Biotinidase deficiency

• Autosomal recessive, BTD (3p25.1)
• Profound deficiency: less than 10% of mean normal serum enzyme activity
• Partial deficiency: 10 to 30% of mean normal activity
• The p.Asp444His (D444H) allele is a common hypomorph that reduces activity by about half. In trans with a profound-deficiency allele it produces partial deficiency, which is how a large share of newborn screening positives arise

Biotinidase cleaves biotin from biocytin so that biotin can be recycled. Without recycling, biotin is lost in the urine and the four biotin-dependent carboxylases progressively lose activity:

• Pyruvate carboxylase
• Propionyl-CoA carboxylase
• 3-methylcrotonyl-CoA carboxylase
• Acetyl-CoA carboxylase

The result is a secondary multiple carboxylase deficiency. This is why a vitamin recycling defect produces an organic acid pattern.

Untreated profound deficiency usually declares itself between 1 week and 6 months, though presentation as late as adolescence occurs.

• Seizures, often myoclonic and often medication-refractory, are the most common presenting sign
• Hypotonia, ataxia, developmental delay
• Alopecia and a seborrheic or eczematous periorificial rash
• Sensorineural hearing loss and optic atrophy, which frequently do not reverse once established, even on treatment. This is the single most important reason newborn screening matters here
• Recurrent candidal infections and other immune dysfunction
• Ketolactic acidosis, mild hyperammonemia, organic aciduria
• Later-onset form: spastic paraparesis with vision loss in older children and adults, commonly misread as a leukodystrophy or as multiple sclerosis

• Serum biotinidase enzyme activity is the diagnostic test, a colorimetric assay. Newborn screening uses the same measurement on a dried blood spot
• Confirm with quantitative enzyme activity plus BTD sequencing to distinguish profound from partial deficiency
• Urine organic acids show 3-hydroxyisovaleric acid (most consistent), 3-methylcrotonylglycine, methylcitrate, and 3-hydroxypropionate. They may be normal between decompensations, so a normal profile does not exclude the diagnosis
• On the Recommended Uniform Screening Panel, so most cases in the United States are now found before symptoms

Holocarboxylase synthetase deficiency (HLCS) is the other biotin-responsive multiple carboxylase deficiency and the one to separate carefully:

Both produce the same urine organic acid pattern and both respond to biotin, so the enzyme assay is what separates them.

• Oral free biotin, 5 to 10 mg daily, lifelong. Free biotin, not protein-bound biotin from food
• Treatment is inexpensive and highly effective. Seizures and skin findings usually resolve within days to weeks; hearing loss and optic atrophy present at diagnosis are generally permanent
• Baseline and periodic audiology and ophthalmology assessment
• Laboratory pitfall worth flagging on every chart: biotin at these doses interferes with biotin-streptavidin immunoassays, producing falsely low troponin and falsely abnormal thyroid function tests and hCG. Advise the patient to tell any treating clinician about the supplement, and to hold it before non-urgent testing where the assay allows
• Partial deficiency is usually treated as well, since the cost is trivial and the untreated risk under metabolic stress is not zero