SN3
SHORT NOTE
5M
★ High-yield
Write a short note on phenylketonuria.
Definition
Phenylketonuria (PKU) = an autosomal recessive inborn error caused by deficiency of phenylalanine hydroxylase, leading to accumulation of phenylalanine and its abnormal metabolites.
- Incidence about 1 in 10,000; the commonest inborn error of amino acid metabolism
Biochemical Basis
Phenylalanine hydroxylase deficient (needs BH4) → Phenylalanine cannot become tyrosine → Blood phenylalanine > 20 mg/dL (normal 1–2) → Diverted to minor pathways by transamination → Phenylpyruvate → phenyllactate → phenylacetate → Excreted in urine
Clinical Features and Their Basis
| Feature | Explanation |
|---|---|
| Mental retardation | Phenylalanine competes for the neutral amino acid transporter at the blood–brain barrier → deprives the brain of tyrosine and tryptophan; also impairs myelination |
| Mousy or musty odour | Phenylacetate in urine and sweat |
| Fair skin, blue eyes, blond hair | Excess phenylalanine inhibits tyrosinase → less melanin |
| Eczema | Common; mechanism uncertain |
| Seizures, hypertonia, tremor | Neurotoxicity |
| Microcephaly | Impaired brain growth |
- The infant is normal at birth, protected in utero by the maternal circulation. Damage begins only after milk feeding starts — which is precisely why screening works
Diagnosis
- Guthrie bacterial inhibition test or tandem mass spectrometry on a heel-prick blood spot
- Taken after 48–72 hours of milk feeding — too early and phenylalanine has not yet risen
- Ferric chloride test on urine — transient green colour; now obsolete
- Confirm with quantitative plasma phenylalanine and tyrosine; measure BH4 and pterins to exclude the malignant variant
Variants
| Type | Defect | Response to diet |
|---|---|---|
| Classical PKU | Phenylalanine hydroxylase | Good |
| Malignant (atypical) PKU | BH4 synthesis or dihydropteridine reductase | Poor — catecholamine and serotonin synthesis also fail. Needs BH4, L-dopa and 5-hydroxytryptophan |
| Benign hyperphenylalaninaemia | Partial enzyme deficiency | May need no treatment |
Treatment and Applied Aspects
- Low phenylalanine diet begun within the first weeks of life — special formula, restricted natural protein, with tyrosine supplementation
- Phenylalanine cannot be eliminated entirely — it is essential; the aim is to keep blood levels in a target range
- Diet for life is now recommended; relaxing it in adolescence causes cognitive and psychiatric problems
- Aspartame must be avoided — it releases phenylalanine; hence the warning on diet drinks
- Maternal PKU — strict control must resume before conception, or the fetus suffers microcephaly and congenital heart disease even though genetically normal
All questions in Amino Acid & Protein Metabolism
- Q1Describe the urea cycle with its reactions, site and energetics. Explain its regulation and add a note on the urea cycle disorders. ★
- Q2Describe transamination and deamination. Explain the sources, transport and disposal of ammonia in the body. ★
- Q3Describe the metabolism of phenylalanine and tyrosine. Discuss the disorders arising from blocks in this pathway. ★
- Q4Describe the metabolism of methionine and cysteine. Explain transmethylation, the role of SAM, and the methyl trap hypothesis. ★
- Q5Define nitrogen balance. Describe protein turnover and protein quality. Compare kwashiorkor with marasmus. ★
- SN1Define transamination. Describe its mechanism, significance and clinical applications. ★
- SN2Define hyperammonaemia. Describe its causes, the basis of ammonia toxicity, and its management. ★
- SN3Write a short note on phenylketonuria. ★
- SN4Describe alkaptonuria and albinism with their biochemical basis. ★
- SN5Describe the structure, synthesis and functions of glutathione. ★
- SN6Write a short note on homocystinuria. Differentiate it from Marfan syndrome. ★
- SN7Describe the synthesis and significance of creatine and creatinine. ★