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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 pathways for GPs.
General practitioners (GPs) may rarely diagnose new cases of inherited metabolic diseases (IMDs), but basic awareness is essential for:
🧠 Recognising red flags
🩺 Initiating emergency management
🔁 Timely referral to specialist services
The RCGP curriculum specifically includes IMDs—such as phenylketonuria (PKU), glycogen storage diseases (GSDs), and porphyrias—as core learning areas for GP trainees [RCGP.org.uk].
The ICIMD ( International Classification of Inherited Metabolic Disorders ) identifies >1,400 disorders, but for clinical use, IMDs are grouped into three practical categories:
| Group | Mechanism | Clinical Clues | Examples |
|---|---|---|---|
| 1️⃣ Intoxication Disorders | Enzyme block → ↑ toxic substrate | Acute crises (vomiting, lethargy), triggered by illness or protein load | PKU, MSUD, Urea cycle defects |
| 2️⃣ Energy Metabolism Disorders | ↓ Energy production/utilisation | Hypoglycaemia, myopathy, exercise intolerance | GSDs, FAODs, Mitochondrial disorders |
| 3️⃣ Complex Molecule Disorders | Defect in handling large molecules | Progressive, multisystem symptoms | Lysosomal & peroxisomal disorders |
IMDs often present with non-specific, episodic, or age-dependent symptoms, making diagnosis challenging. While many are identified via newborn screening, some cases present later—or in adulthood—with subtle or unexplained clinical features.
🩺 GPs should consider IMDs when encountering unexplained symptoms, especially if triggered by illness, fasting, or diet, or when there's a relevant FHx (family history) or consanguinity.
Age Group Clues & Red Flags Possible IMDs Neonates/Infants Poor feeding, vomiting, seizures, FTT¹, unusual odor (e.g. musty in PKU), hepatomegaly + hypoglycaemia PKU, GSD I, urea cycle defects Children Recurrent “crises” after fasting or illness (lethargy, coma), regression of milestones Organic acidurias, GSDs, mitochondrial disorders Adolescents/Adults Unexplained abdominal pain + neuro/psych signs (e.g. AIP), exercise-induced rhabdomyolysis (dark urine) Porphyrias, GSD V (McArdle), urea cycle disorders Any Age Recurrent hypoglycaemia, metabolic acidosis, ↑ ammonia (encephalopathy), FHx, consanguinity Consider broad IMD work-up
Phenylketonuria (PKU) is a rare but well-known inherited metabolic disorder that exemplifies the impact of early detection and treatment.
📊 UK incidence: ~1 in 12,420 births (West Midlands data)
🌍 Global incidence: 1 in 10,000–15,000 births; varies by ethnicity
🧪 Screening milestone: The UK began newborn screening in the late 1950s using the historic “nappy test” (urine-based phenylalanine detection), now replaced by bloodspot testing on day 5.
Phenylketonuria (PKU) is inherited in an autosomal recessive pattern—both parents must be carriers for a child to be affected, with a 25% chance of inheritance in each pregnancy.
Although most UK cases are picked up early via screening, GPs play a continuing role in managing and supporting patients with PKU across the lifespan:
🍽️ Dietary issues: Monitoring adherence to low-phenylalanine diets
🤰 Maternal PKU: Managing women during pregnancy to prevent fetal complications
🧠 Adult symptoms: “Brain fog” or mood symptoms after high-protein intake
🧬 Family planning: Genetic counselling and testing in known or at-risk families
| Aspect | Summary |
|---|---|
| Cause | Deficiency of phenylalanine hydroxylase (PAH) → can’t convert phenylalanine → tyrosine |
| Result | ↑ Phenylalanine in blood → neurotoxicity (especially in infancy and childhood) |
| Detection | Detected on UK newborn screening (heel prick test, day 5) |
| Pathophysiology Clue | ↓ Tyrosine affects melanin and dopamine → fair skin, low mood, cognitive symptoms |
| Clinical Features | Untreated: intellectual disability, seizures, eczema-like rash, musty odour |
| Later Clues | Adults may report “brain fog” or mood issues after protein meals |
| Management | Lifelong low-protein diet + phenylalanine-free formula; some benefit from sapropterin |
| Monitoring | Keep Phe between 120–360 μmol/L (2–6 mg/dL); metabolic team oversees |
| GP Role | Prescribe metabolic products, support adherence, monitor growth and mental health |
| Pregnancy | Poor control in mother → fetal harm (maternal PKU syndrome: ID, microcephaly, heart defects) |
| Referral Points | Non-adherence, pregnancy planning, cognitive decline → liaise with metabolic clinic |
Phenylketonuria (PKU) is frequently used in AKT questions to test knowledge of:
Newborn screening protocols
Inborn errors of metabolism
Nutritional management in chronic disease
Pre-conception and antenatal care in inherited conditions
High-yield AKT topics include:
Recognising features of untreated PKU (e.g. developmental delay, musty odour)
Understanding management principles (low-Phe diet, specialist referral)
Risks of maternal PKU syndrome and GP responsibilities in pre-pregnancy counselling
📌 Tip for AKT: Questions may focus on what the GP should do next—e.g. refer a woman with PKU who wants to conceive, or interpret symptoms like brain fog in a non-adherent adult.
