Clinical scenario: Lethargy | Vomiting | Rash | Developmental delay | High anion gap
A 3-month-old infant is admitted with recurrent episodes of vomiting, lethargy, and abnormal movements. He was well until 2 months of age when parents noticed poor feeding, hypotonia, and intermittent seizures. He has had two previous admissions for “sepsis-like episodes,” but cultures were negative.
On examination, the infant has:
- Periorificial erythematous rash with scaling
- Sparse hair
- Hypotonia
- Developmental delay
Laboratory investigations during an acute episode show:
- High anion gap metabolic acidosis
- Elevated lactate
- Mild hyperammonemia
- Ketonuria
- Increased urinary excretion of 3-hydroxyisovaleric acid
Which of the following is the most appropriate initial treatment?
A. Intravenous glucose infusion only
B. Oral biotin supplementation
C. Sodium benzoate therapy
D. Restriction of branched-chain amino acids
E. Nitisinone therapy
Correct answer & Explanation:
Correct Answer: B. Oral biotin supplementation
Explanation
This infant has multiple carboxylase deficiency, a disorder of biotin-dependent carboxylation reactions.
The clue combination is:
- Recurrent metabolic decompensation
- High anion gap metabolic acidosis
- Ketonuria
- Rash and alopecia
- Elevated 3-hydroxyisovaleric acid
Multiple carboxylase deficiency results from either:
- Holocarboxylase synthetase deficiency
- Usually presents in early infancy
- Defective attachment of biotin to carboxylase enzymes
or
- Biotinidase deficiency
- Usually presents later in infancy/childhood
- Failure to recycle free biotin
Both lead to impaired activity of:
- Pyruvate carboxylase
- Propionyl-CoA carboxylase
- 3-methylcrotonyl-CoA carboxylase
- Acetyl-CoA carboxylase
The result is accumulation of organic acids, especially:
↑ 3-hydroxyisovaleric acid → classic clue for multiple carboxylase deficiency
Treatment with high-dose biotin produces dramatic improvement.
Why the Other Options Are Incorrect
A. Intravenous glucose infusion only
- Useful during acute metabolic crises but does not treat the underlying defect.
C. Sodium benzoate therapy
- Used for urea cycle defects with hyperammonemia.
- Hyperammonemia here is secondary and mild.
D. Restriction of branched-chain amino acids
- Used in maple syrup urine disease.
- The presence of rash and 3-hydroxyisovaleric acid suggests a carboxylase defect.
E. Nitisinone therapy
- Used for tyrosinemia type I.
High-Yield Pearls
Multiple carboxylase deficiency:
- Inheritance: Autosomal recessive
- Defect: Biotin-dependent carboxylase activity
- Key metabolites:
- ↑ 3-hydroxyisovaleric acid
- ↑ Methylcrotonylglycine
- ↑ Lactate
- ↑ Propionate metabolites
Clinical triad:
- Metabolic acidosis
- Neurological symptoms (seizures, hypotonia, developmental delay)
- Skin findings (rash, alopecia)
Important distinction:
| Disorder | Key clue |
|---|---|
| Multiple carboxylase deficiency | Rash + alopecia + 3-hydroxyisovaleric acid |
| Propionic acidemia | Hyperammonemia + ketosis + propionate metabolites |
| MCAD deficiency | Hypoketotic hypoglycemia |
| Biotinidase deficiency | Similar picture but later onset |
Exam Pearl
A young infant with:
- Recurrent “sepsis-like” episodes
- Metabolic acidosis
- Ketonuria
- Periorificial dermatitis
- Alopecia
- Elevated 3-hydroxyisovaleric acid
→ Multiple carboxylase deficiency → treat with biotin.
