1. Background

• MCAD is one of four enzymes in the mitochrondria responsible for the breakdown of medium-chain (C4-C14) fatty acids to 2-carbon fragments (acetyl-CoA) in the beta oxidation pathway
• there are 3 straight-chain acyl-CoA dehydrogenases to deal with long, medium, and short chain fatty acids

2. History

• 1982 - Kolvraa et al.
  • first to recognize MCAD Deficiency
• 1986 - Matsubara et al.
  • assigned MCAD to chrom. 1p31
• 1987 - Kelly et al.
  • MCAD cDNA clone sequenced
• 1990 - Matsubara et al.
  • first point mutation identified: G985 (Lys -> Glutamine)
  • accounts for 85-90% of the mutant MCAD alleles
  • incidence of the G985 allele is about 1/70

3. Genetic Defect

• genetic defect -> deficiency of MCAD activity -> homozygous patients are unable to mobilize large fat stores and are thus at risk for becoming hypoglycemic when stressed (i.e., during infection or fasting) during which time the long and short acyl-CoA dehydrogenases are unable to compensate for the lack of MCAD
• may present as recurrent episodes of hypoglycemic coma with medium-chain dicarboxylicaciduria, impaired ketogenesis (hypo-ketotic), and low plasma & tissue carnitine levels
• characterized by an intolerance to prolonged fasting
• the patient may remain asymptomatic and appear healthy for long periods of time but then present suddenly and fatally as a SIDS-like illness
• MCAD Deficient patients may present with a family history of
• SIDS or Reye's Syndrome

1. Episodic Manifestations

• the first episode usually occurs between .5 to 2 years of age after a 12-16 hour period of stress

1. Serum

• wide anion gap metabolic acidosis (anion = dicarboxylic acid)
• hypoketotic hypoglycemia
• secondary hyperammonemia
• elevated urea, uric acid, transaminases
• prolonged PT, PTT
• secondary carnitine deficiency (25% decline in level)

2. Urine

3. Diagnosis

• deficiency of MCAD activity in leukocytes and cultured skin fibroblasts
• prenatal
  • deficiency of MCAD activity in cultured chorionic villi or amniocytes
  • point mutations identified by PCR

4. Pathology

1. Supportive

• a chronic disease with a life-long risk of episodes of hypoketotic hypoglycemia and thus must:
  • provide long-term follow-up
  • moniter serum glucose (for hypoglycemia)
  • coordinate a multidisciplinary approach:
    • Paediatrics, Neurology, Dietary, Genetics, Metabolics
  • plan for acute episodes
  • provide a medic alert bracelet

2. Goals of Therapy

• symptomatic control of and avoidance of acute episodes (stress)
• not curative

3. Diet

4. Carnitine Therapy

• 100 mg/kg/day po
• acts to eliminate potentially toxic metabolites which may accumulate

5. Prognosis

• life threatening and up to 25% die during the first attack
• excellent if patient survives initial episodes