Approach to IEM

1. INTRODUCTION

• Definition: A heterogeneous group of genetic disorders caused by mutations impairing specific enzymes, transport proteins, or cofactors.
• Pathophysiology ("Metabolic Block"):
  • Toxic accumulation of substrates proximal to the block.
  • Deficiency of essential end-products distal to the block.
• Epidemiology: Individually rare, but collectively common (1 in 500 to 1 in 5,000 births). Most are Autosomal Recessive.

2. FUNCTIONAL CLASSIFICATION

Based on the pathophysiology and clinical presentation:

A. Intoxication Disorders

• Mechanism: Accumulation of toxic compounds proximal to the metabolic block.
• Examples: Urea Cycle Disorders (UCD), Organic Acidemias (OA), Galactosemia, MSUD.
• Clinical Pattern: Symptom-free interval after birth $\to$ Rapid deterioration once feeding (protein/sugar) is introduced.

B. Energy Deficiency Disorders

• Mechanism: Failure to produce or utilize energy (ATP).
• Examples: Mitochondrial disorders, Fatty Acid Oxidation Defects (FAOD), Glycogen Storage Diseases (GSD).
• Clinical Pattern: Hypoglycemia, lactic acidosis, multi-system involvement (heart, liver, muscle), hypotonia.

C. Complex Molecule (Storage) Disorders

• Mechanism: Defects in organelles (lysosomes/peroxisomes) causing accumulation of large molecules.
• Examples: Gaucher disease, MPS, Zellweger syndrome.
• Clinical Pattern: Slowly progressive, permanent symptoms, dysmorphism, organomegaly.

3. CLINICAL APPROACH: "WHEN TO SUSPECT"

Key Red Flags (Index of Suspicion)

1. Sepsis Mimicry: Neonates appearing septic (lethargy, refusal to feed) with negative cultures or no response to antibiotics.
2. Sudden Deterioration: Rapid decline in a previously healthy neonate after a symptom-free interval.
3. Family History: Consanguinity, unexplained sibling deaths, or SIDS.
4. Neurological: Unexplained encephalopathy, intractable seizures, loss of milestones.
5. GI: Recurrent vomiting, poor feeding, hepatosplenomegaly.

Physical Examination Pointers

Search for specific signs to narrow the differential:

Characteristic Urine Odors

"Smelling the urine" is a high-yield bedside test:

4. DIAGNOSTIC INVESTIGATIONS

Tier 1: The "Metabolic Screen" (Acute Phase)

Essential investigations for any sick child with suspected IEM:

1. Arterial Blood Gas (ABG): Check for metabolic acidosis and anion gap.
2. Blood Glucose: Check for hypoglycemia.
3. Plasma Ammonia: Check for hyperammonemia (Neonate >100-150 µmol/L).
4. Plasma Lactate: Check for lactic acidosis (indicates energy failure).
5. Urine Ketones: Always pathological in a newborn. Presence indicates organic acidemia or defects in ketoneolysis.

Tier 2: Confirmatory Tests

Based on Tier 1 results:

1. Plasma Amino Acids (PAA): For Amino acidopathies and UCDs.
2. Urine Organic Acids (UOA): For Organic acidemias.
3. Plasma Acylcarnitine Profile (TMS): For FAODs and some OAs.
4. Lactate/Pyruvate Ratio: For mitochondrial disorders.

5. ALGORITHMIC INTERPRETATION (High Yield)

The diagnosis is approached by grouping results into Acidosis, Ketosis, Ammonia, and Lactate.

A. Metabolic Acidosis Present

1. With Ketosis (High Anion Gap)

• Elevated Ammonia:
  • Diagnosis: Organic Acidemias (Propionic Acidemia, Methylmalonic Acidemia).
  • Note: Hyperammonemia is secondary to urea cycle inhibition by organic acids.
• Normal Ammonia:
  • Diagnosis: Maple Syrup Urine Disease (MSUD), Beta-ketothiolase deficiency.
  • Also consider: Succinyl-CoA transferase deficiency.

2. Without Ketosis (No Ketones)

• Hypoglycemia + High Lactate:
  • Diagnosis: Fatty Acid Oxidation Defects (FAOD) (e.g., MCAD, LCHAD).
  • Mechanism: Inability to generate ketones during fasting (hypoketotic hypoglycemia).
• Normal Glucose + Normal Lactate:
  • Diagnosis: Renal Tubular Acidosis (RTA) (Note: This is a renal, not metabolic, cause of acidosis).
• Normal Glucose + High Lactate:
  • Diagnosis: Disorders of Pyruvate Metabolism (Pyruvate Dehydrogenase deficiency), Mitochondrial disorders.

B. No Metabolic Acidosis

1. Hyperammonemia (Primary Feature)

• Respiratory Alkalosis is often present (due to central hyperventilation).
• Diagnosis: Urea Cycle Disorders (UCD).
  • Examples: OTC Deficiency, Citrullinemia, CPS1 Deficiency.
  • Feature: Very high ammonia (>200-500+) with normal glucose and usually no acidosis initially.

2. Isolated Lactic Acidosis

• With Hyperammonemia: Pyruvate Carboxylase Deficiency (Type B).
• With Normal Ammonia:
  • Mitochondrial Disorders (MELAS, MERRF).
  • Pyruvate Carboxylase Deficiency (Type A).
  • Electron Transport Chain (Complex I-IV) disorders.

C. Hypoglycemia Approach

• Ketones Present (+): Organic Acidemias, Carbohydrate metabolism disorders (GSD).
• Ketones Absent (-): Fatty Acid Oxidation Defects (FAOD), Hyperinsulinism.

