Inherited Metabolic Diseases in Primary Care

Inherited Metabolic Diseases (IMDs) are a group of rare genetic disorders caused by defects in enzymes, transport proteins, or cofactors that disrupt key metabolic pathways. This disrupts normal biochemical pathways in cells.

Basic Pathophysiology of Inherited Metabolic Diseases (IMDs)

Step	What Happens	Result
1️⃣	Gene mutation	Defective or absent enzyme/cofactor
2️⃣	Metabolic block	Normal pathway is interrupted
3️⃣	Substrate accumulation	Toxic buildup (e.g., ↑ phenylalanine in PKU)
4️⃣	Product deficiency	Essential molecules not formed (e.g., ↓ glucose in GSDs)
⚠️	Cellular damage	Multisystem effects (brain, liver, muscle)

Toxicity from accumulated substances → neurotoxicity, organ damage
Energy failure in metabolically active tissues → lethargy, seizures, coma
Metabolic crises may be triggered by:
- Illness
- Fasting
- Physical stress (e.g., surgery)

🧬 Collectively affect ~1 in 2,500 births, making them more common than many individual rare conditions seen in general practice.
🧠 Early recognition is vital—especially in children—to prevent complications such as intellectual disability, organ failure, or death.
⏳ Some IMDs, like porphyrias, may present in adolescence or adulthood, requiring GP awareness beyond paediatrics.

This guide focuses on three IMDs relevant to primary care:
Phenylketonuria (PKU), Glycogen Storage Diseases (GSDs), and Porphyrias—highlighting practical diagnostic clues, red flags, and referral...

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