Biotinidase Deficiency: The First Reported Case from Nepal

Biotinidase Deficiency: The First Reported Case from Nepal | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Biotinidase Deficiency: The First Reported Case from Nepal Jagdish Kunwar, Bijay Kunwar, Anup Ghimire, Aramva Bikram Adhikari, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5762621/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Jun, 2025 Read the published version in BMC Pediatrics → Version 1 posted 15 You are reading this latest preprint version Abstract Background Biotinidase deficiency (BTD) is a rare genetic condition inherited in an autosomal recessive pattern that affects multiple systems. Biotinidase (EC 3.5.1.12) cleaves the vitamin, biotin, from the biocytin and the dietary protein-bound sources, and recycles the biotin. It manifests with a range of neurocutaneous symptoms, including seizures, hypotonia, ataxia, skin rashes, alopecia, hearing loss, optic atrophy, and metabolic crises that resemble sepsis, delay in identification and prompt treatment, results in irreversible brain damage, coma, and, in severe cases, death. Newborn screening can help in early diagnosis as it is amenable to treatment with pharmacological doses of biotin. There has been no study from Nepal about Biotinidase deficiency highlighting the clinical features, diagnosis and response to treatment. Case presentation An 18-month-old male, born at term via normal delivery to non-consanguineous parents, with a normal neonatal period, presented to Kanti Children’s Hospital (KCH) with a 3-month history of multiple abnormal body movements and developmental regression. There were no known familial or genetic illnesses. Developmentally, he achieved milestones appropriately until 12 months of age, since then 15 months of age he had development regression. Ophthalmology study showed bilateral pallor of optic disc. MRI, EEG was done thinking of the inborn error of metabolism. A whole genome sequencing identified a heterozygous pathogenic variant (c.38_44delinsTCC, p.Cys13Phefs*36) in the BTD gene. Serum biotinidase enzyme activity was quantified, 3.20 nmol/min/mL (Normal > 5.00 nmol/min/mL) measured via spectrophotometry, The diagnosis of biotinidase deficiency (BTD) was confirmed. He was then managed with oral biotin 10 mg and supportive care. Follow-up assessments at 3, 6, and 12 months post-treatment showed remarkable improvement. Conclusions This case highlights the clinical and diagnostic challenges of biotinidase deficiency (BTD) in resource-limited settings like Nepal, where the absence of newborn screening and limited molecular diagnostic capacity delay timely intervention. Increased clinician awareness, and local research to better understand the spectrum of BTD mutations, their clinical implications and to analyze the effectiveness of implementation of newborn screening programs. Early recognition and treatment of BTD can significantly improve patient outcomes and reduce the burden of this potentially devastating yet treatable disorder. Biotinidase Biotin MCD Newborn screening Figures Figure 1 Background Biotinidase deficiency (BTD) is a rare genetic condition inherited in an autosomal recessive pattern that affects multiple systems ( 1 , 2 ). The global incidence of BTD varies from 1:40,000 to 1:60,000 births ( 3 ). Biotinidase (EC 3.5.1.12) cleaves the vitamin, biotin, from the biocytin and the dietary protein-bound sources, and recycles the biotin ( 1 ). The BTD gene is located on chromosome 3p25 and consists of four exons, with a total length of 1629 base pairs ( 4 , 5 ). More than 200 mutations have been identified in BTD gene ( 6 ). The diagnosis of BTD is made by biotinidase enzyme activity in plasma or serum ( 1 ). Detection of increased urinary levels of 3-hydroxyisovaleric, 3-hydroxypropionic, lactic acid, and 3-methylcrotonyl glycine on untreated patients can aid the diagnosis ( 7 ). Whole genome sequencing (WGS) leads to diagnosis. BTD can develop at any ages, ranging from infancy to adulthood but is more common in infancy ( 8 ). BTD manifests with a range of neurocutaneous symptoms, including seizures, hypotonia, ataxia, skin rashes, alopecia, hearing loss, optic atrophy, and metabolic crises that resemble sepsis, delay in identification and prompt treatment, results in irreversible brain damage, coma, and, in severe cases, death ( 9 ). Newborn screening is important for early diagnosis and treatment as it can be treated with pharmacological doses of biotin ( 3 , 8 ). There have been no studies conducted from Nepal about Biotinidase deficiency highlighting the clinical features, diagnosis and response to treatment ( 10 ). Here we describe the first reported case of biotinidase deficiency from Nepal. Case Presentation Clinical Presentation An 18-month-old male, born at term via normal vaginal delivery to non-consanguineous parents, with an unremarkable neonatal period, presented to Kanti Children’s Hospital with a three-month history of multiple abnormal body movements and developmental regression. The child was exclusively breastfed until six months of age, followed by the gradual introduction of complementary feeding. There was no known family history (Supplementary file S1) of genetic or neurological disorders. Developmental milestones were appropriate until 12 months of age, at which point he was able to stand with support, walk with occasional falls, and attempt independent standing. He demonstrated a mature pincer grasp, responded to his name, engaged in simple ball games, vocalized 1–2 meaningful words, recognized sounds, and oriented toward their source. The first seizure episode occurred at seven months of age and was associated with fever. By 13 months, he had experienced three episodes of generalized tonic-clonic seizures (GTCS). At 12 months, he had an episode of status epilepticus requiring intervention at another center. At 15 months, he was admitted to the pediatric intensive care unit (PICU) at our center due to a lower respiratory tract infection and GTCS. Following this admission, he exhibited significant developmental regression, losing previously acquired motor, cognitive, and social milestones. He was unable to walk independently, creep upstairs, initiate scribbling, speak words, or imitate parental activities. His mother reported that he only adjusted his head position to follow objects instead of actively tracking them. At the presentation, the child exhibited spontaneous limb movements and cooing but lacked neck holding and rolling over. There were no noted comorbidities. Anthropometric measurements revealed a weight of 9 kg (10th percentile), length of 76 cm (15th percentile), and head circumference of 45 cm (10th percentile). Neurological examination showed that the child was awake but unresponsive to his surroundings. Examination of the skull, neck, and spine revealed no signs of meningeal irritation, malformations, injuries, pain, or tenderness. Cranial nerve assessment showed normal pupillary response to light and the ability to follow objects. Fundoscopic examination revealed bilateral optic disc pallor. Facial symmetry was preserved with an intact smile response. The child responded to auditory stimuli and was able to swallow milk. The tongue appeared normal without fasciculations or asymmetry. Motor examination revealed symmetrical muscle bulk without fasciculations or involuntary movements. Muscle tone was decreased (hypotonia) in all flexor and extensor groups. Muscle power was 2/5 in both the upper and lower extremities. Bilateral deep tendon reflexes at the knee and ankle were hyperreflexic. Clonus was absent, and the bilateral plantar response was mute. Systemic examination revealed no abnormalities. Investigations The working diagnosis of neurodegenerative delay prompted an extensive evaluation. EEG revealed an abnormal sleep pattern with epileptiform discharges in the right centro-temporal region, suggestive of encephalopathy. Brain MRI demonstrated prominent frontal sulcal spaces, consistent with benign enlargement of the subarachnoid spaces in infancy (BESSI), along with delayed myelination of the rostrum, genu, and trunk/body of the corpus callosum. Ophthalmological examination revealed