πŸ”‘ Key Learning

  • Genetic disorders affecting metabolism - most are autosomal recessive
  • The UK newborn blood spot test screens for PKU, MCADD, MSUD, IVA, GA1, and HCU.
  • Early dietary and pharmacological management is essential to prevent metabolic crises, neurodevelopmental delay, and mortality.
  • Typical features include lethargy, hypoglycaemia, encephalopathy, developmental delay, and characteristic odours.
  • Management often includes dietary restriction, emergency plans for illness, and specific supplements like carnitine or riboflavin.

πŸ§ͺ Conditions Screened in UK Newborn Blood Spot Test

  • Phenylketonuria (PKU)
  • Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
  • Maple Syrup Urine Disease (MSUD)
  • Isovaleric Acidaemia (IVA)
  • Glutaric Aciduria Type 1 (GA1)
  • Homocystinuria (HCU)

🧬 Phenylketonuria (PKU)

Pathophysiology

  • Autosomal recessive defect in phenylalanine hydroxylase
    • Leads to toxic accumulation of phenylalanine
      • Disrupts brain development

πŸ‘€ Clinical Features

  • Developmental delay
  • Intellectual disability
  • Seizures
  • Hypopigmentation (fair skin, hair)
  • Musty/mousy body odour

πŸ’Š Management

  • Lifelong low-phenylalanine diet
  • Regular monitoring of phenylalanine levels
  • Sapropterin (tetrahydrobiopterin) in responsive cases

🧬 Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

Pathophysiology

  • Autosomal recessive defect in fatty acid Ξ²-oxidation
  • Energy deficiency during fasting or illness

πŸ‘€ Clinical Features

  • HypoglycaemiaΒ without ketonesΒ (hypoketotic hypoglycemia)
  • Lethargy
  • Vomiting
  • Seizures
  • Sudden death during illness

πŸ’Š Management

  • Avoid fasting
  • Regular feeding
  • High-carbohydrate intake during illness
  • Emergency treatment for hypoglycaemia

🧬 Maple Syrup Urine Disease (MSUD)

Pathophysiology

  • Autosomal recessive defect in branched-chain ketoacid dehydrogenase
  • Accumulation of leucine, isoleucine, valine

πŸ‘€ Clinical Features

  • Maple syrup odour in urine
  • Seizures
  • Developmental delay

πŸ’Š Management

  • Restriction of branched-chain amino acids (leucine, isoleucine, valine)

🧬 Isovaleric Acidaemia (IVA)

Pathophysiology

  • Autosomal recessive defect in isovaleryl-CoA dehydrogenase
    • Accumulation of isovaleric acid
      • Interferes with Krebs cycle and mitochondrial function

πŸ‘€ Clinical Features

  • Vomiting
  • Failure to thrive
  • Sweaty feet odour
  • Lethargy
  • Seizures, coma during crises

πŸ’Š Management

  • Low-leucine diet
  • Glycine or carnitine to aid acid clearance

🧬 Glutaric Aciduria Type 1 (GA1)

Pathophysiology

  • Autosomal recessive defect in glutaryl-CoA dehydrogenase
  • Accumulation of glutaric acid β†’ basal ganglia toxicity

πŸ‘€ Clinical Features

  • Macrocephaly
  • Dystonia
  • Extrapyramidal signs (chorea, spasticity)
  • Encephalopathic crises during illness

πŸ’Š Management

  • Low-lysine diet
  • Riboflavin and carnitine supplementation
  • Emergency care: IV glucose, avoid fasting

🧬 Homocystinuria (HCU)

Pathophysiology

  • Autosomal recessive defect in cystathionine Ξ²-synthase
    • Accumulation of homocysteine and methionine

πŸ‘€ Clinical Features

  • Marfanoid habitus
  • Ectopia lentis (lens dislocation)
  • Intellectual disability
  • Thrombosis (DVT, stroke)
  • Osteoporosis

πŸ’Š Management

  • Pyridoxine (vitamin B6) if responsive
  • Low-methionine diet + cysteine supplementation
  • Folic acid and betaine
  • Anticoagulation in high-risk patients

πŸ“ Exam Clues & Clinchers

  • Musty odour, fair skin, intellectual delay β†’ PKU
  • Hypoglycaemia without ketones β†’ MCADD
  • Sweet-smelling urine + encephalopathy β†’ MSUD
  • Sweaty feet odour + vomiting β†’ IVA
  • Macrocephaly + movement disorder post-illness β†’ GA1
  • Marfanoid + lens dislocation + thrombosis β†’ HCU