RARE DISEASE
Biotinidase deficiency
Biotinidase deficiency
Biotinidase deficiency
Synonyms: Juvenile-onset multiple carboxylase deficiency, Late-onset multiple carboxylase deficiency
Synonyms: Juvenile-onset multiple carboxylase deficiency, Late-onset multiple carboxylase deficiency
Synonyms: Juvenile-onset multiple carboxylase deficiency, Late-onset multiple carboxylase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Biotinidase deficiency is an autosomal recessive disorder caused by BTD gene mutations, impairing biotin recycling and leading to defective carboxylase enzyme activity. Untreated, it results in metabolic acidosis, neurological symptoms (seizures, hypotonia, developmental delay), and cutaneous manifestations (alopecia, rash). Newborn screening enables early diagnosis, and lifelong biotin supplementation (5–20 mg/day) prevents complications [1][2][9].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare skin diseases
Research Papers
148 drug discovery papers about Biotinidase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
148 drug discovery papers about Biotinidase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Characterization of a Novel BTD Hypomorphic Variant in a Patient with Complex Neurodevelopmental Delay: Resolving Actionable Metabolic Vulnerabilities Beyond Borderline Plasma Biochemistry.
Plasma biochemistry often presents significant limitations in diagnosing borderline metabolic disorders, particularly within complex neurodevelopmental phenotypes. Here, we present the clinical genomic evaluation of a six-year patient presenting with early-onset hypotonia and severe gastrointestinal complications whose newborn screening panel did not evaluate biotinidase (BTD) activity. While initial baseline plasma biochemistry yielded borderline residual BTD function (46% of the population mean), targeted sequencing identified a novel, compound heterozygous hypomorphic variant (p.Thr459Met) in trans with the common p.Asp424His allele. In vitro functional validation confirmed that p.Thr459Met induces severe protein misfolding and intracellular retention, impairing enzyme secretion. Biotin supplementation triggered a documented and favorable therapeutic improvement, establishing this borderline enzymatic background as an actionable metabolic vulnerability unmasked by chronic gastrointestinal stressors. This study underscores the critical value of functional genomic characterization over static enzymatic biomarkers to identify highly treatable metabolic components within heterogeneous clinical landscapes.
2026-07-03 | The gut microbiome as a therapeutic potential for inborn errors of metabolism disorders
Therapeutic approaches for treating inborn abnormalities by modifying the gut microbiome have recently received new focus on diseases. Inborn errors of metabolism (IEMs), which are monogenic inherited metabolic disorders, represent a significant category of conditions characterised by various neurological symptoms in humans. The gut microbiome contains trillions of microorganisms and has emerged as a dynamic and metabolically active ecosystem, playing critical roles in host physiology, digestion, nutrient metabolism, vitamin synthesis, immune system modulation, and neuronal regulation. This narrative review will examine the complex interaction between gut microbiome dysbiosis and specific IEMs, including congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, phenylketonuria, biotinidase deficiency, galactosemia, and G6PD deficiency. Previous studies on the importance of manipulating the microbiome and IEM disorders are scarce. We will also discuss the interrelation between the microbiome and a few IEM treatment strategies and explain the role of future therapeutic development in controlling IEM disorders. Additionally, this review article looks closely at the possible benefits of strategies that change the microbiome, like specific diet changes, probiotics, prebiotics, and customised advanced therapies. In conclusion, harnessing the inner ecosystem of the human gut microbiome offers a compelling and innovative avenue for improving the management and outcomes for individuals affected by inborn errors of metabolism.
2026-06-25 | Multiple Carboxylase Deficiency in an Infant Presenting With Severe Metabolic Acidosis and Sepsis-Like Features: A Case Report and Literature Review.