bilateral optic disc pallor, while hearing assessment was normal. Laboratory tests, including thyroid function, vitamin D levels, and electrolytes, were within normal limits. Arterial blood gas (ABG) analysis performed during the ICU stay showed a pH of 7.30 (normal range: 7.35–7.45), indicating metabolic acidosis with elevated lactate levels. Whole-genome sequencing (WGS) identified a heterozygous pathogenic variant (c.38_44delinsTCC, p.Cys13Phefs*36) in the biotinidase (BTD) gene and a heterozygous variant of uncertain significance (c.2921A > G (p.His974Arg)) in the IFIH1 gene (Supplementary file S1). Given that IFIH1 mutations are associated with Aicardi–Goutières syndrome, a condition with overlapping clinical features of neuroregression, seizures, and encephalopathy, and that biotinidase deficiency (BTD) is an autosomal recessive disorder, there was initial diagnostic uncertainty. However, as BTD deficiency is a treatable condition, biotinidase enzyme activity was retrospectively assessed, revealing a reduced level of 3.20 nmol/min/mL (normal > 5.00 nmol/min/mL). Given the significant clinical response to biotin supplementation, a diagnosis of biotinidase deficiency was confirmed. Table 1 Report of whole exome sequencing + mitochondrial genome sequencing using next generation sequencing (NGS) of EDTA blood sample. Report of whole exome sequencing + mitochondrial genome sequencing using next generation sequencing (NGS) of EDTA blood sample Gene Disease and Inheritance (OMIM phenotype number) Genomic Position Variant details BTD Biotinidase deficiency (AR - Autosomal Recessive) (OMIM ID- 253260) Chr3:g.15635477 15635483 Exon/ Intron No: Exon 2 Nucleotide change: c.38_44delinsTCC Amino Acid Change: (p.Cys13Phefs*36) Transcript Id: NM_001370658.1 Molecular consequence Allele Frequency Zygosity ACMG Classification Frameshift 1000 Genome: Novel Heterozygous Pathogenic (PVS1, PM2, PP5) gnomAD: 0.055% Management and Outcome The child was started on oral biotin at a dose of 10 mg daily, based on clinical guidelines for biotinidase deficiency. No other pharmacological treatments were administered. Supportive care included physiotherapy and developmental interventions to address hypotonia and developmental delays. Follow-up assessments at 3, 6, and 12 months post-treatment showed remarkable improvement. At 3 months of starting treatment, neurodevelopmental milestones were appropriate for age, and the child had resumed head control and rolling over, he ran, scribbled on paper, played games and toys, made simple sentences like asking for food. By 12 months of follow up, his development was normal, with significant improvements in gross and fine motor skills, language, and social interactions. These milestones were monitored using the Denver Developmental Screening Test (DDST). A genetic counseling consultation was held with the family. Detailed information about how the condition is inherited, the risks of being carriers, and the chances of passing it on to future children. The options like carrier screening, prenatal testing, and possible reproductive choices, ensuring the parents were aware of their options moving forward. Beyond the medical details, the family was educated about the disorder itself, its symptoms and available treatments and how it might affect other relatives. Counselling also discussed the implications for other family members, including the possibility that siblings or extended relatives may also be carriers or affected. Discussion Biotin is a vital cofactor for four human carboxylases essential to glucose, fatty acid, and amino acid metabolism ( 3 ). Biotinidase's main function is to recycle biotin from biocytin, degraded holo-carboxylases, and biotin bound to dietary proteins ( 3 , 11 , 12 ). The free biotin then replenishes the biotin pool and activates carboxylases—propionyl-CoA carboxylase, β-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase that is essential for gluconeogenesis, breakdown of branched-chain amino acids, and fatty acid synthesis ( 3 , 11 , 12 ). The BTD gene, located on chromosome 3p25, comprises four exons spanning 1,629 base pairs ( 4 , 5 ). More than 200 mutations have been documented in patients with biotinidase deficiency, including missense, nonsense, and compound allelic mutations( 6 ). The deficiency of this enzyme was first reported and characterized by Wolf et al. ( 3 ). This case underscores the clinical significance of biotinidase deficiency (BTD), emphasizing the challenges of early diagnosis in resource-limited settings like Nepal. In such contexts, the absence of newborn screening and limited molecular diagnostic capacity hinder timely intervention, making clinical acumen and symptomatic presentation crucial for diagnosis. MCD has two forms: neonatal and juvenile ( 13 ). The neonatal form, resulting from holocarboxylase synthetase deficiency, typically presents between birth to 15 months and is characterized by feeding problems, seizures, hypotonia, developmental delays, and ketoacidotic coma ( 13 , 14 ). Skin manifestations are rare but may include a seborrheic rash and alopecia( 13 – 15 ). The juvenile form, due to biotinidase deficiency, starts after 3 months with predominant neurocutaneous features, including seizures, hypotonia, ataxia, skin rash, alopecia, hearing loss, optic atrophy, and metabolic crises like sepsis ( 13 ). Dermatological manifestations range from seborrheic dermatitis-like eruptions to severe crusting and secondary infections, likely due to abnormalities in lipid metabolism and altered skin composition ( 15 ). Neurological complications, including developmental delays, optic atrophy, and sensorineural hearing loss, may persist if biotin therapy is delayed ( 8 , 13 ). Significantly, about 76% of untreated patients with profound BTD develop sensorineural hearing loss ( 16 ). However, our case though being a juvenile form didn’t have any immunological or cutaneous manifestations. A review by Tankeu et al. ( 14 ) highlights that of 1,113 individuals diagnosed with BTD over 40 years, 51.5% were identified through newborn screening, 43.3% presented symptomatically, and 5.2% were identified via family screening ( 14 ). Multisystem involvement was common, affecting the nervous system (67.2%), skin (53.7%), eyes (34.4%), auditory system (26.9%), and respiratory system (17.8%). Although mortality is rare (1.6%), it is associated with delayed diagnosis or unavailability of biotin therapy( 14 , 17 ). The metabolic disorders (fatty acid oxidation defects, organic acidurias), neurological conditions (cerebral palsy, seizure disorders), vitamin deficiencies (B12), inborn errors of metabolism (homocystinuria, maple syrup urine disease), mitochondrial disorders and genetic syndromes (Rett, Angelman) were taken into consideration. In this case, provisional diagnosis of inborn error of metabolism was based on clinical and laboratory findings, which was further confirmed by biochemical evaluation, which showed genetic mutation and enzyme activity below normal. Differential diagnoses, including other metabolic and primary immune deficiencies, were excluded through metabolic profiles and clinical presentation. As molecular genetic testing to identify biallelic pathogenic variants in BTD is definitive, in this case it was found to have heterozygous variants in both the IFIH1 and BTD genes on whole-genome sequencing (WGS). IFIH1 gene mutations may manifest as Aicardi–Goutières syndrome having a presentation similar to BTD deficiency ( 18 ). Since the clinical presentation overlapped with features of both conditions, and although heterozygous BTD variants are typically non-pathogenic, epigenetic alterations may contribute to variable disease severity. Given that biotinidase deficiency is a treatable disorder, we retrospectively assessed biotinidase enzyme activity to confirm or rule out its involvement in the patient’s condition. Whole-genome sequencing (WGS) may not always detect all types of pathogenic variants, such as deep intronic mutations, large deletions, or structural variations that affect gene function ( 19 , 20 ). The patient may harbor a second pathogenic variant that was missed due to technical limitations of sequencing or coverage gaps ( 19 , 20 ). Variants in non-coding regulatory regions of the BTD gene could reduce gene expression, effectively mimicking a biallelic loss-of-function state. Altered splicing due to deep intronic mutations could lead to significantly reduced biotinidase enzyme activity. IFIH1 gene may be a genetic modifier in biotin metabolism pathways and thus may have contributed to a phenotypic expression of BTD deficiency even in heterozygous condition, which may need further genetic analysis. However due to limited availability and cost constraints in Nepal pose significant barriers, incorporating cost-effective diagnostic strategies is critical to improving detection and outcomes. Pharmacological doses of biotin have demonstrated remarkable efficacy in preventing or reversing symptoms. However, irreversible complications, such as hearing and vision loss, highlight the importance of early intervention ( 21 , 22 ). The normalization of biotinidase activity, particularly in patients with partial deficiency harboring the p.Asp444His variant, illustrates the efficacy of biotin therapy ( 23 ). Although genotype-phenotype correlations in BTD remain poorly understood, mutations such as c.38_44delinsTCC, identified in this case, warrant further study to elucidate their clinical significance. Comparison with existing literature reveals variability in the age of onset and phenotypic severity of BTD. While symptoms typically manifest between 2 weeks and 2 years of age, late presentations have been reported ( 24 , 25 ). Mutations such as p.Cys13Phefs*36 have been associated with diverse phenotypic outcomes, underscoring the need for comprehensive studies to better understand genotype-phenotype relationships ( 26 ). Newborn screening (NBS) for BTD is an effective tool for early detection which is already adopted by various highly prevalent countries like Israel. As the real epidemiology of BTD deficiency in Nepal is not known the clinical applicability of newborn screening cannot be emphasized. Raising awareness among clinicians is critical, especially in regions lacking newborn screening programs. Introducing such programs could substantially reduce the burden of delayed diagnosis and its associated complications. Additionally, antenatal biotin supplementation in at-risk pregnancies represents a potential strategy to mitigate early complications ( 27 ), Despite the global burden, the clinical profile, diagnostic challenges, and treatment outcomes of BTD remain unstudied in Nepal. This case emphasizes the urgent need for local research to inform diagnostic and therapeutic strategies. Conclusion This case highlights the clinical and diagnostic challenges of biotinidase deficiency (BTD) in resource-limited settings like Nepal, where the absence of newborn screening and limited molecular diagnostic capacity delay timely intervention. Despite these challenges, the patient responded favorably to pharmacological doses of biotin, underscoring the efficacy of this readily available and economical therapy. However, the persistence of irreversible complications, such as hearing loss, reiterates the critical importance of early diagnosis and intervention. This report emphasizes the need for increased clinician awareness, and local research to better understand the spectrum of BTD mutations, their clinical implications and to analyze the effectiveness of implementation of newborn screening programs. Early recognition and treatment of BTD can significantly improve patient outcomes and reduce the burden of this potentially devastating yet treatable disorder. Abbreviations BTD: Biotinidase Deficiency WGS: Whole Genome Sequencing KCH: Kanti Children’s Hospital GTCS: Generalised Tonic Clonic Seizure DDST: Denver Developmental Screening Test Declarations Ethical Approval Case reports are exempt from ethical approval in our institution, Kanti Children’s Hospital, Maharajgunj, Kathmandu. Consent to Participate and Publication Written informed consent was obtained from the patient’s parents for participation and publication of this case reports and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests None Source of funding No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Clinical trial number Not applicable Authors contribution BK and AG conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. ABA, BA and ST designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. JK and BPM conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Acknowledgements The authors thank the staff and participants of this study for their important contributions. References Wolf B, Grier RE, Allen RJ, Goodman SI, Kien CL. Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. Clinica Chimica Acta. 1983 Jul 15;131(3):273–81. Wolf B, Grier RE, Secor McVoy JR, Heard GS. Biotinidase deficiency: A novel vitamin recycling defect. J Inherit Metab Dis. 1985 Mar;8(1 Supplement):53–8. Canda E, Uçar SK, Çoker M. Biotinidase Deficiency: Prevalence, Impact And Management Strategies. Pediatric Health Med Ther [Internet]. 2020 [cited 2024 Sep 9];11:127. Available from: /pmc/articles/PMC7211084/ Knight HC, Reynolds TR, Meyers GA, Pomponio RJ, Buck GA, Wolf B. Structure of the human biotinidase gene. Mammalian Genome. 1998 Apr;9(4):327–30. Cole$ H, Reynolds$ TR, Lockyern JM, Buck% ’i’d Denson% GA, Spence$ll JE, Hymess J, et al. Human serum biotinidase. cDNA cloning, sequence, and characterization. ASBMB [Internet]. 1994 [cited 2024 Sep 10];269(9):6566–70. Available from: https://www.jbc.org/article/S0021-9258(17)37409-4/fulltext Procter M, Wolf B, Mao R. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab. 2016 Mar 1;117(3):369–72. Strovel ET, Cowan TM, Scott AI, Wolf B. Laboratory diagnosis of biotinidase deficiency, 2017 update: A technical standard and guideline of the American College of Medical Genetics and Genomics. Genetics in Medicine. 2017 Oct 1;19(10). Wolf B. Biotinidase deficiency: “If you have to have an inherited metabolic disease, this is the one to have.” Genetics in Medicine. 2012 Jun;14(6):565–75. Wolf B, Heard GS, Weissbecker KA, McVoy JRS, Grier RE, Leshner RT. Biotinidase deficiency: Initial clinical features and rapid diagnosis. Ann Neurol [Internet]. 1985 Nov 1 [cited 2024 Sep 9];18(5):614–7. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ana.410180517 Pandey AS, Joshi S, Rajbhandari R, Kansakar P, Dhakal S, Fingerhut R. Newborn Screening for Selected Disorders in Nepal: A Pilot Study. Int J Neonatal Screen [Internet]. 2019 Apr 10 [cited 2024 Sep 7];5(2). Available from: /pmc/articles/PMC7510202/ Wolf B, Hsia Y, Sweetman L, … GF, 1981 undefined. Multiple carboxylase deficiency: clinical and biochemical improvement following neonatal biotin treatment. publications.aap.org [Internet]. [cited 2024 Sep 7]; Available from: https://publications.aap.org/pediatrics/article-abstract/68/1/113/50722 Moss J, Lane MD. The Biotin-Dependent Enzymes. Adv Enzymol Relat Areas Mol Biol. 2006 Nov 27;35:321–442. Sweetman L. Two forms of biotin-responsive multiple carboxylase deficiency. J Inherit Metab Dis [Internet]. 1981 Dec [cited 2025 Jan 2];4(2):53–4. Available from: https://pubmed.ncbi.nlm.nih.gov/6790844/ Tankeu A, Winckel G Van, Elmers J, … EJM genetics and, 2023 undefined. Biotinidase deficiency: What have we learned in forty years? Elsevier [Internet]. [cited 2024 Oct 26]; Available from: https://www.sciencedirect.com/science/article/pii/S1096719223001907 Dermatology DMS in, 1991 undefined. Skin manifestations of biotin deficiency. europepmc.orgDM MockSeminars in Dermatology, 1991•europepmc.org [Internet]. [cited 2024 Sep 9]; Available from: https://europepmc.org/article/med/1764357 Wolf B. Children with profound biotinidase deficiency should be treated with biotin regardless of their residual enzyme activity or genotype [2]. Eur J Pediatr. 2002;161(3):167–8. Devanapalli B, Sze Hui Wong R, Lim N, Ian Andrews P, Vijayan K, Kim WT, et al. Biotinidase deficiency: A treatable neurometabolic disorder. Brain and Development Case Reports. 2024 Jun 1;2(2):100021. Liu A, Ying S. Aicardi–Goutières syndrome: A monogenic type I interferonopathy. Scand J Immunol [Internet]. 2023 Oct 1 [cited 2025 Mar 25];98(4):e13314. