Inherited Metabolic Diseases in Children

Related Subjects: |Phenylketonuria (PKU) |Inherited Metabolic defects |Maple Syrup Urine disease |MCAD deficiency |Urea Cycle defects |Galactosaemia

Inherited metabolic diseases (IMDs), also called inborn errors of metabolism, are a heterogeneous group of genetic enzyme or transporter defects that disrupt normal biochemical pathways. The clinical picture arises from three core mechanisms: toxic metabolite accumulation, deficiency of essential products, and energy failure (particularly affecting brain, liver, and muscle). Most are autosomal recessive and present in infancy, but some may present later with subtle or episodic features.

⚠️ When to Suspect (Red Flags)

• 👶 Neonate with poor feeding, vomiting, lethargy, or unexplained encephalopathy
• 🧠 Developmental delay or regression
• ⚡ Seizures (especially refractory or metabolic-triggered)
• 🫁 Apnoea or respiratory distress without clear cause
• 🧪 Metabolic acidosis ± raised anion gap
• 🧬 Hyperammonaemia (very important clue)
• 🍬 Hypoglycaemia (especially without ketosis)
• 👃 Unusual odours (e.g. maple syrup urine disease)
• 👨‍👩‍👧 Family history of consanguinity or unexplained neonatal deaths

🧠 Pathophysiology (Exam Gold)

• 🧪 Substrate accumulation → toxic effects (e.g. ammonia in urea cycle defects)
• ⬇️ Product deficiency → impaired function (e.g. neurotransmitter deficiency)
• 🔋 Energy failure → mitochondrial dysfunction → brain injury
• 🧠 The brain is highly vulnerable due to high metabolic demand

📚 Major Categories

• 🍬 Carbohydrate disorders – e.g. galactosaemia, glycogen storage diseases
• 🧪 Amino acid disorders – e.g. phenylketonuria (PKU), maple syrup urine disease
• 🧬 Organic acidaemias – e.g. methylmalonic acidaemia
• ⚗️ Urea cycle defects – cause severe hyperammonaemia
• 🔋 Mitochondrial disorders – impaired ATP production
• 🧴 Lysosomal storage diseases – e.g. Tay-Sachs, Gaucher disease
• 🧪 Fatty acid oxidation defects – e.g. MCAD deficiency

🚨 Acute Presentation (Neonatal Collapse)

• 📉 Initially well → then rapid deterioration after feeding starts
• 🧠 Lethargy → seizures → coma
• 🧪 Metabolic acidosis or hyperammonaemia
• ⚠️ Often mistaken for sepsis → always consider IMD if cultures negative

🧪 Key Investigations

• 🩸 Blood gas – metabolic acidosis ± raised anion gap
• 🧪 Ammonia level – urgent test (very high = urea cycle defect)
• 🍬 Glucose – hypoglycaemia ± ketosis
• 🧬 Plasma amino acids
• 🧪 Urine organic acids
• 🧴 Acylcarnitine profile
• 🧫 Lactate – suggests mitochondrial disease

💊 Emergency Management (Very High Yield)

• 🚫 Stop protein intake immediately
• 🍬 Give high-dose IV glucose (prevent catabolism)
• 💧 IV fluids for hydration and metabolic support
• 🧪 Treat hyperammonaemia urgently (can require dialysis)
• 💊 Give disease-specific treatments if known (e.g. carnitine)
• 📞 Early involvement of metabolic specialist team

🧠 Key Conditions to Know

• 🧪 Phenylketonuria (PKU) – musty odour, developmental delay → treat with low phenylalanine diet
• 🍁 Maple Syrup Urine Disease – sweet-smelling urine, encephalopathy
• 🧪 MCAD deficiency – hypoglycaemia without ketosis → risk of sudden death
• 🧬 Urea cycle defects – severe hyperammonaemia → cerebral oedema
• 🍬 Galactosaemia – vomiting, jaundice after milk feeds

👶 Newborn Screening (UK Context)

• 🧪 Heel prick test (day 5) screens for several IMDs
• 📌 Includes: PKU, MCAD deficiency, maple syrup urine disease
• 🎯 Early detection prevents irreversible neurological damage

💡 Exam & Clinical Tips

• ⚠️ Always think IMD in a sick neonate with normal infection screen
• 🧪 Check ammonia early – often forgotten but critical
• 🍬 Hypoglycaemia without ketosis = fatty acid oxidation defect
• 🧠 Rapid deterioration after feeding = strong metabolic clue
• 📉 Early treatment can be life-saving and neuroprotective

From a clinical reasoning perspective, IMDs are fundamentally disorders of metabolic flux: when a pathway is blocked, upstream substrates accumulate and become toxic, while downstream products are deficient. The neonatal transition to feeding is a key stressor, as it shifts metabolism from placental supply to endogenous processing, unmasking defects. Hyperammonaemia is particularly dangerous because ammonia crosses the blood–brain barrier and leads to cerebral oedema and encephalopathy. In UK practice, early recognition and rapid escalation to specialist metabolic services are crucial, as outcomes are highly time-dependent.