Multiple carboxylase deficiency (MCD) is a rare, treatable inborn error of biotin metabolism that may present in children in the first year of life with life-threatening metabolic crises. We report a 4-month-old child presenting with persistent seizures, eczematous rash near the orifices, unjustified loss of hair with baldness, and severe metabolic acidosis, initially mimicking septicemia. Urine organic acid investigation showed elevated levels of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxypropionic acid, methylcitrate, and lactate that lead towards MCD. This diagnosis remains unconfirmed, as confirmatory testing (serum biotinidase activity and genetic analysis) was not available at our center. Early initiation of biotin (10 mg/day) led to rapid clinical and biochemical recovery. This particular case depicts the importance of biotin-responsive metabolic disorders in the first year of a child presenting with the classic triad of seizures, dermatitis, and alopecia with metabolic acidosis. Early recognition and prompt initiation of biotin therapy can result in rapid clinical recovery. Timely diagnosis is crucial to prevent avoidable morbidity and long-term neurological sequelae. This case highlights the importance of considering MCD in children. In the first year of life, unexplained metabolic acidosis as timely treatment can be lifesaving.
2026-05-10 | Liver-originated selective autophagy of BTD by alectinib underlies concurrent hepatotoxicity and dermatotoxicity.
Alectinib serves as an indispensable treatment for ALK (ALK receptor tyrosine kinase)-positive non-small-cell lung cancer (NSCLC), yet its hepatotoxicity and dermatotoxicity pose significant clinical concerns due to poorly understood mechanisms. This study demonstrated that alectinib-induced dermatotoxicity was secondary to hepatotoxicity. Integrated multi-omics analysis revealed that alectinib triggered excessive macroautophagic/autophagic degradation of hepatic BTD (biotinidase), causing systemic biotin deficiency that drove both hepatocyte apoptosis and skin barrier dysfunction. Mechanistically, we discovered increased phosphorylation of NBR1 at Ser656, a previously uncharacterized site, which conferred protein stability and contributed to selective BTD degradation. Importantly, exogenous biotin supplementation concurrently mitigated alectinib-induced hepatotoxicity and dermatotoxicity, providing a strategy for safer clinical application. These results uncovered a novel paradigm in drug-induced multi-organ toxicity, in which dysregulated inter-organ crosstalk served as a central mechanistic element.Abbreviations: AAV: adeno-associated virus; ALK: ALK receptor tyrosine kinase; BTD: biotinidase; c-CASP3: cleaved CASP3; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DHE: dihydroethidium; ELISA: enzyme-linked immunosorbent assay; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic--pyruvic transaminase; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HPH: human primary hepatocyte; HRP: horseradish peroxidase; KEGG: Kyoto Encyclopedia of Genes and Genomes; KRT1: keratin 1; KRT5: keratin 5; KRT10: keratin 10; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPHs: mouse primary hepatocytes; MSEA: metabolite set enrichment analysis; OCR: oxygen consumption rates; PBS: phosphate-buffered saline; PCA: principal component analysis; PLS-DA: partial least squares discriminant analysis; PTMs: post-translational modifications; ROS: reactive oxygen species; RSD: relative standard deviation; SD: standard deviation; SQSTM1/p62: sequestosome 1; SRB: sulforhodamine B; TBIL: total bilirubin; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
2026-05-08 | Biotinidase Deficiency in Children: Clinical Outcomes and Neuroimaging Correlations.
Biotinidase Deficiency (BTD) is an autosomal recessive metabolic disorder caused by mutations in the BTD gene, leading to impaired Biotin metabolism and resulting in severe neurological impairments, including seizures and developmental delays. Early diagnosis and treatment are crucial for improving patient outcomes.This study aims to investigate the clinical outcomes and neuroimaging findings in pediatric patients diagnosed with BTD, emphasizing the importance of early detection and multidisciplinary management. This retrospective review was conducted over seven years, analyzing medical records of five patients diagnosed with BTD based on clinical, radiological, and genetic criteria. Brain MRIs were performed, and genetic analyses confirmed the presence of pathogenic mutations in the BTD gene. All patients exhibited characteristic clinical symptoms of BTD, including seizures and developmental delays. MRI findings revealed bilateral symmetrical increased signal intensity on T2-weighted images and low signal intensity on T1-weighted images in subcortical white matter. Treatment with Biotin resolved seizures in all cases; however, irreversible complications such as sensorineural hearing loss were noted in three patients. Early initiation of Biotin therapy correlated with better clinical outcomes. This study highlights the necessity of a multidisciplinary approach to managing BTD, integrating genetic testing, clinical assessments, and neuroimaging. Early diagnosis through newborn screening is vital for improving long-term outcomes in affected children. Future studies should focus on expanding screening initiatives and investigating long-term treatment effects.
proteins
2026-01-28 | Untargeted Metabolomic and Lipidomic Profiling Reveals Distinct Biochemical Patterns in Treated Biotinidase Deficiency.