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/sji.13314 Bagger FO, Borgwardt L, Jespersen AS, Hansen AR, Bertelsen B, Kodama M, et al. Whole genome sequencing in clinical practice. BMC Medical Genomics 2024 17:1 [Internet]. 2024 Jan 29 [cited 2025 Mar 25];17(1):1–16. Available from: https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01795-w Royer-Bertrand B, Rivolta C. Whole genome sequencing as a means to assess pathogenic mutations in medical genetics and cancer. Cell Mol Life Sci [Internet]. 2014 [cited 2025 Mar 25];72(8):1463. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11113357/ Wolf B, Spencer R, Gleason T. Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. Journal of Pediatrics. 2002;140(2):242–6. Wolf B. Clinical issues and frequent questions about biotinidase deficiency. Mol Genet Metab. 2010 May 1;100(1):6–13. Forny P, Wicht A, Rüfenacht V, Cremonesi A, Häberle J. Recovery of enzyme activity in biotinidase deficient individuals during early childhood. Wiley Online Library [Internet]. 2022 May 1 [cited 2024 Oct 26];45(3):605–20. Available from: https://www.zora.uzh.ch/id/eprint/229876/ Wolf B. Biotinidase Deficiency. GeneReviews® [Internet]. 2023 May 25 [cited 2024 Sep 9]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK1322/ Ferreira P, Chan A, Wolf B. Irreversibility of symptoms with biotin therapy in an adult with profound biotinidase deficiency. JIMD Rep. 2017;36:117–20. Swango K, Demirkol M, Hüner G, genetics EPH, 1998 undefined. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. SpringerKL Swango, M Demirkol, G Hüner, E Pronicka, J Sykut-Cegielska, A Schulze, B WolfHuman genetics, 1998•Springer [Internet]. 2014 [cited 2024 Oct 26];102(5):571–5. Available from: https://link.springer.com/article/10.1007/s004390050742 Mishra R, Gupta M, Mukherjee S, Lomash A, Gupta S, Kapoor S. Biotin supplementation in children with symptomatic profound biotinidase deficiency and their pregnant mothers. Indian Pediatrics Case Reports [Internet]. 2022 [cited 2024 Sep 7];2(1):12. Available from: https://journals.lww.com/ipcr/fulltext/2022/02010/biotin_supplementation_in_children_with.4.aspx Additional Declarations No competing interests reported. Supplementary Files SupplementaryfileS1.docx Cite Share Download PDF Status: Published Journal Publication published 04 Jun, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 07 Apr, 2025 Reviews received at journal 06 Apr, 2025 Reviews received at journal 05 Apr, 2025 Reviews received at journal 03 Apr, 2025 Reviewers agreed at journal 03 Apr, 2025 Reviews received at journal 01 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviewers agreed at journal 30 Mar, 2025 Reviews received at journal 30 Mar, 2025 Reviewers agreed at journal 30 Mar, 2025 Reviewers agreed at journal 29 Mar, 2025 Reviewers invited by journal 29 Mar, 2025 Submission checks completed at journal 28 Mar, 2025 First submitted to journal 28 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5762621","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":437060982,"identity":"46ae54f8-eb28-42b3-b2f5-ee269943575b","order_by":0,"name":"Jagdish Kunwar","email":"","orcid":"","institution":"National Academy of Medical Sciences, Kanti Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jagdish","middleName":"","lastName":"Kunwar","suffix":""},{"id":437060983,"identity":"d782105b-1b42-4a15-8ca6-c81761242cc2","order_by":1,"name":"Bijay Kunwar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIie3PMYvCMBTA8ZfL4BLxA/gluon4UW5JKcQpLi4dPCkc6HJw6xVEv4IuXU15UJeIa8HFW5wcCrcUbjHWwanRUTD/4cGD/EIC4HI9YR4FDqCui+KhmZRGDxOiCn0h5A65Xl9NmsaTitpJpwG/f0zjwNtsD9icf7y3poaUYVJLup8QtFmOQ0/3PWwmG/mDJCJfel//MATeZgX6iRJgSCYjQyiZWEnwX5Hd0ZBZJhcPEHF5mJ/kAtI4GsnlPWL+Iroz3ffX+RFUkSm5MiS1/aXT0kF+ynp+/C1owUdjOd9heijDegLA+Bu7bVhNZTlvaihS3rax/bDL5XK9ZGefi2h2JLz5BwAAAABJRU5ErkJggg==","orcid":"","institution":"Tribhuvan University Institute of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Bijay","middleName":"","lastName":"Kunwar","suffix":""},{"id":437060984,"identity":"79a57865-b6d4-496f-8bf8-4c4e2294ed90","order_by":2,"name":"Anup Ghimire","email":"","orcid":"","institution":"Tribhuvan University Institute of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Anup","middleName":"","lastName":"Ghimire","suffix":""},{"id":437060985,"identity":"d22a47f8-2cc1-4ffd-a5a8-c427170f43f2","order_by":3,"name":"Aramva Bikram Adhikari","email":"","orcid":"","institution":"Tribhuvan University Institute of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Aramva","middleName":"Bikram","lastName":"Adhikari","suffix":""},{"id":437060986,"identity":"e1350b54-ac4c-451e-becb-2e587822199c","order_by":4,"name":"Binay Aryal","email":"","orcid":"","institution":"Tribhuvan University Institute of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Binay","middleName":"","lastName":"Aryal","suffix":""},{"id":437060987,"identity":"6eccc82c-9f03-4ab2-a5fc-6bda57825133","order_by":5,"name":"Sachchu Thapa","email":"","orcid":"","institution":"National Academy of Medical Sciences, Bir Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sachchu","middleName":"","lastName":"Thapa","suffix":""},{"id":437060988,"identity":"c42dd8cf-5d00-4f1a-b346-e9e45772d5a3","order_by":6,"name":"Bina Prajapati Manandhar","email":"","orcid":"","institution":"National Academy of Medical Sciences, Kanti Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bina","middleName":"Prajapati","lastName":"Manandhar","suffix":""}],"badges":[],"createdAt":"2025-01-04 09:23:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5762621/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5762621/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-025-05822-2","type":"published","date":"2025-06-04T15:57:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79812795,"identity":"3d326253-d9ff-4396-ac61-05a8a6f7adee","added_by":"auto","created_at":"2025-04-03 07:05:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1014433,"visible":true,"origin":"","legend":"\u003cp\u003eAxial T2 section of Brain showing:\u003c/p\u003e\n\u003cp\u003eWidening of bifrontal (red arrow) and anterior inter hemispheric CSF spaces (black arrow) without flattening of adjacent Gyri, Normal sulci posteriorly and normal ventricular size with no pressure effects on surrounding brain tissue. Normal cortical veins within. Normal white matter myelination in splenium (yellow arrow) and non-myelination of body (*) and genu (x) of corpus callosum.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5762621/v1/fab08187bfea91caa5ae26aa.png"},{"id":84242374,"identity":"02885980-9589-463e-bfbf-95b91b6143af","added_by":"auto","created_at":"2025-06-09 16:06:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2012269,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5762621/v1/a37ffa41-5dcd-41e1-8e4c-e7ab827c839d.pdf"},{"id":79812798,"identity":"3d22b12b-12ed-4160-8f98-5b8d24b26dc5","added_by":"auto","created_at":"2025-04-03 07:05:36","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":294930,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryfileS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5762621/v1/47af82b82e09daad2337c99c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Biotinidase Deficiency: The First Reported Case from Nepal","fulltext":[{"header":"Background","content":"\u003cp\u003eBiotinidase deficiency (BTD) is a rare genetic condition inherited in an autosomal recessive pattern that affects multiple systems (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The global incidence of BTD varies from 1:40,000 to 1:60,000 births (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Biotinidase (EC 3.5.1.12) cleaves the vitamin, biotin, from the biocytin and the dietary protein-bound sources, and recycles the biotin (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The BTD gene is located on chromosome 3p25 and consists of four exons, with a total length of 1629 base pairs (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). More than 200 mutations have been identified in BTD gene (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The diagnosis of BTD is made by biotinidase enzyme activity in plasma or serum (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Detection of increased urinary levels of 3-hydroxyisovaleric, 3-hydroxypropionic, lactic acid, and 3-methylcrotonyl glycine on untreated patients can aid the diagnosis (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Whole genome sequencing (WGS) leads to diagnosis. BTD can develop at any ages, ranging from infancy to adulthood but is more common in infancy (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). BTD manifests with a range of neurocutaneous symptoms, including seizures, hypotonia, ataxia, skin rashes, alopecia, hearing loss, optic atrophy, and metabolic crises that resemble sepsis, delay in identification and prompt treatment, results in irreversible brain damage, coma, and, in severe cases, death (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Newborn screening is important for early diagnosis and treatment as it can be treated with pharmacological doses of biotin (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). There have been no studies conducted from Nepal about Biotinidase deficiency highlighting the clinical features, diagnosis and response to treatment (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Here we describe the first reported case of biotinidase deficiency from Nepal.