Phenylketonuria MCQ — NEET PG Practice Question | NEETPGAI
Phenylketonuria
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A 3-month-old infant presents with progressive developmental delay, seizures, and a distinctive mousy odour to the urine. Newborn screening was not performed. The inheritance pattern shown in the pedigree is marked as **A** (autosomal recessive, both parents carriers). Which of the following best explains the biochemical defect underlying this clinical presentation?
A. Deficiency of tetrahydrofolate reductase, leading to elevated homocysteine and neurological damage
B. Deficiency of tyrosine hydroxylase, leading to reduced dopamine synthesis and hyperpigmentation
C. Deficiency of phenylalanine hydroxylase (PAH) enzyme, leading to accumulation of phenylalanine and depletion of tyrosine
D. Deficiency of ornithine transcarbamylase (OTC), leading to hyperammonaemia and encephalopathy
Explanation
Why option 1 is correct
Phenylketonuria (PKU) is the prototypical autosomal recessive inborn error of amino-acid metabolism caused by deficiency of phenylalanine hydroxylase (PAH), the hepatic enzyme encoded on chromosome 12q23.2 that converts phenylalanine to tyrosine using tetrahydrobiopterin (BH4) as cofactor. Loss of PAH activity causes plasma phenylalanine to rise to neurotoxic levels (>1,200 micromol/L in classic PKU), while tyrosine becomes depleted. Excess phenylalanine is transaminated to phenylpyruvate (the namesake "phenylketone"), phenyllactate, and phenylacetate, which are excreted in urine and produce the distinctive mousy odour. The depletion of tyrosine deprives the brain of substrate for dopamine and noradrenaline synthesis, contributing to the intellectual disability and seizures seen in untreated classic PKU. The inheritance pattern A (autosomal recessive with both parents as carriers) is pathognomonic for PKU.
Why each distractor is wrong
Option 2 (Tyrosine hydroxylase deficiency): Tyrosine hydroxylase catalyzes the conversion of tyrosine to L-DOPA and is not the primary defect in PKU. Moreover, tyrosine hydroxylase deficiency would cause hyperpigmentation (excess melanin precursor), not the hypopigmentation (fair skin, blond hair, blue eyes) characteristic of untreated PKU due to tyrosine depletion.
Option 3 (Tetrahydrofolate reductase deficiency): This enzyme is involved in folate metabolism and homocysteine remethylation, not phenylalanine metabolism. Deficiency causes elevated homocysteine and neurological damage but does not produce the mousy odour or the specific biochemical pattern of PKU.
Option 4 (Ornithine transcarbamylase deficiency): OTC deficiency is an X-linked urea-cycle disorder causing hyperammonaemia and encephalopathy. It does not produce the mousy odour, hypopigmentation, or the characteristic elevated plasma phenylalanine seen in PKU, and it does not follow an autosomal recessive inheritance pattern.
High-YieldNEET PG
PKU = PAH deficiency → phenylalanine accumulation + tyrosine depletion → neurotoxicity + mousy odour + hypopigmentation; autosomal recessive; detected by universal newborn screening (Guthrie test or tandem MS at 48–72 hours); treated with lifelong low-phenylalanine diet and medical formulas.
Nelson 21e Ch 102; Harrison's 21e Ch 408
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