss. Ophthalmologic examination, Brain MRI, and several laboratory tests such as Aquaporin-4 IgG level and biotinidase level were done on the patient. Bilateral optic atrophy and impaired visual acuity were detected on examination. The patient had a biotin level of 1.25 U/min/ml (normal range 3-9 U/min/ml), favoring the BD. In this study, we report a 9-year-old boy with vision loss diagnosed with BD. We also reviewed the literature to highlight the ophthalmic manifestations of BD. Ophthalmologists must consider BD in children with unexplained ophthalmologic complaints, especially when other characteristic signs of BD (e.g., developmental delay, seizure) are present. Also, patients with BD should undergo regular annual ophthalmologic examinations to be checked for any signs of eye involvement. [ABSTRACT FROM AUTHOR]

Objective: Biotinidase deficiency (BTD) is characterized by a wide range of genetic variants. However, the correlation between these variants and the biochemical phenotypes of BTD is not well-established due to the diversity of the BTD gene, the variable nature of biotinidase, and difficulties in measuring enzyme activity. This study aims to identify BTD gene variants in newborns screened for biotinidase deficiency in Southeastern Anatolia and to examine the correlation between these variants and biochemical phenotypes. Materials and methods: BTD variant analysis and biotinidase enzyme (BT) activity measurements were performed on 711 newborns. Enzyme activity was measured using the colorimetric method. Biochemical phenotyping was categorized into three groups based on mean residual enzyme activity: profound (≤ 10%), partial (10.1–30%), and normal (> 30.1%). The pathogenicity of BTD gene variants was determined using BTD databases. Results: The biochemical phenotypes were distributed as follows: a) profound: n = 22 (3%), b) partial: n = 95 (13.3%), and c) normal: n = 594 (83.7%). The mean enzyme activities (%) for these groups were 8.79 ± 1.87, 22.67 ± 4.55, and 97.98 ± 17.45, respectively. The most common alleles and their frequencies were p.D444H (n = 526) (37%), p.R157H (n = 172) (12.1%), and p.C33Ffster*36 (n = 73) (9%). The pathogenicity of the variants was as follows: pathogenic: 481 (33.8%), likely pathogenic: 4 (0.2%), and variant of uncertain significance (VUS): 538 (37.8%). Conclusion: In this large cohort in Southeastern Anatolia, the most common alleles were p.D444H, p.R157H, and p.C33Ffster*36 in BTD variants. The results indicate a low concordance between the biochemical phenotype and genotype in newborns with BTD. This study highlights the inadequacy of predicting the biochemical phenotype based solely on variant pathogenicity in biotinidase deficiency during the neonatal period. [ABSTRACT FROM AUTHOR]

Biotinidase deficiency (BD) is an autosomal recessive inherited metabolic disorder which results from the inability of biotin-dependent carboxylase enzymes to function due to the release and absorption of biotin, leading to neurological and cutaneous findings. In the present study, evaluation of demographic characteristics, clinical findings, laboratory results, molecular genetic characteristics, and genotype–phenotype correlations of cases with BD. Two hundred forty-seven cases were included in the study who were admitted to the Department of Pediatric Metabolism of Ankara Bilkent City Hospital after being identified with potential BD through the Newborn Screening Program (NBS), during family screening or based on suspicious clinical findings, or following the detection of a pathogenic variant in a BTD genetic analysis during the period of October 2020 and February 2022. The medical files of the cases were reviewed retrospectively. An analysis of the admission routes of all cases to our clinic revealed 89.5% NBS, 5.7% family screening, and 4.9% suspicious clinical findings suggestive of BD. Complete enzyme deficiency was identified in 19.8%, partial enzyme deficiency in 55.1%, and heterogenous enzyme deficiency in 9.7%. The most common pathogenic variants were c.1270G > C (p.Asp424His), c.410G > A (p.Arg137His), and c.38_44delGCGCTGinsTCC (p.Cys13Phefs*36) in BTD gene. The c.1270G > C variant was most common in patients with cutaneous symptoms. The c.410G > A and c.38_44delGCGCTGinsTCC variants were more common in the patients with neurological symptoms. The mean activity level in patients with the c.1270G > C homozygous variant was statistically significantly higher than the mean activity level in the c.1270G > C compound heterozygous patients and the activity level of patients without the c.1270G > C variant. The mean activity level in c.410G > A homozygous patients was statistically significantly lower than the mean activity level of the c.410G > A compound heterozygous patients and the activity level of patients without the c.410G > A variant. In the course of our study, four new pathogenic variants were detected, namely: c.190G > A (p.Glu64Lys), c.249 + 5G > T, c.228delA (p.Val77*), and c.682A > G (p.Ile228Val). Conclusions: The present study has determined the clinical and genetic spectrum of a large group of patients with BD in a single center. The frequent mutations in our study were similar to those reported in literature, and four novel variants were also described. What is Known: • Biotinidase deficiency is an autosomal recessive, treatable inborn error of metabolism. Two hundred ninety-four pathogenic variants in the BTD gene have been identified and the c.1270G > C variant is the most frequent BTD gene mutation in both Turkey and around the world. What is New: • Four new pathogenic variants (c.190G > A, p.Glu64Lys; c.249 + 5G > T; c.228delA, p.Val77*; and c.682A > G, p.Ile228Val) have been identified. It is believed that the c.38_44delGCGGCTGinsTCC variant is more commonly seen in individuals with ocular issues; however, further genotype–phenotype correlations are needed. [ABSTRACT FROM AUTHOR]