Biotinidase deficiency is an autosomal recessive disorder that disrupts biotin recycling and multiple carboxylase-dependent pathways. Early and continuous biotin therapy prevents major clinical manifestations, but its long-term biochemical effects remain unclear. This study applied untargeted metabolomic and lipidomic profiling in 54 pediatric patients with genetically confirmed BD receiving regular biotin supplementation and 30 age- and sex-matched controls. Multivariate analyses and pathway enrichment revealed distinct biochemical signatures involving amino acid, energy, and lipid metabolism. Reduced levels of serine, glycine, threonine, and tricarboxylic acid cycle intermediates suggested modified mitochondrial flux, while octopine, exhibiting an approximately 11-fold increase, was the metabolite best able to discriminate between the groups. Lipidomic profiling indicated elevations in sphingolipids, phosphatidylcholines, long-chain fatty acids, and acylcarnitines, consistent with systemic lipid remodeling. These coordinated alterations imply metabolic adaptations to sustained biotin exposure rather than ongoing pathology. Octopine and selected lipid species may represent biochemical indicators of this adaptive state. Overall, the findings highlight that clinically stable children with Biotinidase deficiency exhibit unique metabolic and lipidomic patterns reflecting long-term compensatory mechanisms, underscoring the value of combined omics approaches for understanding disease-specific homeostasis and informing personalized follow-up strategies.
1995-01-01 | Biotinylation of biotinidase following incubation with biocytin
Human serum biotinidase, purified to homogeneity (1920 units/mg protein), was incubated with biocytin prior to electrophoresis and transblotting with avidin-peroxidase. Avidin reacted with biotinidase maximally when incubated at pH 7.5–9, less at pH 7 and none below pH 7. No avidin reactivity occurred when biotinidase was incubated with biotin or in the absence of biocytin. Inclusion of the nucleophilic acceptors, ethanolamine or hydroxylamine, to the incubation mixture with biocytin and biotinidase resulted in loss of avidin reactivity. High concentrations of mercaptoethanol also prevented avidin reactivity. These results suggest that biotinidase can be biotinylated in the presence of biocytin at neutral to alkaline pH probably through a thioester bond formed with a cysteine residue in the active site of the enzyme. Biotinidase may then function as a biotinylating enzyme when incubated with appropriate nucleophilic acceptors.
vaccines
2022-10-04 | Developing a Next-generation Multitudinous Epitope-based Vaccine Against Biotinidase Deficiency; An Immunoinformatics-based Approach
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.
gene therapies
2025-09-27 | Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study.
Background: Biotinidase deficiency (BD) is a common autosomal recessive metabolic disorder in Qatar and the Arab world. It is treatable if detected early, making it essential to understand the genetic variants involved. This study aimed to investigate the carrier frequency of BD-related variants in a healthy Qatari population, reflecting the genetic landscape of the broader Middle Eastern region; classify them using bioinformatics tools; and compare findings with global datasets. Methods: Whole-genome sequencing data from 14,669 participants in the Qatar Genome Program (QGP), a multiethnic cohort including Qatari nationals and long-term residents (≥15 years), were analyzed to identify BTD variants. A total of 723, including 653 single-nucleotide polymorphisms (SNPs) and 70 structural variants (SVs) in BTD associated with BD, were screened against the Qatari cohort and compared with international data. In silico tools were used to assess variant pathogenicity, conservation, and protein stability. Molecular dynamics (MD) simulations were performed to evaluate structural and functional changes in the BTD. Results: A total of 80 SNPs and 3 SVs were identified, among which 21 variants (19 SNPs and 2 SVs) were classified as pathogenic or likely pathogenic, according to ClinVar. The carrier frequency of BTD-related variants in Qatar was 1:20, primarily driven by rs13078881 (D444H). Molecular dynamics (MD) simulations revealed significant conformational changes with H323R, D444H, and P497S, which demonstrated increased flexibility (higher RMSD/RMSF and PCA trace values). Additionally, R209C and D444H showed reduced compactness (higher Rg) and distinct energy minima, suggesting altered conformational states. Conclusions: This study demonstrates a high carrier frequency of pathogenic BTD variants in the Qatari population, underscoring the need to integrate these SNPs and SVs into the national genomic neonatal screening program (gNBS) for enhanced early detection and treatment strategies. The mild structural deviations observed in the D444H mutant through MD simulations may explain its association with milder clinical phenotypes of BTD, offering valuable insights for personalized therapeutic approaches.
