Fatty-Acid Oxidation Disorders

Question 1

VLCAD deficiency - enzyme/gene info

Answer 1

• Very long-chain acyl-coA dehydrogenase
• Catalyzes the first step of the beta-oxidation pathway
• Breaks down long-chain and very long-chain fatty acids (14 carbons or more)
• ACADVL gene
• Autosomal recessive inheritance
• Strong genotype/phenotype correlation - truncating mutations associated with NO residual enzyme activity
• Mild phenotype associated with residual enzyme activity and common p.Val283Ala mutation

Question 2

VLCAD deficiency - phenotype

Answer 2

-3 phenotypes
Severe early-onset cardiac and multi-organ failure VLCAD deficiency:
-HCM or DCM, hepatomegaly, pericardial effusions, cardiac arrhythmias, hypoglycemia
-Lethality from cardiac symptoms
-No associated cognitive impairment

Hypoketotic hypoglycemic VLCAD deficiency:

• Hypoketotic hypoglycemia without associated cardiomyopathy
• Onset in early childhood

Late-onset episodic myopathic VLCAD deficiency:

• Most common phenotype
• Muscle cramps and pain
• Exercise intolerance
• Intermittent rhabdomyolysis
• Hypoglycemia may not be present

Question 3

LCHAD deficiency - enzyme/gene info

Answer 3

• Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
• Breaks down long-chain fatty acids (13-21 carbons)
• HADHA gene
• Autosomal recessive inheritance
• Most people with LCHADD are homozygous for the common mutation c.1528G>C

Question 4

LCHAD deficiency - phenotype

Answer 4

• Severe early-onset (infancy to 12 months)
• Hypoketotic hypoglycemia
• Metabolic acidosis
• Hepatic encephalopathy
• Cardiomyopathy and arrhythmia

Question 5

MCAD deficiency - enzyme/gene info

Answer 5

• Medium-chain acyl-coA dehydrogenase deficiency
• Breaks down medium-chain fatty acids (6-12 carbons)
• ACADM gene
• Autosomal recessive inheritance
• No strong genotype/phenotype correlation
• Common p.Lys304Gly mutation

Question 6

MCAD deficiency - phenotype

Answer 6

• Onset typically by age 2 (may not present until adulthood)
• Previously healthy child presents with:
• Hypoketotic hypoglycemia
• Vomiting
• Lethargy
• Seizures
• Hepatomegaly
• Can progress to coma/death

Question 7

SCAD deficiency - enzyme/gene info

Answer 7

• Short-chain acyl-coA dehydrogenase deficiency
• Breaks down short-chain fatty acids (2-5 carbons)
• ACADS gene
• Autosomal recessive inheritance
• No strong genotype/phenotype correlation
• c.319C>T common mutation

Question 8

Fatty Acid Oxidation Disorders - Treatment

Answer 8

• Avoid fasting for more than 12 hours
• Avoid illness - severe illness in LCHADD and VLCADD can trigger metabolic crisis, routine illness in MCAD and SCAD can trigger metabolic crisis
• Avoid high-fat diets
• Supplement calories with frequent feedings to maintain glucose levels
• Calorie supplementation for LCHADD and VLCADD through C7 (tripheptanoin) and MCT oil
• C7 can reverse/prevent cardiac symptoms in VLCADD patients

Question 9

Fatty Acid Oxidation Disorders - Testing

Answer 9

• All disorders are part of NBS panels
• Acylcarnitine profile
• Urine organic acids can show dicarboxylic acidosis
• Enzyme activity analysis can be useful for VLCADD, but not MCAD/SCAD
• Molecular genetic testing

Question 10

Other Fatty Acid Oxidation Disorders

Answer 10

• Carnitine Palmitoyltransferase I and II Deficiency (CPT I and CPTII) - cardiomyopathy, liver failure, seizures/coma
• Carnitine Transporter Deficiency - hypoglycemia, hepatomegaly, cardiac problems, hyperammonemia