Biotinidase (BTD) enzyme deficiency is a congenital metabolic disorder with autosomal recessive inheritance. Main symptoms in its deficiency are nervous system and skin manifestations. A 15-month-old patient who was diagnosed with Li-Campeau syndrome, was also diagnosed with BTD deficiency and his clinic rapidly improved with biotin treatment. With the awareness of different clinical presentations of BTD deficiency, patients presenting with clinical symptoms raising the suspicion of this disorder must be evaluated for enzyme activity and genetic analysis must be planned. It is of great importance to keep in mind the possibility of this rare but treatable neurometabolic disorder, even in countries with neonatal screening programme and include it in differential diagnoses in order to prevent irreversible symptoms.

Biotin (vitamin B7, or vitamin H) is a water-soluble B-vitamin that functions as a cofactor for carboxylases, i.e., enzymes involved in the cellular metabolism of fatty acids and amino acids and in gluconeogenesis; moreover, as reported, biotin may be involved in gene regulation. Biotin is not synthesized by human cells, but it is found in food and is also produced by intestinal bacteria. Biotin status/homeostasis in human individuals depends on several factors, including efficiency/deficiency of the enzymes involved in biotin recycling within the human organism (biotinidase, holocarboxylase synthetase), and/or effectiveness of intestinal uptake, which is mainly accomplished through the sodium-dependent multivitamin transporter. In the last years, administration of biotin at high/“pharmacological” doses has been proposed to treat specific defects/deficiencies and human disorders, exhibiting mainly neurological and/or dermatological symptoms and including biotinidase deficiency, holocarboxylase synthetase deficiency, and biotin–thiamine-responsive basal ganglia disease. On the other hand, according to warnings of the Food and Drug Administration, USA, high biotin levels can affect clinical biotin-(strept)avidin assays and thus lead to false results during quantification of critical biomarkers. In this review article, recent findings/advancements that may offer new insight in the abovementioned research fields concerning biotin will be presented and briefly discussed.

Objective: It is known that the number of diseases associated with autosomal recessive inheritance pattern is increasing in our country where consanguineous marriages (including within the same village/region) are high. In this study, we aimed to evaluate the carrier rate of Phenylketonuria, Biotinidase Deficiency and Cystic Fibrosis by evaluating the next generation sequencing (NGS) data collected. Methods: The data of 279 cases who underwent NGS between March 2021 and April 2022 for different clinical indications were investigated retrospectively. Cases with pathogenic variants in PAH, BTD, and CFTR genes were figured out as carriers. Results: In this study, pathogenic variants were found in the PAH gene in 9, BTD gene in 23 and CFTR genes in 14 of a total of 279 individuals. Additionally, 2 people had pathogenic variants in both the BTD and the PAH genes. The carrier rates for phenylketonuria, biotinidase deficiency and cystic fibrosis were 3.2%, 8.2%, and 5%, respectively. Conclusion: These results suggest that carrier rate of Phenylketonuria, Biotinidase Deficiency, and Cystic fibrosis may be significantly high in our country. Carrier screening is very important in diseases with high carrier rates. When both couples are known to be carriers, prenatal or pre-implantation genetic diagnosis testing options can be offered. [ABSTRACT FROM AUTHOR]