2024-08-15 | Oxford nanopore sequencing-based assay for BTD gene screening: Design, clinical validation, and variant frequency assessment in the Turkish population.
Biotinidase deficiency (BTD) is an autosomal recessive disorder characterized by impaired recycling of the water-soluble vitamin biotin which leads to a spectrum of clinical manifestations ranging from mild to severe, including mainly neurological and cutaneous symptoms. Biotin supplementation is a cornerstone of treatment, but diagnosis often relies on measuring serum enzyme activity, which needs to be confirmed by genetic analysis. Thus, molecular methods become necessary in the differential diagnosis of BTD. Accordingly, countries with a high-incidence have implemented next-generation sequencing (NGS) techniques to newborn screening programs for BT. Nevertheless, NGS platforms, while well-established, present challenges in cost, labor, accessibility, and duration for newborn screening programs targeting BTD, therefore these limitations necessitate the exploration of alternative systems to ensure efficient and widespread screening. Here, third-generation sequencing platforms, notably Oxford Nanopore Technology (ONT), present promising solutions to the associated challenges. Hence, in the present study, we aimed to develop an ONT-based assay for the screening of BTD gene. After designing and optimizing primers for long-PCR using reference DNA, we assessed the performance of the ONT assay in BTD patients previously diagnosed by enzyme assay and confirmed using Illumina-based sequencing. The results demonstrate a strong correlation between the two methods, indicating the reliability of the ONT-based assay. Moreover, this first in-house single gene testing specifically tailored for BTD successfully detected previously known genetic variants with high sequencing depths, affirming the effectiveness of ONT-based sequencing in human genetics.
small molecules
2026-08-13 | Characterization of a Novel BTD Hypomorphic Variant in a Patient with Complex Neurodevelopmental Delay: Resolving Actionable Metabolic Vulnerabilities Beyond Borderline Plasma Biochemistry.
Plasma biochemistry often presents significant limitations in diagnosing borderline metabolic disorders, particularly within complex neurodevelopmental phenotypes. Here, we present the clinical genomic evaluation of a six-year patient presenting with early-onset hypotonia and severe gastrointestinal complications whose newborn screening panel did not evaluate biotinidase (BTD) activity. While initial baseline plasma biochemistry yielded borderline residual BTD function (46% of the population mean), targeted sequencing identified a novel, compound heterozygous hypomorphic variant (p.Thr459Met) in trans with the common p.Asp424His allele. In vitro functional validation confirmed that p.Thr459Met induces severe protein misfolding and intracellular retention, impairing enzyme secretion. Biotin supplementation triggered a documented and favorable therapeutic improvement, establishing this borderline enzymatic background as an actionable metabolic vulnerability unmasked by chronic gastrointestinal stressors. This study underscores the critical value of functional genomic characterization over static enzymatic biomarkers to identify highly treatable metabolic components within heterogeneous clinical landscapes.
