Introduction
This topic covers phenylketonuria (clinical and genetic characteristics, treatment), the other hereditary aminoacidurias and related amino acid metabolism defects (aminoacidopathies, organic acidopathies, urea cycle defects), and mass screening of newborns for hereditary diseases.
I. Introduction: defects of amino acid metabolism
Inborn errors of metabolism affecting amino acid catabolism are rare genetic disorders caused by mutations in enzymes responsible for amino acid degradation.
- Accumulation of toxic metabolites (amino acids, organic acids, ammonia).
- Deficiency of downstream products (e.g., neurotransmitters, energy molecules).
- Most are inherited in an autosomal recessive manner.
- Onset: often in infancy or early childhood, with neurological, developmental, or metabolic crises.
They can be grouped into:
- Aminoacidopathies: defects in direct amino acid metabolism.
- Organic acidopathies: defects in pathways producing intermediate organic acids.
- Urea cycle defects: defects in detoxification of ammonia.
II. Aminoacidopathies
Disorders where the amino acid itself accumulates in blood/urine.
1. Phenylketonuria (PKU)
- Defect: deficiency of phenylalanine hydroxylase (PAH) or tetrahydrobiopterin (BH₄) cofactor.
- Pathogenesis: phenylalanine accumulates → converted into phenylketones → neurotoxicity.
- Clinical features:
- Intellectual disability if untreated.
- Seizures, microcephaly.
- Hypopigmentation (↓ tyrosine → ↓ melanin).
- Musty/mousy odor of urine.
- Diagnosis: newborn screening (Guthrie test, tandem MS).
- Management: low-phenylalanine diet, tyrosine supplementation; BH₄ therapy in responsive cases.
2. Maple syrup urine disease (MSUD)
- Defect: branched-chain α-ketoacid dehydrogenase complex.
- Pathogenesis: accumulation of leucine, isoleucine, valine → ketoacidosis, neurotoxicity.
- Clinical features:
- Poor feeding, vomiting.
- Neurological signs (lethargy, seizures, developmental delay).
- Sweet “maple syrup” odor of urine.
- Diagnosis: elevated branched-chain AAs in plasma, organic acids in urine.
- Management: dietary restriction of branched-chain AAs, thiamine supplementation (cofactor).
3. Homocystinuria
- Defect: cystathionine β-synthase (CBS) deficiency (most common).
- Pathogenesis: ↑ homocysteine → endothelial damage, connective tissue defects.
- Clinical features:
- Marfanoid habitus (tall, lens dislocation).
- Intellectual disability.
- Thrombosis (major cause of mortality).
- Diagnosis: ↑ plasma homocysteine, ↑ methionine.
- Management: vitamin B₆ (pyridoxine) responsive in some; also folate and B₁₂ supplementation; betaine therapy.