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical Presentation\u003c/h2\u003e \u003cp\u003eAn 18-month-old male, born at term via normal vaginal delivery to non-consanguineous parents, with an unremarkable neonatal period, presented to Kanti Children\u0026rsquo;s Hospital with a three-month history of multiple abnormal body movements and developmental regression. The child was exclusively breastfed until six months of age, followed by the gradual introduction of complementary feeding. There was no known family history (Supplementary file S1) of genetic or neurological disorders. Developmental milestones were appropriate until 12 months of age, at which point he was able to stand with support, walk with occasional falls, and attempt independent standing. He demonstrated a mature pincer grasp, responded to his name, engaged in simple ball games, vocalized 1\u0026ndash;2 meaningful words, recognized sounds, and oriented toward their source.\u003c/p\u003e \u003cp\u003eThe first seizure episode occurred at seven months of age and was associated with fever. By 13 months, he had experienced three episodes of generalized tonic-clonic seizures (GTCS). At 12 months, he had an episode of status epilepticus requiring intervention at another center. At 15 months, he was admitted to the pediatric intensive care unit (PICU) at our center due to a lower respiratory tract infection and GTCS. Following this admission, he exhibited significant developmental regression, losing previously acquired motor, cognitive, and social milestones. He was unable to walk independently, creep upstairs, initiate scribbling, speak words, or imitate parental activities. His mother reported that he only adjusted his head position to follow objects instead of actively tracking them.\u003c/p\u003e \u003cp\u003eAt the presentation, the child exhibited spontaneous limb movements and cooing but lacked neck holding and rolling over. There were no noted comorbidities. Anthropometric measurements revealed a weight of 9 kg (10th percentile), length of 76 cm (15th percentile), and head circumference of 45 cm (10th percentile).\u003c/p\u003e \u003cp\u003eNeurological examination showed that the child was awake but unresponsive to his surroundings. Examination of the skull, neck, and spine revealed no signs of meningeal irritation, malformations, injuries, pain, or tenderness. Cranial nerve assessment showed normal pupillary response to light and the ability to follow objects. Fundoscopic examination revealed bilateral optic disc pallor. Facial symmetry was preserved with an intact smile response. The child responded to auditory stimuli and was able to swallow milk. The tongue appeared normal without fasciculations or asymmetry.\u003c/p\u003e \u003cp\u003eMotor examination revealed symmetrical muscle bulk without fasciculations or involuntary movements. Muscle tone was decreased (hypotonia) in all flexor and extensor groups. Muscle power was 2/5 in both the upper and lower extremities. Bilateral deep tendon reflexes at the knee and ankle were hyperreflexic. Clonus was absent, and the bilateral plantar response was mute. Systemic examination revealed no abnormalities.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInvestigations\u003c/h3\u003e\n\u003cp\u003eThe working diagnosis of neurodegenerative delay prompted an extensive evaluation. EEG revealed an abnormal sleep pattern with epileptiform discharges in the right centro-temporal region, suggestive of encephalopathy. Brain MRI demonstrated prominent frontal sulcal spaces, consistent with benign enlargement of the subarachnoid spaces in infancy (BESSI), along with delayed myelination of the rostrum, genu, and trunk/body of the corpus callosum. Ophthalmological examination revealed bilateral optic disc pallor, while hearing assessment was normal. Laboratory tests, including thyroid function, vitamin D levels, and electrolytes, were within normal limits. Arterial blood gas (ABG) analysis performed during the ICU stay showed a pH of 7.30 (normal range: 7.35\u0026ndash;7.45), indicating metabolic acidosis with elevated lactate levels.\u003c/p\u003e \u003cp\u003eWhole-genome sequencing (WGS) identified a heterozygous pathogenic variant (c.38_44delinsTCC, p.Cys13Phefs*36) in the biotinidase (BTD) gene and a heterozygous variant of uncertain significance (c.2921A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.His974Arg)) in the IFIH1 gene (Supplementary file S1). Given that IFIH1 mutations are associated with Aicardi\u0026ndash;Gouti\u0026egrave;res syndrome, a condition with overlapping clinical features of neuroregression, seizures, and encephalopathy, and that biotinidase deficiency (BTD) is an autosomal recessive disorder, there was initial diagnostic uncertainty. However, as BTD deficiency is a treatable condition, biotinidase enzyme activity was retrospectively assessed, revealing a reduced level of 3.20 nmol/min/mL (normal\u0026thinsp;\u0026gt;\u0026thinsp;5.00 nmol/min/mL). Given the significant clinical response to biotin supplementation, a diagnosis of biotinidase deficiency was confirmed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eReport of whole exome sequencing\u0026thinsp;+\u0026thinsp;mitochondrial genome sequencing using next generation sequencing (NGS) of EDTA blood sample.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eReport of whole exome sequencing\u0026thinsp;+\u0026thinsp;mitochondrial genome sequencing using next generation sequencing (NGS) of EDTA blood sample\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGene\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eDisease and Inheritance\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(OMIM phenotype number)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eGenomic Position\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eVariant details\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eBTD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eBiotinidase deficiency (AR\u003c/p\u003e \u003cp\u003e- Autosomal Recessive)\u003c/p\u003e \u003cp\u003e(OMIM ID- 253260)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eChr3:g.15635477\u003c/p\u003e \u003cp\u003e15635483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExon/ Intron No:\u003c/p\u003e \u003cp\u003eExon 2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNucleotide change:\u003c/p\u003e \u003cp\u003ec.38_44delinsTCC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAmino Acid\u003c/p\u003e \u003cp\u003eChange: (p.Cys13Phefs*36)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTranscript Id: NM_001370658.