2026-07-03 | The gut microbiome as a therapeutic potential for inborn errors of metabolism disorders
Therapeutic approaches for treating inborn abnormalities by modifying the gut microbiome have recently received new focus on diseases. Inborn errors of metabolism (IEMs), which are monogenic inherited metabolic disorders, represent a significant category of conditions characterised by various neurological symptoms in humans. The gut microbiome contains trillions of microorganisms and has emerged as a dynamic and metabolically active ecosystem, playing critical roles in host physiology, digestion, nutrient metabolism, vitamin synthesis, immune system modulation, and neuronal regulation. This narrative review will examine the complex interaction between gut microbiome dysbiosis and specific IEMs, including congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, phenylketonuria, biotinidase deficiency, galactosemia, and G6PD deficiency. Previous studies on the importance of manipulating the microbiome and IEM disorders are scarce. We will also discuss the interrelation between the microbiome and a few IEM treatment strategies and explain the role of future therapeutic development in controlling IEM disorders. Additionally, this review article looks closely at the possible benefits of strategies that change the microbiome, like specific diet changes, probiotics, prebiotics, and customised advanced therapies. In conclusion, harnessing the inner ecosystem of the human gut microbiome offers a compelling and innovative avenue for improving the management and outcomes for individuals affected by inborn errors of metabolism.
2026-06-25 | Multiple Carboxylase Deficiency in an Infant Presenting With Severe Metabolic Acidosis and Sepsis-Like Features: A Case Report and Literature Review.
Multiple carboxylase deficiency (MCD) is a rare, treatable inborn error of biotin metabolism that may present in children in the first year of life with life-threatening metabolic crises. We report a 4-month-old child presenting with persistent seizures, eczematous rash near the orifices, unjustified loss of hair with baldness, and severe metabolic acidosis, initially mimicking septicemia. Urine organic acid investigation showed elevated levels of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxypropionic acid, methylcitrate, and lactate that lead towards MCD. This diagnosis remains unconfirmed, as confirmatory testing (serum biotinidase activity and genetic analysis) was not available at our center. Early initiation of biotin (10 mg/day) led to rapid clinical and biochemical recovery. This particular case depicts the importance of biotin-responsive metabolic disorders in the first year of a child presenting with the classic triad of seizures, dermatitis, and alopecia with metabolic acidosis. Early recognition and prompt initiation of biotin therapy can result in rapid clinical recovery. Timely diagnosis is crucial to prevent avoidable morbidity and long-term neurological sequelae. This case highlights the importance of considering MCD in children. In the first year of life, unexplained metabolic acidosis as timely treatment can be lifesaving.
2026-05-10 | Liver-originated selective autophagy of BTD by alectinib underlies concurrent hepatotoxicity and dermatotoxicity.
Alectinib serves as an indispensable treatment for ALK (ALK receptor tyrosine kinase)-positive non-small-cell lung cancer (NSCLC), yet its hepatotoxicity and dermatotoxicity pose significant clinical concerns due to poorly understood mechanisms. This study demonstrated that alectinib-induced dermatotoxicity was secondary to hepatotoxicity. Integrated multi-omics analysis revealed that alectinib triggered excessive macroautophagic/autophagic degradation of hepatic BTD (biotinidase), causing systemic biotin deficiency that drove both hepatocyte apoptosis and skin barrier dysfunction. Mechanistically, we discovered increased phosphorylation of NBR1 at Ser656, a previously uncharacterized site, which conferred protein stability and contributed to selective BTD degradation. Importantly, exogenous biotin supplementation concurrently mitigated alectinib-induced hepatotoxicity and dermatotoxicity, providing a strategy for safer clinical application. These results uncovered a novel paradigm in drug-induced multi-organ toxicity, in which dysregulated inter-organ crosstalk served as a central mechanistic element.Abbreviations: AAV: adeno-associated virus; ALK: ALK receptor tyrosine kinase; BTD: biotinidase; c-CASP3: cleaved CASP3; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DHE: dihydroethidium; ELISA: enzyme-linked immunosorbent assay; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic--pyruvic transaminase; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HPH: human primary hepatocyte; HRP: horseradish peroxidase; KEGG: Kyoto Encyclopedia of Genes and Genomes; KRT1: keratin 1; KRT5: keratin 5; KRT10: keratin 10; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPHs: mouse primary hepatocytes; MSEA: metabolite set enrichment analysis; OCR: oxygen consumption rates; PBS: phosphate-buffered saline; PCA: principal component analysis; PLS-DA: partial least squares discriminant analysis; PTMs: post-translational modifications; ROS: reactive oxygen species; RSD: relative standard deviation; SD: standard deviation; SQSTM1/p62: sequestosome 1; SRB: sulforhodamine B; TBIL: total bilirubin; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
2026-05-08 | Biotinidase Deficiency in Children: Clinical Outcomes and Neuroimaging Correlations.
