Question

A child presents with an abnormally large head (macrocephaly) and abnormal, involuntary muscle movements (dystonia). Which of the following enzyme deficiencies is the most likely underlying cause of this presentation?

• A. Isovaleric acidemia
• B. Glutaric acidemia type I
• C. Methylmalonic acidemia
• D. Biotinidase deficiency

Hint:

Radiological buzzwords for Glutaric acidemia type I: "Bat-wing" dilation of the Sylvian fissures and frontotemporal atrophy, combined with hyperintensities in the basal ganglia on T2-weighted MRI.

Answer 1

The Correct Option is B

Concept:
The clinical triad of macrocephaly, movement disorders (dystonia/choreoathetosis), and acute encephalopathic crises in infancy is highly characteristic of a specific inborn error of metabolism.
(The accompanying MRI typically shows widening of the Sylvian fissures resulting in a "bat-wing" appearance, and bilateral basal ganglia signal abnormalities).
Explanation:
• Glutaric acidemia type I (GA-1) is an autosomal recessive organic acid disorder caused by a severe deficiency of the enzyme glutaryl-CoA dehydrogenase.

• This enzyme is essential for the catabolic pathways of the amino acids lysine, hydroxylysine, and tryptophan. Its deficiency leads to the toxic accumulation of glutaric acid and 3-hydroxyglutaric acid.

• Clinically, infants with GA-1 often present early on with macrocephaly (an abnormally large head).

• The devastating phase of the disease typically occurs during an acute catabolic stress (such as a simple viral infection or fasting) between 6 and 36 months of age. The acute accumulation of toxic metabolites causes selective, irreversible necrosis of the striatum (caudate and putamen in the basal ganglia).

• This basal ganglia destruction manifests clinically as severe, permanent extrapyramidal movement disorders, predominantly dystonia and choreoathetosis.

• Option (A), Isovaleric acidemia, typically presents with a "sweaty feet" odor and overwhelming metabolic acidosis, not classically macrocephaly and isolated dystonia.

• Option (C), Methylmalonic acidemia, causes severe recurrent metabolic acidosis, hyperammonemia, and failure to thrive, but macrocephaly is not a defining cardinal feature.

• Option (D), Biotinidase deficiency, typically presents with skin rashes, alopecia, hearing loss, and seizures.
Final answer:
The combination of macrocephaly and dystonia due to basal ganglia injury is the hallmark of Glutaric acidemia type I.