Biotinidase (BTD) enzyme deficiency is a congenital metabolic disorder with autosomal recessive inheritance. Main symptoms in its deficiency are nervous system and skin manifestations. A 15-month-old patient who was diagnosed with Li-Campeau syndrome, was also diagnosed with BTD deficiency and his clinic rapidly improved with biotin treatment. With the awareness of different clinical presentations of BTD deficiency, patients presenting with clinical symptoms raising the suspicion of this disorder must be evaluated for enzyme activity and genetic analysis must be planned. It is of great importance to keep in mind the possibility of this rare but treatable neurometabolic disorder, even in countries with neonatal screening programme and include it in differential diagnoses in order to prevent irreversible symptoms. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing (WES) is an excellent method for the diagnosis of diseases of uncertain or heterogeneous genetic origin. However, it has limitations for detecting structural variations such as InDels, which the bioinformatics analyzers must be aware of. This study aimed at using WES to evaluate the genetic cause of the metabolic crisis in a 3-day-old neonate admitted to the neonatal intensive care unit (NICU) and deceased after a few days. Tandem mass spectrometry (MS/MS) showed a significant increase in propionyl carnitine (C3), proposing methylmalonic acidemia (MMA) or propionic acidemia (PA). WES demonstrated a homozygous missense variant in exon 4 of the BTD gene (NM_000060.4(BTD):c.1330G > C), responsible for partial biotinidase deficiency. Segregation analysis of the BTD variant revealed the homozygous status of the asymptomatic mother. Furthermore, observation of the bam file, around genes responsible for PA or MMA, by Integrative Genomics Viewer (IGV) software displayed a homozygous large deletion in the PCCA gene. Comprehensive confirmatory studies identified and segregated a novel outframe deletion of 217,877 bp length, "NG_008768.1:g.185211_403087delinsTA", extended from intron 11 to 21 of the PCCA, inducing a premature termination codon and activation of nonsense-mediated mRNA decay (NMD). Homology modeling of the mutant PCCA demonstrated eliminating the protein's active site and critical functional domains. Thereupon, this novel variant is suggested as the largest deletion in the PCCA gene, causing an acute early-onset PA. These results could expand the PCCA variants spectrum, and improve the existing knowledge on the molecular basis of PA, as well as provide new evidence of pathogenicity of the variant (NM_000060.4(BTD):c.1330G > C. [ABSTRACT FROM AUTHOR]