Biotinidase Deficiency (BTD) is an autosomal recessive metabolic disorder caused by mutations in the BTD gene, leading to impaired Biotin metabolism and resulting in severe neurological impairments, including seizures and developmental delays. Early diagnosis and treatment are crucial for improving patient outcomes.This study aims to investigate the clinical outcomes and neuroimaging findings in pediatric patients diagnosed with BTD, emphasizing the importance of early detection and multidisciplinary management. This retrospective review was conducted over seven years, analyzing medical records of five patients diagnosed with BTD based on clinical, radiological, and genetic criteria. Brain MRIs were performed, and genetic analyses confirmed the presence of pathogenic mutations in the BTD gene. All patients exhibited characteristic clinical symptoms of BTD, including seizures and developmental delays. MRI findings revealed bilateral symmetrical increased signal intensity on T2-weighted images and low signal intensity on T1-weighted images in subcortical white matter. Treatment with Biotin resolved seizures in all cases; however, irreversible complications such as sensorineural hearing loss were noted in three patients. Early initiation of Biotin therapy correlated with better clinical outcomes. This study highlights the necessity of a multidisciplinary approach to managing BTD, integrating genetic testing, clinical assessments, and neuroimaging. Early diagnosis through newborn screening is vital for improving long-term outcomes in affected children. Future studies should focus on expanding screening initiatives and investigating long-term treatment effects.
proteins
2026-01-28 | Untargeted Metabolomic and Lipidomic Profiling Reveals Distinct Biochemical Patterns in Treated Biotinidase Deficiency.
Biotinidase deficiency is an autosomal recessive disorder that disrupts biotin recycling and multiple carboxylase-dependent pathways. Early and continuous biotin therapy prevents major clinical manifestations, but its long-term biochemical effects remain unclear. This study applied untargeted metabolomic and lipidomic profiling in 54 pediatric patients with genetically confirmed BD receiving regular biotin supplementation and 30 age- and sex-matched controls. Multivariate analyses and pathway enrichment revealed distinct biochemical signatures involving amino acid, energy, and lipid metabolism. Reduced levels of serine, glycine, threonine, and tricarboxylic acid cycle intermediates suggested modified mitochondrial flux, while octopine, exhibiting an approximately 11-fold increase, was the metabolite best able to discriminate between the groups. Lipidomic profiling indicated elevations in sphingolipids, phosphatidylcholines, long-chain fatty acids, and acylcarnitines, consistent with systemic lipid remodeling. These coordinated alterations imply metabolic adaptations to sustained biotin exposure rather than ongoing pathology. Octopine and selected lipid species may represent biochemical indicators of this adaptive state. Overall, the findings highlight that clinically stable children with Biotinidase deficiency exhibit unique metabolic and lipidomic patterns reflecting long-term compensatory mechanisms, underscoring the value of combined omics approaches for understanding disease-specific homeostasis and informing personalized follow-up strategies.
1995-01-01 | Biotinylation of biotinidase following incubation with biocytin
Human serum biotinidase, purified to homogeneity (1920 units/mg protein), was incubated with biocytin prior to electrophoresis and transblotting with avidin-peroxidase. Avidin reacted with biotinidase maximally when incubated at pH 7.5–9, less at pH 7 and none below pH 7. No avidin reactivity occurred when biotinidase was incubated with biotin or in the absence of biocytin. Inclusion of the nucleophilic acceptors, ethanolamine or hydroxylamine, to the incubation mixture with biocytin and biotinidase resulted in loss of avidin reactivity. High concentrations of mercaptoethanol also prevented avidin reactivity. These results suggest that biotinidase can be biotinylated in the presence of biocytin at neutral to alkaline pH probably through a thioester bond formed with a cysteine residue in the active site of the enzyme. Biotinidase may then function as a biotinylating enzyme when incubated with appropriate nucleophilic acceptors.
vaccines
2022-10-04 | Developing a Next-generation Multitudinous Epitope-based Vaccine Against Biotinidase Deficiency; An Immunoinformatics-based Approach
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.
gene therapies
2025-09-27 | Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study.
