BTD – Biotinidase Deficiency

Biotinidase (BTD) deficiency is an autosomal recessive neurometabolic disorder caused by biallelic loss-of-function variants in BTD, leading to systemic biotin recycling failure and secondary multiple carboxylase deficiency. Affected individuals present with a spectrum of neurological and cutaneous manifestations—including seizures, hypotonia, ataxia, spastic paraparesis, hearing impairment, alopecia, and dermatitis—that are preventable or reversible with timely pharmacologic biotin supplementation (PMID:8352834, PMID:11033293). Newborn screening programs worldwide facilitate early detection and presymptomatic treatment, markedly reducing morbidity and mortality.

AR Inheritance and Segregation
BTD deficiency follows autosomal recessive inheritance. Segregation analyses in consanguineous families and multi-sibling cohorts have confirmed co-segregation of pathogenic BTD alleles with enzyme deficiency and clinical phenotype; for example, a homozygous c.528_542del (p.Val178_Asn182del) variant was identified in an Iranian consanguineous pedigree with full concordance between genotype and phenotype (PMID:32281057). Segregation in additional affected relatives further supports pathogenicity.

Case Series and Variant Spectrum
Over 400 unrelated affected individuals have been reported across multiple cohorts, including 203 patients in southeastern Turkey (PMID:29353266) and 259 patients in Western Turkey (PMID:29995633), all harboring biallelic BTD variants. The mutation spectrum exceeds 165 unique alleles, spanning missense (e.g., c.1330G>C (p.Gly444Arg)), nonsense, frameshift, splice-site, and intronic variants, as well as complex founder alleles such as c.98_104delinsTCC (p.Cys33PhefsTer36) (PMID:9099842, PMID:10206677). The p.Asp444His allele is particularly prevalent and associated with partial enzyme activity in compound heterozygotes (PMID:25795614).

Mechanism and Functional Concordance
Pathogenic BTD variants result in defective enzyme secretion or rapid degradation, abrogating biotinidase activity (<10% mean normal in profound deficiency; 10–30% in partial) and compromising biotin recycling. In vitro expression studies demonstrate severely reduced or absent enzymatic activity for frameshift and missense alleles (e.g., p.Arg518Leu, p.Leu446Pro) and partial activity for p.Asp444His (PMID:9099842, PMID:31337602). Structural modeling corroborates the disruptive impact of in-frame deletions near the active site (PMID:32281057).

Therapeutic Response and Reversibility
Oral biotin supplementation (5–20 mg/day) leads to rapid metabolic correction and clinical improvement in most patients, including reversal of optic neuropathy, spastic paraparesis, neuropathy, and hearing loss when initiated early (PMID:8352834, PMID:11033293). Delayed diagnosis can result in irreversible neurological sequelae in adults (PMID:28220409).

Conflicting Evidence and Phenotypic Variability
Partial deficiency alleles such as p.Asp444His exhibit age-dependent enzyme activity recovery in ~48% of cases, prompting reconsideration of lifelong supplementation in select individuals (PMID:35195902). However, genotype-phenotype correlations remain variable, and comprehensive molecular testing is essential for accurate diagnosis and management.

Conclusion
The BTD–biotinidase deficiency association is Definitive with robust genetic and functional concordance. Early newborn screening and prompt biotin therapy prevent or reverse most clinical manifestations. Clinicians should maintain high vigilance for atypical presentations (e.g., myelopathy, hearing loss) to enable timely intervention.

Key Take-home: Biotinidase deficiency is a treatable autosomal recessive disorder; early molecular diagnosis and biotin supplementation are critical to prevent irreversible neurological damage.

References

• Neuropediatrics • 1993 • Recovery from neurological deficits following biotin treatment in a biotinidase Km variant. PMID:8352834
• Molecular genetics and metabolism • 1998 • Mutation in a putative glycosylation site (N489T) of biotinidase in the only known Japanese child with biotinidase deficiency. PMID:9705240
• Human genetics • 1997 • Arg538 to Cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of profound biotinidase deficiency in symptomatic children. PMID:9099842
• Pediatric neurology • 2000 • Reversible deafness caused by biotinidase deficiency. PMID:11033293
• BMJ case reports • 2011 • Biotinidase deficiency--clinching the diagnosis rapidly can make all the difference! PMID:22679321
• Pediatric neurology • 2011 • Biotinidase deficiency presenting as recurrent myelopathy in a 7-year-old boy and a review of the literature. PMID:21907891
• Clinica chimica acta • 2015 • Biotinidase deficiency due to a de novo mutation or gonadal mosaicism in a first child. PMID:25795614
• JIMD reports • 2017 • Irreversibility of Symptoms with Biotin Therapy in an Adult with Profound Biotinidase Deficiency. PMID:28220409
• Human genetics • 1998 • Double mutation (A171T and D444H) is a common cause of profound biotinidase deficiency in children ascertained by newborn screening the the United States. PMID:10206677
• Molecular genetics and metabolism • 2019 • Effect of BTD gene variants on in vitro biotinidase activity. PMID:31337602

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