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMolecular\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003econsequence\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eAllele Frequency\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eZygosity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eACMG Classification\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFrameshift\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1000 Genome: Novel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePathogenic (PVS1, PM2,\u003c/p\u003e \u003cp\u003ePP5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egnomAD: 0.055%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eManagement and Outcome\u003c/h3\u003e\n\u003cp\u003eThe child was started on oral biotin at a dose of 10 mg daily, based on clinical guidelines for biotinidase deficiency. No other pharmacological treatments were administered. Supportive care included physiotherapy and developmental interventions to address hypotonia and developmental delays.\u003c/p\u003e \u003cp\u003eFollow-up assessments at 3, 6, and 12 months post-treatment showed remarkable improvement. At 3 months of starting treatment, neurodevelopmental milestones were appropriate for age, and the child had resumed head control and rolling over, he ran, scribbled on paper, played games and toys, made simple sentences like asking for food. By 12 months of follow up, his development was normal, with significant improvements in gross and fine motor skills, language, and social interactions. These milestones were monitored using the Denver Developmental Screening Test (DDST).\u003c/p\u003e \u003cp\u003eA genetic counseling consultation was held with the family. Detailed information about how the condition is inherited, the risks of being carriers, and the chances of passing it on to future children. The options like carrier screening, prenatal testing, and possible reproductive choices, ensuring the parents were aware of their options moving forward. Beyond the medical details, the family was educated about the disorder itself, its symptoms and available treatments and how it might affect other relatives. Counselling also discussed the implications for other family members, including the possibility that siblings or extended relatives may also be carriers or affected.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBiotin is a vital cofactor for four human carboxylases essential to glucose, fatty acid, and amino acid metabolism (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Biotinidase's main function is to recycle biotin from biocytin, degraded holo-carboxylases, and biotin bound to dietary proteins (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The free biotin then replenishes the biotin pool and activates carboxylases\u0026mdash;propionyl-CoA carboxylase, β-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase that is essential for gluconeogenesis, breakdown of branched-chain amino acids, and fatty acid synthesis (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The BTD gene, located on chromosome 3p25, comprises four exons spanning 1,629 base pairs (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). More than 200 mutations have been documented in patients with biotinidase deficiency, including missense, nonsense, and compound allelic mutations(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The deficiency of this enzyme was first reported and characterized by Wolf et al. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis case underscores the clinical significance of biotinidase deficiency (BTD), emphasizing the challenges of early diagnosis in resource-limited settings like Nepal. In such contexts, the absence of newborn screening and limited molecular diagnostic capacity hinder timely intervention, making clinical acumen and symptomatic presentation crucial for diagnosis.\u003c/p\u003e \u003cp\u003eMCD has two forms: neonatal and juvenile (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The neonatal form, resulting from holocarboxylase synthetase deficiency, typically presents between birth to 15 months and is characterized by feeding problems, seizures, hypotonia, developmental delays, and ketoacidotic coma (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Skin manifestations are rare but may include a seborrheic rash and alopecia(\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The juvenile form, due to biotinidase deficiency, starts after 3 months with predominant neurocutaneous features, including seizures, hypotonia, ataxia, skin rash, alopecia, hearing loss, optic atrophy, and metabolic crises like sepsis (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Dermatological manifestations range from seborrheic dermatitis-like eruptions to severe crusting and secondary infections, likely due to abnormalities in lipid metabolism and altered skin composition (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Neurological complications, including developmental delays, optic atrophy, and sensorineural hearing loss, may persist if biotin therapy is delayed (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Significantly, about 76% of untreated patients with profound BTD develop sensorineural hearing loss (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, our case though being a juvenile form didn\u0026rsquo;t have any immunological or cutaneous manifestations.\u003c/p\u003e \u003cp\u003eA review by Tankeu et al. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) highlights that of 1,113 individuals diagnosed with BTD over 40 years, 51.5% were identified through newborn screening, 43.3% presented symptomatically, and 5.2% were identified via family screening (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Multisystem involvement was common, affecting the nervous system (67.2%), skin (53.7%), eyes (34.4%), auditory system (26.9%), and respiratory system (17.8%). Although mortality is rare (1.6%), it is associated with delayed diagnosis or unavailability of biotin therapy(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe metabolic disorders (fatty acid oxidation defects, organic acidurias), neurological conditions (cerebral palsy, seizure disorders), vitamin deficiencies (B12), inborn errors of metabolism (homocystinuria, maple syrup urine disease), mitochondrial disorders and genetic syndromes (Rett, Angelman) were taken into consideration. In this case, provisional diagnosis of inborn error of metabolism was based on clinical and laboratory findings, which was further confirmed by biochemical evaluation, which showed genetic mutation and enzyme activity below normal. Differential diagnoses, including other metabolic and primary immune deficiencies, were excluded through metabolic profiles and clinical presentation. As molecular genetic testing to identify biallelic pathogenic variants in BTD is definitive, in this case it was found to have heterozygous variants in both the IFIH1 and BTD genes on whole-genome sequencing (WGS). IFIH1 gene mutations may manifest as Aicardi\u0026ndash;Gouti\u0026egrave;res syndrome having a presentation similar to BTD deficiency (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Since the clinical presentation overlapped with features of both conditions, and although heterozygous BTD variants are typically non-pathogenic, epigenetic alterations may contribute to variable disease severity. Given that biotinidase deficiency is a treatable disorder, we retrospectively assessed biotinidase enzyme activity to confirm or rule out its involvement in the patient\u0026rsquo;s condition. Whole-genome sequencing (WGS) may not always detect all types of pathogenic variants, such as deep intronic mutations, large deletions, or structural variations that affect gene function (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The patient may harbor a second pathogenic variant that was missed due to technical limitations of sequencing or coverage gaps (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Variants in non-coding regulatory regions of the BTD gene could reduce gene expression, effectively mimicking a biallelic loss-of-function state. Altered splicing due to deep intronic mutations could lead to significantly reduced biotinidase enzyme activity. IFIH1 gene may be a genetic modifier in biotin metabolism pathways and thus may have contributed to a phenotypic expression of BTD deficiency even in heterozygous condition, which may need further genetic analysis. However due to limited availability and cost constraints in Nepal pose significant barriers, incorporating cost-effective diagnostic strategies is critical to improving detection and outcomes.