Background: Biotinidase deficiency (BD) is a common autosomal recessive metabolic disorder in Qatar and the Arab world. It is treatable if detected early, making it essential to understand the genetic variants involved. This study aimed to investigate the carrier frequency of BD-related variants in a healthy Qatari population, reflecting the genetic landscape of the broader Middle Eastern region; classify them using bioinformatics tools; and compare findings with global datasets. Methods: Whole-genome sequencing data from 14,669 participants in the Qatar Genome Program (QGP), a multiethnic cohort including Qatari nationals and long-term residents (≥15 years), were analyzed to identify BTD variants. A total of 723, including 653 single-nucleotide polymorphisms (SNPs) and 70 structural variants (SVs) in BTD associated with BD, were screened against the Qatari cohort and compared with international data. In silico tools were used to assess variant pathogenicity, conservation, and protein stability. Molecular dynamics (MD) simulations were performed to evaluate structural and functional changes in the BTD. Results: A total of 80 SNPs and 3 SVs were identified, among which 21 variants (19 SNPs and 2 SVs) were classified as pathogenic or likely pathogenic, according to ClinVar. The carrier frequency of BTD-related variants in Qatar was 1:20, primarily driven by rs13078881 (D444H). Molecular dynamics (MD) simulations revealed significant conformational changes with H323R, D444H, and P497S, which demonstrated increased flexibility (higher RMSD/RMSF and PCA trace values). Additionally, R209C and D444H showed reduced compactness (higher Rg) and distinct energy minima, suggesting altered conformational states. Conclusions: This study demonstrates a high carrier frequency of pathogenic BTD variants in the Qatari population, underscoring the need to integrate these SNPs and SVs into the national genomic neonatal screening program (gNBS) for enhanced early detection and treatment strategies. The mild structural deviations observed in the D444H mutant through MD simulations may explain its association with milder clinical phenotypes of BTD, offering valuable insights for personalized therapeutic approaches.
2024-08-15 | Oxford nanopore sequencing-based assay for BTD gene screening: Design, clinical validation, and variant frequency assessment in the Turkish population.
Biotinidase deficiency (BTD) is an autosomal recessive disorder characterized by impaired recycling of the water-soluble vitamin biotin which leads to a spectrum of clinical manifestations ranging from mild to severe, including mainly neurological and cutaneous symptoms. Biotin supplementation is a cornerstone of treatment, but diagnosis often relies on measuring serum enzyme activity, which needs to be confirmed by genetic analysis. Thus, molecular methods become necessary in the differential diagnosis of BTD. Accordingly, countries with a high-incidence have implemented next-generation sequencing (NGS) techniques to newborn screening programs for BT. Nevertheless, NGS platforms, while well-established, present challenges in cost, labor, accessibility, and duration for newborn screening programs targeting BTD, therefore these limitations necessitate the exploration of alternative systems to ensure efficient and widespread screening. Here, third-generation sequencing platforms, notably Oxford Nanopore Technology (ONT), present promising solutions to the associated challenges. Hence, in the present study, we aimed to develop an ONT-based assay for the screening of BTD gene. After designing and optimizing primers for long-PCR using reference DNA, we assessed the performance of the ONT assay in BTD patients previously diagnosed by enzyme assay and confirmed using Illumina-based sequencing. The results demonstrate a strong correlation between the two methods, indicating the reliability of the ONT-based assay. Moreover, this first in-house single gene testing specifically tailored for BTD successfully detected previously known genetic variants with high sequencing depths, affirming the effectiveness of ONT-based sequencing in human genetics.
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