Biotinidase Deficiency

Biotinidase deficiency is an autosomal recessive disorder of biotin recycling caused by variants in BTD (3p25), which impairs the release of biotin from biocytin and dietary protein bound biotin. The result is secondary multiple carboxylase deficiency (acetyl-CoA carboxylase, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase), causing organic aciduria and lactic acidosis.

Incidence is about 1 in 60,000 (profound deficiency, activity under 10% of mean normal, about 1 in 137,000; partial deficiency, 10 to 30% of mean normal, about 1 in 110,000). It is the most readily treatable inherited metabolic disorder.

Symptoms usually appear between 1 week and 10 years (median about 3 months) in untreated profound deficiency:

• Neurological: seizures (including infantile spasms and myoclonic seizures; often the first sign), hypotonia, developmental delay, ataxia, spastic paraparesis, optic atrophy, hearing loss (sensorineural; often irreversible), and visual impairment
• Cutaneous: seborrhoeic or atopic like dermatitis, alopecia (including loss of eyelashes and eyebrows), and recurrent skin and mucosal candidiasis
• Metabolic: metabolic acidosis, organic aciduria, ketolactic acidosis, hyperammonaemia, and breathing abnormalities (hyperventilation, apnoea, stridor); coma and death in severe cases
• Partial deficiency: usually asymptomatic or mild symptoms with illness or fasting (hypotonia, skin rash, hair loss)
• Delayed treatment can leave permanent sequelae (hearing loss, optic atrophy, developmental delay)

1. Newborn screening by dried blood spot (colorimetric or fluorometric biotinidase activity), universally recommended.
2. Confirmation: serum biotinidase activity (quantitative; below 10% of normal mean indicates profound deficiency, 10 to 30% partial), with parental testing (activity of heterozygotes typically half of normal).
3. BTD gene sequencing (identifies common variants such as c.98_104del7ins3, p.Q456H, p.D444H for partial deficiency).
4. Metabolic abnormalities when symptomatic: urinary organic acids (3-hydroxyisovaleric acid, 3-methylcrotonylglycine, methylcitrate, lactate), and acylcarnitines (elevated C5-OH).
5. Hearing and visual evaluation.

• Lifelong oral free biotin supplementation: 5 to 10 mg/day for profound deficiency (up to 20 mg/day in some patients) given as a single dose, in infants and adults alike.
• Partial deficiency is generally treated with 1 to 5 mg/day (some guidelines treat only with illness or stress).
• Initiate immediately, without waiting for confirmation, in suspected symptomatic cases.
• Clinical response is rapid (days to weeks): seizures, hypotonia, skin and hair changes improve quickly. Hearing and optic damage and developmental impairment may not reverse, so early treatment is essential.
• Monitoring: regular clinic follow up with developmental, hearing and ophthalmologic assessments; adherence is key because missed doses can cause relapse.
• Acute metabolic decompensation: IV fluids with dextrose, bicarbonate for severe acidosis, and biotin 10 to 20 mg.
• Avoid raw egg white (avidin binds biotin), although this is mainly relevant in large quantities.
• Genetic counselling: 25% recurrence risk, carrier testing for siblings, and newborn testing of subsequent children; prenatal diagnosis is available.