\u003c/p\u003e \u003cp\u003ePharmacological doses of biotin have demonstrated remarkable efficacy in preventing or reversing symptoms. However, irreversible complications, such as hearing and vision loss, highlight the importance of early intervention (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The normalization of biotinidase activity, particularly in patients with partial deficiency harboring the p.Asp444His variant, illustrates the efficacy of biotin therapy (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Although genotype-phenotype correlations in BTD remain poorly understood, mutations such as c.38_44delinsTCC, identified in this case, warrant further study to elucidate their clinical significance.\u003c/p\u003e \u003cp\u003eComparison with existing literature reveals variability in the age of onset and phenotypic severity of BTD. While symptoms typically manifest between 2 weeks and 2 years of age, late presentations have been reported (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Mutations such as p.Cys13Phefs*36 have been associated with diverse phenotypic outcomes, underscoring the need for comprehensive studies to better understand genotype-phenotype relationships (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNewborn screening (NBS) for BTD is an effective tool for early detection which is already adopted by various highly prevalent countries like Israel. As the real epidemiology of BTD deficiency in Nepal is not known the clinical applicability of newborn screening cannot be emphasized. Raising awareness among clinicians is critical, especially in regions lacking newborn screening programs. Introducing such programs could substantially reduce the burden of delayed diagnosis and its associated complications. Additionally, antenatal biotin supplementation in at-risk pregnancies represents a potential strategy to mitigate early complications (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), Despite the global burden, the clinical profile, diagnostic challenges, and treatment outcomes of BTD remain unstudied in Nepal. This case emphasizes the urgent need for local research to inform diagnostic and therapeutic strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the clinical and diagnostic challenges of biotinidase deficiency (BTD) in resource-limited settings like Nepal, where the absence of newborn screening and limited molecular diagnostic capacity delay timely intervention. Despite these challenges, the patient responded favorably to pharmacological doses of biotin, underscoring the efficacy of this readily available and economical therapy. However, the persistence of irreversible complications, such as hearing loss, reiterates the critical importance of early diagnosis and intervention. This report emphasizes the need for increased clinician awareness, and local research to better understand the spectrum of BTD mutations, their clinical implications and to analyze the effectiveness of implementation of newborn screening programs. Early recognition and treatment of BTD can significantly improve patient outcomes and reduce the burden of this potentially devastating yet treatable disorder.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBTD: Biotinidase Deficiency\u003c/p\u003e\n\u003cp\u003eWGS: Whole Genome Sequencing\u003c/p\u003e\n\u003cp\u003eKCH: Kanti Children\u0026rsquo;s Hospital\u003c/p\u003e\n\u003cp\u003eGTCS: Generalised Tonic Clonic Seizure\u003c/p\u003e\n\u003cp\u003eDDST: Denver Developmental Screening Test\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCase reports are exempt from ethical approval in our institution, Kanti Children’s Hospital, Maharajgunj, Kathmandu.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate and Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient’s parents for participation and publication of this case reports and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSource of funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBK and AG conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eABA, BA and ST designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eJK and BPM conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the staff and participants of this study for their important contributions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWolf B, Grier RE, Allen RJ, Goodman SI, Kien CL. Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. Clinica Chimica Acta. 1983 Jul 15;131(3):273\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eWolf B, Grier RE, Secor McVoy JR, Heard GS. Biotinidase deficiency: A novel vitamin recycling defect. J Inherit Metab Dis. 1985 Mar;8(1 Supplement):53\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eCanda E, U\u0026ccedil;ar SK, \u0026Ccedil;oker M. Biotinidase Deficiency: Prevalence, Impact And Management Strategies. Pediatric Health Med Ther [Internet]. 2020 [cited 2024 Sep 9];11:127. Available from: /pmc/articles/PMC7211084/\u003c/li\u003e\n\u003cli\u003eKnight HC, Reynolds TR, Meyers GA, Pomponio RJ, Buck GA, Wolf B. Structure of the human biotinidase gene. Mammalian Genome. 1998 Apr;9(4):327\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eCole$ H, Reynolds$ TR, Lockyern JM, Buck% \u0026rsquo;i\u0026rsquo;d Denson% GA, Spence$ll JE, Hymess J, et al. Human serum biotinidase. cDNA cloning, sequence, and characterization. ASBMB [Internet]. 1994 [cited 2024 Sep 10];269(9):6566\u0026ndash;70. Available from: https://www.jbc.org/article/S0021-9258(17)37409-4/fulltext\u003c/li\u003e\n\u003cli\u003eProcter M, Wolf B, Mao R. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab. 2016 Mar 1;117(3):369\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eStrovel ET, Cowan TM, Scott AI, Wolf B. Laboratory diagnosis of biotinidase deficiency, 2017 update: A technical standard and guideline of the American College of Medical Genetics and Genomics. Genetics in Medicine. 2017 Oct 1;19(10). \u003c/li\u003e\n\u003cli\u003eWolf B. Biotinidase deficiency: \u0026ldquo;If you have to have an inherited metabolic disease, this is the one to have.\u0026rdquo; Genetics in Medicine. 2012 Jun;14(6):565\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eWolf B, Heard GS, Weissbecker KA, McVoy JRS, Grier RE, Leshner RT. Biotinidase deficiency: Initial clinical features and rapid diagnosis. Ann Neurol [Internet]. 1985 Nov 1 [cited 2024 Sep 9];18(5):614\u0026ndash;7. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ana.410180517\u003c/li\u003e\n\u003cli\u003ePandey AS, Joshi S, Rajbhandari R, Kansakar P, Dhakal S, Fingerhut R. Newborn Screening for Selected Disorders in Nepal: A Pilot Study. Int J Neonatal Screen [Internet]. 2019 Apr 10 [cited 2024 Sep 7];5(2). Available from: /pmc/articles/PMC7510202/\u003c/li\u003e\n\u003cli\u003eWolf B, Hsia Y, Sweetman L, \u0026hellip; GF, 1981 undefined. Multiple carboxylase deficiency: clinical and biochemical improvement following neonatal biotin treatment. publications.aap.org [Internet]. [cited 2024 Sep 7]; Available from: https://publications.aap.org/pediatrics/article-abstract/68/1/113/50722\u003c/li\u003e\n\u003cli\u003eMoss J, Lane MD. The Biotin-Dependent Enzymes. Adv Enzymol Relat Areas Mol Biol. 2006 Nov 27;35:321\u0026ndash;442. \u003c/li\u003e\n\u003cli\u003eSweetman L. Two forms of biotin-responsive multiple carboxylase deficiency. J Inherit Metab Dis [Internet]. 1981 Dec [cited 2025 Jan 2];4(2):53\u0026ndash;4. Available from: https://pubmed.ncbi.nlm.nih.gov/6790844/\u003c/li\u003e\n\u003cli\u003eTankeu A, Winckel G Van, Elmers J, \u0026hellip; EJM genetics and, 2023 undefined. Biotinidase deficiency: What have we learned in forty years? Elsevier [Internet]. [cited 2024 Oct 26]; Available from: https://www.sciencedirect.com/science/article/pii/S1096719223001907\u003c/li\u003e\n\u003cli\u003eDermatology DMS in, 1991 undefined. Skin manifestations of biotin deficiency. europepmc.orgDM MockSeminars in Dermatology, 1991\u0026bull;europepmc.org [Internet]. [cited 2024 Sep 9]; Available from: https://europepmc.org/article/med/1764357\u003c/li\u003e\n\u003cli\u003eWolf B. Children with profound biotinidase deficiency should be treated with biotin regardless of their residual enzyme activity or genotype [2]. Eur J Pediatr. 