Methylmalonic Acidemia (MMA)

1. DEFINITION AND CLASSIFICATION

• Definition: An autosomal recessive organic acidemia caused by a defect in the conversion of L-methylmalonyl-CoA to succinyl-CoA.
• Classification:
  • Isolated MMA:
    • Mutase Deficiency: MMUT gene defects. Subtypes: mut⁰ (complete deficiency) and mut⁻ (partial activity).
    • Cobalamin Disorders: Defects in synthesis of adenosylcobalamin cofactor (cblA, cblB, cblD-MMA).
  • Combined MMA and Homocystinuria: Defects in cytosolic cobalamin metabolism (cblC, cblD, cblF, cblJ, cblX).

2. ETIOLOGY AND PATHOPHYSIOLOGY

• Metabolic Block: Deficiency of Methylmalonyl-CoA Mutase (MCM) or its cofactor 5-deoxyadenosylcobalamin.
• Precursors: Isoleucine, Valine, Methionine, Threonine (VOMIT), odd-chain fatty acids, and cholesterol side chains.
• Toxic Accumulation: Methylmalonic acid, propionyl-CoA, methylcitrate.
• Consequences:
  • Mitochondrial Toxicity: Inhibition of Krebs cycle (citrate synthase) and oxidative phosphorylation.
  • Hyperammonemia: Inhibition of N-acetylglutamate synthase (NAGS) by propionyl-CoA (urea cycle dysfunction).
  • Hyperglycinemia: Inhibition of glycine cleavage system.
  • Bone Marrow Suppression: Neutropenia, thrombocytopenia.

3. CLINICAL FEATURES

A. Neonatal Onset (Severe - typically mut⁰)

• "Sepsis-like" Presentation: Onset in first week of life.
• Symptoms: Poor feeding, vomiting, profound lethargy, hypotonia.
• Signs: Dehydration, hypothermia, respiratory distress (Kussmaul breathing due to acidosis).
• Neurologic: Rapid progression to seizures, coma, and death if untreated.

B. Chronic/Intermittent (Late Onset - mut⁻ or cbl types)

• GI: Recurrent vomiting, protein aversion, failure to thrive, chronic constipation.
• Neurologic: Developmental delay, hypotonia, regression during intercurrent illness.
• Acute Decompensation: Triggered by infection, fasting, or high protein intake.

4. COMPLICATIONS (LONG-TERM)

• Neurologic (Metabolic Stroke): Acute injury to the globus pallidus (basal ganglia) causing movement disorders (dystonia, chorea) and spasticity.
• Renal (Unique to MMA): Chronic tubulointerstitial nephritis leading to progressive Chronic Kidney Disease (CKD). Most common in mut⁰.
• Other:
  • Acute Pancreatitis.
  • Optic Atrophy.
  • Cardiomyopathy (less common than in Propionic Acidemia).
  • Skin rashes (acrodermatitis enteropathica-like due to iatrogenic amino acid deficiency).

5. INVESTIGATIONS

• Screening Labs:
  • Metabolic Acidosis: High anion gap.
  • Ketosis/Ketonuria: Marked.
  • Hyperammonemia: Mild to severe.
  • Complete Blood Count: Neutropenia, thrombocytopenia, pancytopenia.
  • Hyperglycinemia.
• Diagnostic Tests:
  • Urine Organic Acids: Massive elevation of Methylmalonic Acid. Presence of methylcitrate and 3-hydroxypropionate.
  • Plasma Acylcarnitine Profile: Elevated C3 (propionylcarnitine) and C4DC (methylmalonylcarnitine).
  • Plasma Homocysteine: To rule out combined MMA+HCU (cblC).
• Confirmation:
  • Molecular Genetics: Panel for MMUT, MMAA, MMAB.
  • B12 Responsiveness Testing: Clinical or in vitro challenge.

6. MANAGEMENT

A. Acute Decompensation

• Stop Protein Intake: Immediate cessation of exogenous protein (max 24-48 hours).
• Reverse Catabolism: High calorie IV fluids (D10 + Intralipids) at 1.5x maintenance.
• Detoxification:
  • L-Carnitine: IV loading dose (100 mg/kg) to excrete propionylcarnitine.
  • Ammonia Scavengers: Sodium Benzoate/Phenylacetate if hyperammonemic.
  • Hemodialysis: For severe acidosis/hyperammonemia refractory to medical management.
• Cofactor: Empirical Hydroxocobalamin (Vitamin B12) IM injection (1 mg/day).

B. Chronic Management

• Dietary:
  • Low protein diet restricted in Isoleucine, Valine, Methionine, Threonine.
  • Medical foods (MMA/PA-free formula).
  • Avoid prolonged fasting.
• Pharmacotherapy:
  • Vitamin B12: Hydroxocobalamin IM for B12-responsive patients (cblA and some mut⁻).
  • L-Carnitine: Maintenance (50-100 mg/kg/day).
  • Gut Sterilization: Metronidazole or Neomycin to reduce gut bacterial production of propionate.
• Transplantation:
  • Liver Transplant: Corrects metabolic instability but does not prevent renal progression or reverse existing brain damage.
  • Combined Liver-Kidney: For patients with renal failure.

7. PROGNOSIS

• Heavily dependent on subtype (mut⁰ has poorest prognosis).
• Major morbidity includes intellectual disability and chronic renal failure.
• Early diagnosis via Newborn Screening improves survival but may not prevent all long-term complications.