Biotinidase (BTD) deficiency (OMIM 253260) is an autosomal recessively inherited metabolic disorder resulting from deficient activity of the BTD enzyme, which can cleave and release biotin from a variety of biotin-dependent carboxylases, and is therefore recognized as a tool to recycle biotin. Being a condition caused by variations on BTD gene with a consequence of free biotin shortage, BTD deficiency may impair the activity of biotin-dependent carboxylases, and thus bring about a buildup of potentially toxic compounds in the body, primarily 3-hydroxyisovaleryl-carnitine in plasma as well as 3-hydroxyisovaleric acid in urine. The phenotype of BTD deficiency may vary dramatically, from asymptomatic adults to severe neurological anomalies, even death in infancy. In the present study, we reported on a 5-month-old boy, whose parents sought for medical consultation in our clinic for their son due to his loss of consciousness, repeated tetany, and motor retardation. Detailed clinical features included severe psychomotor retardation, hypotonia, as well as failure to thrive. The brain MRI at 12 months showed cerebellar hypoplasia and multiple foci of leukodystrophy. The result of antiepileptic therapy was not satisfying. During hospitalization, BTD deficiency was suggested by elevated concentration of 3-hydroxyisovaleryl-carnitine in the blood spots and 3-hydroxyisovaleric acid in the urine. The child was then diagnosed with profound BTD deficiency based on the above findings and low BTD enzyme activity. Subsequent mutational analysis revealed a novel homozygous variant, c.637_637delC (p.H213Tfs*51) in exon 4 of BTD gene in the proband, which was recognized as a further support to the diagnosis. Therefore, biotin treatment was started immediately, eventually with satisfactory outcomes achieved in terms of prevention of epileptic seizure, performance in deep tendon reflexes, and improvement of muscular hypotonia, but unfortunately, the therapy failed to show any evident effects on poor feeding and intellectual disability. This painful lesson suggests that newborn screening for inherited metabolic diseases is essential for early identification and treatment, which should have been performed in this case to avoid this tragedy. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the clinical, demographic and laboratory characteristics of the patients referred with a preliminary diagnosis of biotinidase deficiency through the national newborn metabolic screening program. We also attempted to determine the cut-off level of the fluorometric method used for screening biotinidase deficiency by the Ministry of Health. A total of 700 subjects who were referred to the Pediatric Metabolism Outpatient Clinic with a preliminary diagnosis of biotinidase deficiency through the national newborn metabolic screening program were retrospectively evaluated. Patients detected by family screening were excluded. Biotinidase enzyme activity was assessed and BTD gene analysis was performed in all patients. Of 700 subjects who were referred by the screening program, 284 (40.5 %) had biotinidase deficiency (BD). The enzyme activity was 0–10, 10–30 and >30 % in 39 (5.5 %), 245 (35 %) and 416 (59.5 %) patients, respectively. The BD was partial in majority of patients (86.2 %). The cut-off level was 59.5 MRU for partial BD and 50.5 MRU for profound BD. The most common mutation detected was p.Arg157His (c.470G>A) among patients with profound BD, and p.D444H (c.1330G>C) among patients with partial BD. Treatment should be initiated promptly in patients who are referred by the newborn screening program. Any mean activity under 59.5 MRU should be considered partial BD, while less than 50.5 MRU should be considered profound BD. It should be kept in mind that clinical manifestations may develop both in profound and partial BD. [ABSTRACT FROM AUTHOR]

This study set out to examine pre-analytical factors affecting the frequency of positive results in newborn screening for biotinidase deficiency. This investigation was prompted by an increase in the annual screen positive rate for biotinidase deficiency in Ontario from 2.65x10−4 in 2016 to 6.57x10−4 in 2017. Season and trend decomposition was used to separate seasonality from an underlying trend in the time series of biotindase activity measurements for the period 2014–01-12 to 2019–07-27 (n = 798,770). This analysis revealed a marked seasonal effect (winter = median + ⩽ 17 MRU, summer = mean - ⩽ 20 MRU) and a non-linear negative trend. Seasonal temperature was correlated with biotinidase results (Pearson's r = 0.79) but not with the observed negative trend (Pearson's r = 0.0025). Time series analysis of biotinidase results grouped by print lot of filter paper revealed that recently printed filter paper cards inhibit biotinidase and that this inhibition resolved over time. This study demonstrates that biotindase activity is inhibited by both increased seasonal temperature and collection on newly printed filter cards. [ABSTRACT FROM AUTHOR]

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Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia. [ABSTRACT FROM AUTHOR]

Background. Phenylketonuria (PKU) and biotinidase deficiency (BD) are autosomal recessive diseases. If they are not identified and treated early, severe intellectual disability and developmental delay occur. This study was conducted to calculate the ten-year incidence of PKU and BD in the Diyarbakır province of Turkey. Methods. This cross-sectional study included patients born between 2011-2020 and diagnosed with PKU and BD. Patients with a clear diagnosis had their records evaluated retrospectively. Results. Between 2011 and 2020, blood was taken from 417,525 newborns’ heels in Diyarbakir province. As a result of further diagnostic testing, 53 PKU (Incidence: 1:7878) and 177 BD (Incidence: 1:2359) were detected. Of the patients with BD, 56% had profound BD and 44% had partial BD. The records of a total of 269 patients (PKU: 25; BD: 123; Hyperphenylalaninemia: 121) were examined. Parents of 65% (n=15) of the patients diagnosed with PKU and 46.6% (n=55) of the patients diagnosed with BD were consanguineous. Conclusions. The incidence of both PKU and BD was found to be high in our region. The high number of consanguineous marriages was regarded as the most important explanation for the high frequency of these illnesses. [ABSTRACT FROM AUTHOR]