This reflects the RCGP curriculum’s emphasis on inherited metabolic conditions and the GP's role in early recognition, coordination of care, and patient education.
Definition:
GSDs are rare inherited disorders caused by enzyme deficiencies in glycogen synthesis or breakdown.
Glycogen is stored in liver and muscle for energy use during fasting or physical activity.
In GSDs, the enzymes needed to make or release glucose from glycogen don’t work properly.
This causes:
Build-up of abnormal glycogen in cells → organ enlargement or damage (e.g. hepatomegaly)
Inability to release glucose when needed → hypoglycaemia during fasting or exertion
In muscle forms, the muscles can’t access energy → cramps, fatigue, rhabdomyolysis (muscle breakdown)
👶 Incidence: ~1 in 20,000–43,000 births
🧬 >12 types, grouped by affected tissue: liver, muscle, or both
Glycogen Storage Diseases (GSDs) are rare, usually autosomal recessive disorders causing fasting hypoglycaemia or exercise-induced muscle symptoms—not detected by newborn screening but essential for GPs to recognise and refer promptly.
Unexplained fasting hypoglycaemia in infants
Hepatomegaly with poor growth
Exercise-induced muscle pain or myoglobinuria in older children or adults
| Investigation | Purpose |
|---|---|
| Blood glucose, lactate, uric acid, lipids | Biochemical clues (e.g. ↑ lactate, ↓ glucose in Type I) |
| Liver enzymes, CK | ↑ in liver or muscle forms |
| Urine ketones | Often absent in fasting hypoglycaemia (unusual finding) |
| Genetic testing | Confirms diagnosis, identifies specific GSD type |
| Enzyme assays (specialist) | Performed in liver/muscle biopsy (less common now) |
Simplified GSD Classification
| GSD Type | Main Organ | Typical Presentation | Key Features |
|---|---|---|---|
| Type I (Von Gierke) | Liver | Infancy: fasting hypoglycaemia, hepatomegaly | Lactic acidosis, ↑ lipids, ↑ uric acid, ↓ growth |
| Type III | Liver + Muscle | Childhood: hypoglycaemia + muscle symptoms | May improve with age |
| Type V (McArdle) | Muscle | Teen/Adult: exercise intolerance, cramps, dark urine | Myoglobinuria, “second wind” phenomenon |
Clinical Red Flags for GPs
| Age Group | Clues to Suspect GSD |
|---|---|
| Infants/Children | Fasting hypoglycaemia, hepatomegaly, tremors, seizures, poor growth |
| Adolescents/Adults | Muscle pain after exertion, tea-coloured urine, exercise-induced fatigue |
| Any Age | Recurrent hypoglycaemia with low/absent ketones, elevated liver enzymes |
📦 Prescribe dietary products (e.g. cornstarch, supplements)
📈 Monitor growth, puberty, bloods (if shared care)
🧴 Sick-day advice: Urgent IV glucose if not feeding or hypoglycaemic
🧬 Support transitions to adult services
📞 Re-refer adults with GSD for new symptoms or pre-pregnancy planning
Hypoglycaemic seizure or unconsciousness in a known/suspected GSD
Dark urine + muscle pain after exercise → rhabdomyolysis
New diagnosis suspected → refer to metabolic specialist.
