Maple Syrup Urine Disease

Definition

Maple Syrup Urine Disease (MSUD) is an autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism.
Caused by a deficiency of the mitochondrial Branched-Chain $α$ -Ketoacid Dehydrogenase (BCKDH) complex.
Results in the accumulation of Leucine, Isoleucine, and Valine and their corresponding $α$ -ketoacids in blood, urine, and cerebrospinal fluid (CSF).

Enzyme Defect: Dysfunction of the BCKDH complex, which catalyzes the oxidative decarboxylation of branched-chain $α$ -ketoacids.
- The complex consists of three catalytic components: $E_{1}$ ( $α$ and $β$ subunits), $E_{2}$ , and $E_{3}$ .
- Genetics:
  - BCKDHA ( $E_{1 α}$ ), BCKDHB ( $E_{1 β}$ ): ~80% of cases (Classic MSUD).
  - DBT ( $E_{2}$ ): ~20% of cases.
  - DLD ( $E_{3}$ ): Rare; $E_{3}$ is shared with Pyruvate Dehydrogenase and $α$ -Ketoglutarate Dehydrogenase complexes.
Neurotoxicity Mechanisms:
- Leucine Accumulation: The primary neurotoxin. Acute high levels cause cerebral edema; chronic elevation causes hypomyelination.
- Transport Competition: Excess Leucine saturates the Large Neutral Amino Acid (LNAA) transporter at the blood-brain barrier, inhibiting uptake of other essential amino acids (Tyrosine, Tryptophan, Histidine, etc.) $\to$ neurotransmitter depletion (Dopamine, Serotonin) and impaired protein synthesis.
- $α$ -Ketoisocaproic Acid (KIC): A leucine metabolite that inhibits the Krebs cycle and oxidative phosphorylation $\to$ energy failure.

1. Classic MSUD (Most Common & Severe)

Enzyme Activity: <2-3%.
Onset: Neonatal (4–7 days of life).
Presentation:
- Initial: Poor feeding, lethargy, irritability.
- Progression: Vomiting, alternating hypertonia/hypotonia, opisthotonos, characteristic "boxing and bicycling" movements.
- Odor: Sweet, malty, maple syrup odor in cerumen (earwax) first, then urine/sweat (due to sotolone).
- Complications: Seizures, cerebral edema, coma, central respiratory failure, death if untreated.
- Imaging: Cerebral edema (localized to cerebellum, dorsal brainstem, cerebral peduncles).

2. Intermediate MSUD

Enzyme Activity: 3–30%.
Presentation: Insidious onset in infancy/childhood.
Features: Failure to thrive, developmental delay, seizures, chronic intellectual disability.
Risk: Can develop acute "classic-like" encephalopathy during catabolic stress.

3. Intermittent MSUD

Enzyme Activity: 5–40%.
Presentation: Normal growth and development.
Course: Asymptomatic intervals interrupted by acute metabolic decompensation (ataxia, lethargy, seizures, odor) triggered by infection, surgery, or high protein load.
Mortality: Risk of death during acute crises due to cerebral edema.

4. Thiamine-Responsive MSUD

5. E3 Deficiency (MSUD Type 3)

Defect: Dihydrolipoamide dehydrogenase (DLD).
Features: Combined phenotype of MSUD + Lactic Acidosis (Pyruvate Dehydrogenase deficiency) + $α$ -Ketoglutaric aciduria.
Clinical: Severe hypotonia, developmental delay, Leigh syndrome-like presentation.

Newborn Screening (NBS):
- Method: Tandem Mass Spectrometry (TMS).
- Marker: Elevated Leucine/Isoleucine and Allo-isoleucine.
Biochemical Diagnosis:
- Plasma Amino Acids:
  - Markedly elevated Leucine, Isoleucine, Valine.
  - Allo-isoleucine: Pathognomonic marker (normally not present).
  - Decreased Alanine.
- Urine Organic Acids: Elevated branched-chain $α$ -ketoacids (BCKA) and hydroxyacids.
- DNPH Test: 2,4-dinitrophenylhydrazine added to urine $\to$ yellow precipitate (screening test for ketoacids).
Molecular Genetics: Panel testing for BCKDHA, BCKDHB, DBT, DLD.
Neuroimaging (MRI Brain):
- Acute: DWI restriction (cytotoxic edema) in deep cerebellar white matter, brainstem, globus pallidus, thalami.
- Chronic: Diffuse cerebral atrophy, hypomyelination.

Goal: Rapid reduction of plasma Leucine (neurotoxic) and reversal of catabolism.
Protocol:
1. Stop Protein Intake: Immediately.
2. Promote Anabolism: High-calorie intravenous fluids (Glucose 10–12 mg/kg/min + Lipids) to suppress proteolysis. Insulin drip may be required to control hyperglycemia and promote anabolism.
3. Active Leucine Removal:
  - Hemodialysis / Hemofiltration: Most effective; indicated if Leucine >250 mg/dL (>1900 $μ$ mol/L) or severe encephalopathy.
  - Peritoneal dialysis is ineffective.
4. Supplementation:
  - Isoleucine and Valine: Administer enteral/IV to compete with Leucine at the blood-brain barrier (LNAA transporter) and prevent deficiency (which halts protein synthesis).
5. Cerebral Edema Management: Hypertonic saline or mannitol; avoid rapid fluid shifts.

Dietary Restriction:
- Lifelong restriction of natural protein (Leucine).
- MSUD Medical Formula: BCAA-free mixture to provide essential amino acids, calories, and micronutrients.
- Goal Leucine: Maintain plasma levels $75 - 300$ $μ$ mol/L (age-dependent).
Thiamine Trial: Trial of 50–200 mg/day for 3–4 weeks in all new patients.
Monitoring: Weekly/monthly amino acid profiles; monitor for specific deficiencies (Zinc, Selenium, essential fatty acids) and skin rashes (acrodermatitis enteropathica-like rash due to Isoleucine deficiency).
Liver Transplantation:
- Curative for metabolic instability (liver restores enough enzyme activity to prevent crises).
- Allows liberalization of diet (not completely normal but no medical formula needed).
- Does not reverse existing brain damage.
Emerging Therapies: Sodium Phenylbutyrate (decreases BCAA levels in some responsive patients).

Untreated: Death in infancy or severe spastic tetraplegia and profound intellectual disability.
Treated:
- Outcome correlates with long-term Leucine control and severity of neonatal crisis.
- Even with treatment, patients are at risk for ADHD, anxiety, executive dysfunction, and metabolic stroke.
- "Metabolic intoxication" can occur at any age with illness.