CHAPTER 16: Metabolism

FATTY ACID OXIDATION DISORDERS

GENERAL PRINCIPLES

Class of metabolic diseases in which enzyme deficiencies in mitochondrial fatty acid import or b-oxidation limit the ability of mitochondria to use fat as an energy source.

EPIDEMIOLOGY

• Overall incidence about 1:10,000; autosomal recessive inheritance

• Medium-chain acyl CoA dehydrogenase (MCAD) deficiency is the most common fatty acid oxidation (FAO) defect

PATHOPHYSIOLOGY

Most significant danger is hypoketotic hypoglycemia, leading to failure of multiple organ systems. General considerations:

• FAO provides energy for heart and liver at baseline, and for skeletal muscle during prolonged exercise. FAO produces ketones used by brain as energy source during prolonged fast

• FAO supports gluconeogenesis by providing ATP, acetyl CoA, and reduced electron carriers

• Risk for hypoketotic hypoglycemia highest when relying on FAO for energy (e.g., prolonged fast, infection)

• Buildup of long-chain fats is toxic to liver, heart, and muscle cells and can result in acute liver injury, cardiomyopathy, or episodic rhabdomyolysis in times of catabolism or excess fat consumption

CLINICAL MANIFESTATIONS

Varies with syndrome but initial presenting symptoms include hypoketotic hypoglycemia; neonatal neurologic symptoms; coma; Reye-like syndrome; cardiac arrhythmia; cardiomyopathy; sudden death, rhabdomyolysis

DIAGNOSTICS

Decompensated Patient

• Dextrose stick; serum Na, K, Cl, HCO₃, hepatic function panel, ammonia, uric acid. CPK, plasma acylcarnitine profile, total and free carnitine

• Blood gas if concern for metabolic acidosis

• Urine for ketones, myoglobin (if blood in U/A), and organic acid profile

• Consider ECG, echocardiography

Other Studies

• Acylcarnitine profiles performed in newborn screening programs have identified FAO disorders (FAOD) in many presymptomatic patients

• Mutation (DNA) diagnosis

• Enzyme assays on fibroblasts for some disorders

MANAGEMENT

Acute

Goal is to reverse hypoglycemia immediately, to curtail anabolism, and to treat associated morbidities:

• Place widest gauge IV catheter immediately. Some patients require central access to maintain high dextrose infusion rates

• Dextrose bolus (initial bolus of 2 cc/kg with D10; bolus may need to be repeated in older patients), then start dextrose infusion with D10 plus electrolytes at 1.5 × maintenance rate. Insulin surge after dextrose infusion inhibits further lipolysis

• Saline boluses if dehydrated, but should not delay establishing euglycemia

• Do not use intralipids

• Early consultation with biochemical geneticist or other specialist

Chronic

• Carnitine supplementation for primary carnitine deficiency (e.g., carnitine transporter defect [CTD]). Use in other FAODs is typically done, but benefit is controversial

• For disorders affecting long-chain FAO, low fat, high carbohydrate diet, limit long-chain fatty acid intake. Diet is unrestricted in medium/short-chain disorders

• For disorders affecting long-chain FAO, supplement diet with medium-chain triglycerides (2–3 g/kg/day for infants; 1 g/kg/day in older children)

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