6. BIOCHEMICAL SUMMARY (Brief)

• Carbohydrates: Disorders of Galactose (Galactosemia) and Fructose (HFI).
• Proteins: Break down into Amino Acids $\to$ Nitrogen (Urea Cycle) and Organic Acids. Defects lead to Amino Acidopathies (PKU, MSUD) or Organic Acidemias.
• Fats: Beta-oxidation defects lead to hypoketotic hypoglycemia.

7. MANAGEMENT PRINCIPLES (ACUTE)

1. INTRODUCTION

• Goal: Prevent permanent neurological damage and death.
• Pathophysiological Basis: Management aims to correct the "metabolic block":
  • Reduce the toxic accumulation of substrates (proximal to block).
  • Supplement the deficiency of essential end-products (distal to block).
• Golden Rule: "Suspect early, treat immediately." Do not wait for confirmatory genetic testing to start acute management.

2. EMERGENCY STABILIZATION (ACUTE PHASE)

The priority is to reverse the catabolic state which exacerbates most IEMs.

A. Initial Resuscitation (A-B-C)

• Airway/Breathing: Secure airway if the child has encephalopathy (GCS < 8) or seizures. Central hyperventilation is common in hyperammonemia.
• Circulation: Treat shock aggressively. Poor perfusion causes secondary lactic acidosis, confusing the metabolic picture.
• Sepsis Coverage (The "Sepsis Mimic"):
  • Infants often present with lethargy, refusal to feed, and temperature instability.
  • Start broad-spectrum antibiotics immediately.
  • Specific Alert: Cover for E. coli sepsis in suspected Galactosemia.

B. Correct Metabolic Derangements

• Hypoglycemia:
  • Common in Energy Deficiency Disorders (e.g., GSD, FAOD).
  • Manage with high-dose IV Dextrose (Glucose Infusion Rate: 8–10 mg/kg/min).
  • Clinical Pearl: In Fatty Acid Oxidation Defects (FAOD), hypoglycemia presents without ketones.
• Metabolic Acidosis:
  • Identify cause: Lactate (perfusion/mitochondrial) vs. Ketones (Organic acidemia).
  • Correct severe acidosis (pH < 7.1) cautiously with bicarbonate.
• Hyperammonemia:
  • A medical emergency leading to cerebral edema and herniation.
  • Medical Management: Nitrogen scavengers (Sodium Benzoate, Phenylbutyrate).
  • Dialysis: Indicated if ammonia levels are critical (Neonates >500 µmol/L) or unresponsive to medical therapy.

3. SPECIFIC MANAGEMENT STRATEGIES

A. Intoxication Type (Small Molecule Disorders)

• Examples: Urea Cycle Disorders (UCD), Organic Acidemias (OA), MSUD.
• Principle 1: Stop the Intake (Substrate Restriction)
  • Strict NPO: Discontinue oral protein/milk immediately upon suspicion.
  • Rationale: Symptoms in these disorders (like MSUD/UCD) typically appear after a symptom-free interval once protein feeding starts.
• Principle 2: Promote Anabolism
  • Provide high calories (Dextrose + Lipids) to suppress catabolism (breakdown of endogenous muscle protein).
  • Note: Avoid lipids if a Fatty Acid Oxidation defect is suspected.
• Principle 3: Toxin Removal
  • Facilitate excretion of toxic metabolites via hydration, medications (scavengers), or dialysis.

B. Energy Deficiency Type

• Examples: Mitochondrial disorders, Fatty Acid Oxidation Defects (FAOD).
• Principle 1: Avoid Fasting
  • Frequent feeding is crucial to prevent hypoglycemia.
• Principle 2: Bypass the Defect
  • MCT Oil: Used in LCAD deficiency (Long-chain defects) to provide energy, as medium-chain fats bypass the carnitine shuttle required for long-chain fats.
  • Uncooked Cornstarch: Used in GSD to maintain blood glucose levels.

C. Cofactor Supplementation (The "Empiric Cocktail")

Administer cofactors that might boost residual enzyme activity pending diagnosis.

• Biotin: For Biotinidase deficiency and Holocarboxylase synthetase defects (treats alopecia/seizures).
• Thiamine (Vitamin B1): For MSUD and Pyruvate Dehydrogenase complex defects.
• Carnitine: For Carnitine deficiency and to help excrete organic acids (as acylcarnitines).
• Vitamin B12: For Methylmalonic Acidemia.

4. LONG-TERM MANAGEMENT PRINCIPLES

Dietary Modification

• Lifelong Restriction:
  • Galactosemia: Soy-based/elemental formula (Strict Lactose/Galactose avoidance).
  • PKU: Low Phenylalanine diet.
  • Fructose Intolerance: Avoidance of fructose/sucrose (fruit juices).
• Medical Formulas: Use of specific amino-acid free formulas (e.g., Leucine-free for MSUD).

Monitoring and Prognosis

• Sick Day Regimen: Parents must be trained to increase glucose intake and stop protein during intercurrent illnesses/fever to prevent catabolic decompensation.
• Organ Surveillance:
  • Eye: Cataracts (Galactosemia).
  • Liver: Hepatomegaly/Dysfunction (Tyrosinemia, GSD).
  • Heart: Cardiomyopathy (Pompe disease, FAOD).
  • Neurological: Developmental milestones and seizure control.
• Genetic Counseling:
  • Most IEMs are Autosomal Recessive (25% recurrence risk).
  • Discussion of prenatal diagnosis options for future pregnancies.