2002;161(3):167\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eDevanapalli B, Sze Hui Wong R, Lim N, Ian Andrews P, Vijayan K, Kim WT, et al. Biotinidase deficiency: A treatable neurometabolic disorder. Brain and Development Case Reports. 2024 Jun 1;2(2):100021. \u003c/li\u003e\n\u003cli\u003eLiu A, Ying S. Aicardi\u0026ndash;Gouti\u0026egrave;res syndrome: A monogenic type I interferonopathy. Scand J Immunol [Internet]. 2023 Oct 1 [cited 2025 Mar 25];98(4):e13314. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/sji.13314\u003c/li\u003e\n\u003cli\u003eBagger FO, Borgwardt L, Jespersen AS, Hansen AR, Bertelsen B, Kodama M, et al. Whole genome sequencing in clinical practice. BMC Medical Genomics 2024 17:1 [Internet]. 2024 Jan 29 [cited 2025 Mar 25];17(1):1\u0026ndash;16. Available from: https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01795-w\u003c/li\u003e\n\u003cli\u003eRoyer-Bertrand B, Rivolta C. Whole genome sequencing as a means to assess pathogenic mutations in medical genetics and cancer. Cell Mol Life Sci [Internet]. 2014 [cited 2025 Mar 25];72(8):1463. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11113357/\u003c/li\u003e\n\u003cli\u003eWolf B, Spencer R, Gleason T. Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. Journal of Pediatrics. 2002;140(2):242\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eWolf B. Clinical issues and frequent questions about biotinidase deficiency. Mol Genet Metab. 2010 May 1;100(1):6\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eForny P, Wicht A, R\u0026uuml;fenacht V, Cremonesi A, H\u0026auml;berle J. Recovery of enzyme activity in biotinidase deficient individuals during early childhood. Wiley Online Library [Internet]. 2022 May 1 [cited 2024 Oct 26];45(3):605\u0026ndash;20. Available from: https://www.zora.uzh.ch/id/eprint/229876/\u003c/li\u003e\n\u003cli\u003eWolf B. Biotinidase Deficiency. GeneReviews\u0026reg; [Internet]. 2023 May 25 [cited 2024 Sep 9]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK1322/\u003c/li\u003e\n\u003cli\u003eFerreira P, Chan A, Wolf B. Irreversibility of symptoms with biotin therapy in an adult with profound biotinidase deficiency. JIMD Rep. 2017;36:117\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eSwango K, Demirkol M, H\u0026uuml;ner G, genetics EPH, 1998 undefined. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. SpringerKL Swango, M Demirkol, G H\u0026uuml;ner, E Pronicka, J Sykut-Cegielska, A Schulze, B WolfHuman genetics, 1998\u0026bull;Springer [Internet]. 2014 [cited 2024 Oct 26];102(5):571\u0026ndash;5. Available from: https://link.springer.com/article/10.1007/s004390050742\u003c/li\u003e\n\u003cli\u003eMishra R, Gupta M, Mukherjee S, Lomash A, Gupta S, Kapoor S. Biotin supplementation in children with symptomatic profound biotinidase deficiency and their pregnant mothers. Indian Pediatrics Case Reports [Internet]. 2022 [cited 2024 Sep 7];2(1):12. Available from: https://journals.lww.com/ipcr/fulltext/2022/02010/biotin_supplementation_in_children_with.4.aspx\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Biotinidase, Biotin, MCD, Newborn screening","lastPublishedDoi":"10.21203/rs.3.rs-5762621/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5762621/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBiotinidase deficiency (BTD) is a rare genetic condition inherited in an autosomal recessive pattern that affects multiple systems. Biotinidase (EC 3.5.1.12) cleaves the vitamin, biotin, from the biocytin and the dietary protein-bound sources, and recycles the biotin. It manifests with a range of neurocutaneous symptoms, including seizures, hypotonia, ataxia, skin rashes, alopecia, hearing loss, optic atrophy, and metabolic crises that resemble sepsis, delay in identification and prompt treatment, results in irreversible brain damage, coma, and, in severe cases, death. Newborn screening can help in early diagnosis as it is amenable to treatment with pharmacological doses of biotin. There has been no study from Nepal about Biotinidase deficiency highlighting the clinical features, diagnosis and response to treatment.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eAn 18-month-old male, born at term via normal delivery to non-consanguineous parents, with a normal neonatal period, presented to Kanti Children\u0026rsquo;s Hospital (KCH) with a 3-month history of multiple abnormal body movements and developmental regression. There were no known familial or genetic illnesses. Developmentally, he achieved milestones appropriately until 12 months of age, since then 15 months of age he had development regression. Ophthalmology study showed bilateral pallor of optic disc. MRI, EEG was done thinking of the inborn error of metabolism. A whole genome sequencing identified a heterozygous pathogenic variant (c.38_44delinsTCC, p.Cys13Phefs*36) in the BTD gene. Serum biotinidase enzyme activity was quantified, 3.20 nmol/min/mL (Normal\u0026thinsp;\u0026gt;\u0026thinsp;5.00 nmol/min/mL) measured via spectrophotometry, The diagnosis of biotinidase deficiency (BTD) was confirmed. He was then managed with oral biotin 10 mg and supportive care. Follow-up assessments at 3, 6, and 12 months post-treatment showed remarkable improvement.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis case highlights the clinical and diagnostic challenges of biotinidase deficiency (BTD) in resource-limited settings like Nepal, where the absence of newborn screening and limited molecular diagnostic capacity delay timely intervention. Increased clinician awareness, and local research to better understand the spectrum of BTD mutations, their clinical implications and to analyze the effectiveness of implementation of newborn screening programs. Early recognition and treatment of BTD can significantly improve patient outcomes and reduce the burden of this potentially devastating yet treatable disorder.\u003c/p\u003e","manuscriptTitle":"Biotinidase Deficiency: The First Reported Case from Nepal","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-03 07:05:31","doi":"10.21203/rs.3.rs-5762621/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-07T05:21:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-06T20:23:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-05T09:57:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-03T21:07:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290727080887638196085140733640587324798","date":"2025-04-03T20:41:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-01T19:55:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"179790847842783457060382675199268864431","date":"2025-04-01T18:58:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"304820902943176827637005915248030771041","date":"2025-04-01T07:12:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"314589428166557232048529534996002829802","date":"2025-03-30T15:37:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-30T11:57:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"95326537454479284571199288247036467657","date":"2025-03-30T11:19:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335644734997113747839886890741215523","date":"2025-03-29T13:14:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-29T13:09:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-29T02:36:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-03-28T07:07:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe44b9a1-04e6-43d1-8df1-923b1d49851d","owner":[],"postedDate":"April 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-09T15:59:01+00:00","versionOfRecord":{"articleIdentity":"rs-5762621","link":"https://doi.org/10.1186/s12887-025-05822-2","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2025-06-04 15:57:01","publishedOnDateReadable":"June 4th, 2025"},"versionCreatedAt":"2025-04-03 07:05:31","video":"","vorDoi":"10.1186/s12887-025-05822-2","vorDoiUrl":"https://doi.org/10.1186/s12887-025-05822-2","workflowStages":[]},"version":"v1","identity":"rs-5762621","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5762621","identity":"rs-5762621","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}