Biotinidase deficiency is a rare autosomal recessive inherited metabolic disorder. If not treated in the early neonatal period, profound biotinidase deficiency can cause serious neurological defects, metabolic abnormalities, coma and death. Screening for biotinidase deficiency in newborns and early treatment with free biotin supplementation can prevent all symptoms from occurring. The biotinidase enzyme is encoded by the BTD gene. More than 165 mutations have been identified in the BTD gene. In this case report; a rare case with homozygous double mutation in the BTD gene is presented; and a new allelic variant and genotype is defined. Especially in societies where consanguineous marriages are common; it should be kept in mind that apart from common mutations, different genetic variants may also be seen. [ABSTRACT FROM AUTHOR]

Biotinidase deficiency is a rare genetic disorder brought out by BTD (Biotinidase gene) mutations. Genetic disorders are not curable but there are drugs available for suppressing Biotinidase deficiency. To overcome this problem a vaccine that is much more effective is needed. The goal of the current research is to construct an effective multitudinous epitope-based vaccine. Biotinidase protein was chosen as an objective; various epitopes like T-cells and B-cells were anticipated. Predicted epitopes were shown stability, anti-allergenic, epigenetic, and responsive. Finalist epitopes were significantly antigenic and overlapped. Using In silico Techniques, we predicted the Primary, secondary, and tertiary structures, as also consistency, ligand-receptor association, and MHC class I and II affinity qualities for vaccine designing. The designed vaccine shows high affinity with the human receptors IL-2 alpha and a beta chain. The sequence was then cloned into the plasmid pET-28a. To improve activation in a prokaryotic cell. Docking studies further demonstrated that the forecasted peptides interacted with the HLA-B7 allele. The predicted vaccine could be a promising starting point for vaccine development against genetic disorders. Furthermore, the suggested vaccine must be subjected to in vitro experiment and further confirm to verify its immunogenic and safety profile. [ABSTRACT FROM AUTHOR]

Introduction: Biotinidase (BTD) deficiency may lead to variable neurologic manifestations. Spinal cord involvement can be an unusual presentation of the late-onset disorder. Case Presentation: We describe a six-year-and-ten-month-old girl with a previous history of recurrent upper respiratory tract infections, frequent falling four years before admission, gradual vision loss, and subacute progressive limb weakness followed by flaccid quadriplegia during admission. The measurements of cerebrospinal fluid (CSF) lactate showed significant elevation. And spinal MRI revealed longitudinally extensive cord involvement, mimicking acquired demyelinating syndrome; however, there was no response to plasma exchange. Profound biotinidase deficiency was confirmed by enzyme assay; the patient revealed dramatic recovery after the biotin prescription. The genetic analysis showed ahomozygous missense variant BTD (NM_001370658.1): c.838A>C (p.Asn280His) in exon 4, thereby predicting pathogenic based on the ACMG guidelines. To the best of our knowledge, this is the first Iranian report on BTD deficiency. Conclusions: In summary, in each patient with longitudinally extensive cord involvement not well responding to the conventional treatment, BTD deficiency should be considered on differential. [ABSTRACT FROM AUTHOR]