Porphyrias are a group of rare inherited disorders of heme biosynthesis, resulting in the accumulation of porphyrin precursors. These substances are toxic in excess and can cause neurovisceral or cutaneous symptoms, depending on the type. The condition is often overlooked in primary care due to its episodic nature and broad symptom spectrum. Early recognition is critical, especially during an acute attack, which may be life-threatening if not treated promptly.
Porphyrias result from enzyme defects in the heme biosynthesis pathway, leading to a build-up of toxic intermediates (e.g. ALA, porphobilinogen, porphyrins).
In acute porphyrias, these neurotoxic substances affect the autonomic and central nervous system, causing abdominal pain, neuropathy, and psychiatric symptoms.
In cutaneous porphyrias, porphyrin accumulation in the skin makes it sensitive to sunlight, leading to blistering and skin fragility.
The specific enzyme deficiency determines which precursors accumulate and the clinical pattern (acute vs. cutaneous).
Porphyrias are broadly classified into acute, cutaneous, or mixed types:
| Type | Main Features | Examples |
|---|---|---|
| Acute (Neurovisceral) | Severe abdominal pain, neuro/psych symptoms | Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria |
| Cutaneous | Photosensitivity, blistering, skin fragility | Porphyria Cutanea Tarda (PCT) |
| Mixed | Combination of both | Variegate Porphyria |
Acute porphyrias, such as AIP, typically present in young adults, often women, with recurrent abdominal pain, neurological disturbances, and psychiatric symptoms like anxiety or hallucinations. One diagnostic clue is dark, reddish-brown urine during attacks due to elevated porphobilinogen. Cutaneous porphyrias, particularly PCT, cause skin fragility, photosensitive blistering, and are often linked with alcohol use, liver disease, or hepatitis C.
Typical Onset: Teens to adulthood; more common in women
Core Symptoms:
Severe abdominal pain (disproportionate to exam/findings)
Neurological: Tingling, limb weakness, even paralysis, seizures
Psychiatric: Anxiety, hallucinations, confusion, agitation
Autonomic: Tachycardia, hypertension, sweating
Urine clue: Dark red or brown urine that darkens on standing
Common Triggers:
Medications (e.g. barbiturates, sulfonamides, OCPs)
Alcohol
Fasting/crash diets
Hormonal changes (e.g. menstrual cycle)
Typical Onset: Adulthood
Key Features:
Photosensitivity: Blistering on sun-exposed areas (hands, face)
Skin fragility, easy scarring, hyperpigmentation
Hypertrichosis: Excess facial/body hair
Associated Conditions:
Liver disease: Hepatitis C, alcohol-related damage, hemochromatosis
Diagnosis is often missed unless specifically considered. During acute attacks, test for urinary porphobilinogen. For cutaneous symptoms, measure plasma/urine porphyrins, LFTs, and screen for Hepatitis C.
Acute porphyria requires prompt treatment with IV glucose and haem arginate, along with removal of triggers. For cutaneous porphyrias, sun avoidance and phlebotomy (in PCT) are central, alongside treating any underlying liver disease.
Porphyria = think multisystem: abdominal + neuro + psych symptoms
Know when to test: Urinary porphobilinogen during attack
Always check drug safety – use the UK Porphyria Drug Database
Refer acute cases urgently; cutaneous forms via routine referral.
Inherited Metabolic Diseases (IMDs) are individually rare but collectively important. While most diagnoses are made in specialist settings, GPs play a vital role in recognising red flags, initiating early investigations, and supporting lifelong care.
Start with basic bloods: glucose, liver function, ammonia, electrolytes
Add specific tests based on clinical suspicion:
↑ Phenylalanine → suspect PKU
↑ Urinary porphobilinogen → suspect AIP
↓ Ketones with hypoglycaemia → suspect GSD
🧬 NHS Metabolic Services – Check local trust for referral links
🩸 Porphyria Support – National Acute Porphyria Service (NAPS)
👨👩👧 Metabolic Support UK – Advocacy and patient education materials
📘 RCGP Curriculum – Highlights IMDs as critical learning for GP trainees and AKT.