Biotinidase (BTD) deficiency (OMIM 253260) is an autosomal recessively inherited metabolic disorder resulting from deficient activity of the BTD enzyme, which can cleave and release biotin from a variety of biotin-dependent carboxylases, and is therefore recognized as a tool to recycle biotin. Being a condition caused by variations on BTD gene with a consequence of free biotin shortage, BTD deficiency may impair the activity of biotin-dependent carboxylases, and thus bring about a buildup of potentially toxic compounds in the body, primarily 3-hydroxyisovaleryl-carnitine in plasma as well as 3-hydroxyisovaleric acid in urine. The phenotype of BTD deficiency may vary dramatically, from asymptomatic adults to severe neurological anomalies, even death in infancy. In the present study, we reported on a 5-month-old boy, whose parents sought for medical consultation in our clinic for their son due to his loss of consciousness, repeated tetany, and motor retardation. Detailed clinical features included severe psychomotor retardation, hypotonia, as well as failure to thrive. The brain MRI at 12 months showed cerebellar hypoplasia and multiple foci of leukodystrophy. The result of antiepileptic therapy was not satisfying. During hospitalization, BTD deficiency was suggested by elevated concentration of 3-hydroxyisovaleryl-carnitine in the blood spots and 3-hydroxyisovaleric acid in the urine. The child was then diagnosed with profound BTD deficiency based on the above findings and low BTD enzyme activity. Subsequent mutational analysis revealed a novel homozygous variant, c.637_637delC (p.H213Tfs*51) in exon 4 of BTD gene in the proband, which was recognized as a further support to the diagnosis. Therefore, biotin treatment was started immediately, eventually with satisfactory outcomes achieved in terms of prevention of epileptic seizure, performance in deep tendon reflexes, and improvement of muscular hypotonia, but unfortunately, the therapy failed to show any evident effects on poor feeding and intellectual disability. This painful lesson suggests that newborn screening for inherited metabolic diseases is essential for early identification and treatment, which should have been performed in this case to avoid this tragedy.

Biotinidase deficiency (BD) is a rare autosomal recessive metabolic disease. Previously the disease was identified only by clinical signs and symptoms, and since recently, it has been included in newborn screening programs (NBS) worldwide, though not commonly. In Europe, BD prevalence varies highly among different countries, e.g., from 1:7 116 in Turkey to 1:75 842 in Switzerland. This paper aimed to present the molecular spectrum of BD (profound and partial forms) in Polish patients diagnosed within the national NBS of 1,071,463 newborns. The initial suspicion of BD was based on an abnormal biotinidase activity result determined in a dry blood spot (DBS) by colorimetric and by fluorimetric methods while biochemical verification was determined by serum biotinidase activity (as quantitative analysis). The final diagnosis of BD was established by serum enzyme activity and the BTD gene direct sequencing. The obtained results allowed for the estimation of disease prevalence (1:66,966 births, while 1:178,577 for profound and 1:107,146 for partial forms), and gave novel data on the molecular etiology of BD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose: to review the available literature on the relationship between hearing disorders and Biotinidase deficiency. Methods: a literature search carried out between October 2018 and August 2021, on the following databases: ELSEVIER, MEDLINE, SciELO, LILACS. Descriptors were used in English, Portuguese, and Spanish. PRISMA tools were used to select the articles and STROBE was used to analyze them. Literature Review: the selected articles were published between 1983 and 2020 and answered the guiding question of the research. Observational studies, case series studies, and case reports were included. Articles without a methodology description, or carried out by the same author and with the same sample were excluded. The initial search strategy identified 152 articles. After applying the inclusion and exclusion criteria, 14 articles were selected for this review. Conclusion: the presence of Biotin was often associated with auditory pathways origins. The literature suggested a relationship between Biotinidase deficiency and hearing disorders.

Hypotonia, lethargy, eczema, alopecia, conjunctivitis, ataxia, hearing loss, optic atrophy, cognitive retardation, and seizures can occur in patients with biotinidase deficiency, and it is inherited as autosomal recessive. The aim of this study was to evaluate the cases followed up with the diagnosis of biotinidase deficiency in our unit, in terms of clinical, biochemical and genetic analyses. A total of 112 cases followed up in our centre with the diagnosis of biotinidase deficiency between August 2018–September 2020 were included in the study. Data were collected retrospectively. A total of 112 cases (55.4% male, mean age: 2.2 ± 2.8 years) diagnosed with biotinidase deficiency were evaluated. Diagnoses were made by newborn screening in 90.2% of the cases, by family screening in 4.5%, and by investigating symptoms in 5.4%. The most frequently (27.5%) detected mutations were c.1330G>C (p.D444H)/c.1330G>C (p.D444H) homozygous mutation, followed by (13.0%) c.1330G>C (p.D444H)/c.470G>A (p.R157H) compound heterozygous mutation, and (13.0%) c.470G>A (p.R157H)/c.470G>A (p.R157H) homozygous mutation. Biotinidase enzyme levels were found to be higher in patients with the p.D444H homozygous mutation than patients with other mutations. Biotin treatment was started in all patients with enzyme deficiency. Since the treatment is inexpensive and easily available, it is vital to detect this disease before symptom onset, especially findings related to the central nervous system, hearing and vision loss. In patients diagnosed with enzyme deficiency, the diagnosis should be definitively confirmed by genetic analysis. [ABSTRACT FROM AUTHOR]

Biotinidase deficiency is a rare autosomal recessive neurometabolic disorder resulting in biotin deficiency. Our patient presented with seizures and developmental delay since infancy and was started on megavitamin supplements. At 14 years, she presented with motor regression with encephalopathy after discontinuation of vitamins. There were no skin and hair changes. Magnetic resonance imaging (MRI) of the brain showed bilateral symmetrical posterior putamen signal changes. Tandem mass spectroscopy showed increased methyl malonyl carnitine and 3-OH isovaleryl carnitine. There was a low biotinidase level, and a pathogenic variant in the BTD gene in the next-generation sequencing was identified. Special importance is placed on the unusual symmetric posterior putamen involvement seen in MRI of the brain.

There continues to be questions and misconceptions about the administration of the vitamin, biotin, to children with the inherited biotin-responsive disorder, especially infants. Therefore, this commentary is intended to address the issues of biotin administration for healthcare workers, parents of children with the biotin-responsive disorders and the individuals with the disorders. [ABSTRACT FROM AUTHOR]

Biotinidase deficiency (BD) is an autosomal recessive disorder caused by bi-allelic mutation in the BTD gene. Clinical manifestations in BD mainly depends on residual biotinidase enzyme activity, although there are some exceptions. Broadly BD disorders are classified as profound BD and partial BD. Further profound BD can be early onset, late onset, and sometimes may be asymptomatic. Clinically late-onset profound BD can present with spectrum of manifestations ranging from single organ to multiple organ involvement, typically affecting function of brain, eye, ear, and skin. Here, a first-born child to consanguineous parents with late-onset profound BD presenting with hyperventilation secondary to lactic acidosis, hypotonia, evolving spasticity, and abnormal neuroimaging findings caused by novel homozygous variant, c.466-3T>G in the BTD gene is reported. [ABSTRACT FROM AUTHOR]

Background: Biotinidase deficiency is caused by absent activity of the biotinidase, encoded by the biotinidase gene (BTD). Affected individuals cannot recycle the biotin, leading to heterogeneous symptoms that are primarily neurological and cutaneous. Early treatment with biotin supplementation can prevent irreversible neurological damage and is recommended for patients with profound deficiency, defined as enzyme activity <10% mean normal (MN). Molecular testing has been utilized along with biochemical analysis for diagnosis and management. In this study, our objective was to correlate biochemical phenotype/enzyme activity to BTD genotype in patients for whom both enzyme and molecular testing were performed at our lab, and to review how the correlations inform on variant severity., Methods: We analyzed results of biotinidase enzyme analysis and BTD gene sequencing in 407 patients where samples were submitted to our laboratory from 2008 to 2020., Results: We identified 84 BTD variants; the most common was c.1330G>C, and 19/84 were novel BTD variants. A total of 36 patients had enzyme activity <10% of MN and the most common variant found in this group was c.528G>T. No variant was reported in one patient in the profound deficiency group. The most common variant found in patients with enzyme activity more than 10% MN was c.1330G>C., Conclusions: Although enzyme activity alone may be adequate for diagnosing profound biotinidase deficiency, molecular testing is necessary for accurate carrier screening and in cases where the enzyme activity falls in the range where partial deficiency and carrier status cannot be discriminated., (© 2024 Quest Diagnostics. Pediatrics International published by John Wiley & Sons Australia, Ltd on behalf of Japan Pediatric Society.)