Fatty Acid Oxidation

Describe the 3 stages of fasting.

1. glycogenolysis -- breakdown of glycogen to maintain blood sugar levels (~24 hrs)

2. gluconeogenesis -- synthesizing glucose from non-carbohydrate precursors

3. ketone utilization -- byproduct of fatty acid breakdown to supply energy to the brain

Describe a fatty acid molecule.

• carboxylic acid group

• chain of carbons linked together

  • trans -- functional groups on the opposite side

  • cis -- functional groups on the same side

Where does fatty acid beta-oxidation occur?

occurs primarily in the mitochondria of liver, skeletal muscle, and heart cells

Describe the carnitine shuttle.

• the mitochondrial membrane is not permeable to long-chain fatty acids

  • fatty acids need to be shuttled into mitochondrial matrix via carnitine

What is the first step in beta-oxidation?

• acyl-CoA dehydrogenase -- fatty acyl-CoA is metabolized

  • short-chain acyl-CoA dehydrogenase

  • medium-chain acyl-CoA dehydrogenase

  • very long-chain acyl-CoA dehydrogenase

What are the general clinical presentations of fatty acid oxidation disorders?

newborns:

• cardiomyopathy, hypoketotic hypoglycemia, liver dysfunction

infantile-onset:

• lethargy and vomiting

late childhood/adult onset:

• muscle weakness, renal damage

What are the general dietary guidelines of FAOD?

• avoid periods of fasting

• complex carbohydrate intake

• low fat meals

• MCT oil & carnitine supplementation

Describe the dysfunctional pathway of medium-chain acyl-CoA dehydrogenase deficiency.

• mutation in the ACADM gene (single nucleotide chain -- lysine to glutamate)

  • medium-chain acyl-CoA dehydrogenase is unable to break down the medium-chain acyl-CoA into acetyl-CoA

What are the symptoms of MCADD?

• newborns/infants: altered mental status, emesis, dehydration, drowsiness, and poor feeding

• adolescents/adults:

  • metabolic crisis -- metabolic acidosis, hyperammonemia, hyperlactacidemia, hypoglycemia

  • multi-organ involvement -- neurological, muscular, hepatic, or cardiac symptoms

What are the biochemical values of MCADD?

• increased hexanoylglycine and dicarboxylic acids in the urine

• elevated acylcarnitines

Describe the dysfunctional pathway of very long-chain acyl-CoA dehydrogenase deficiency.

• mutation in the ACADVL gene

  • very long-chain acyl-CoA dehydrogenase is unable to break down the very long-chain acyl-CoA into acetyl-CoA

  • results in toxic derivatives that accumulate and cause damage to the cardiac, hepatic, and muscular tissues

What are the symptoms of VLCADD?

• acute cardiomyopathy

• hypotonia

• hepatomegaly

• intermittent hypoglycemia

• myopathy

How is VLCADD diagnosed?

• positive newborn screening test

  • increase in long-chain acylcarnitines

• other testing: genetic testing, enzymatic assays

What is the tri-functional protein?

• enzyme complex that catalyzes the last 3 steps in beta-oxidation

  • bound to inner-mitochondrial membrane

Describe the dysfunctional pathway of tri-functional protein defect (TFPD).

• mutations in HADHA or HADHB cause TFPD to lose enzymatic functions

What are the clinical presentations of TFPD?

• neonatal onset -- severe form

• infantile onset -- intermediate form

• late adolescent onset -- mild form

How is TFDP diagnosed?

• elevated levels of 3-hydroxy palmitoyl carnitine

  • other testing: enzymatic assays, identify bi-allelic mutations in HADHA/HADHB

Describe the dysfunctional pathway of carnitine uptake defect (CUD).

• mutations in SLC22A5 gene that encodes for the organic carnitine transporter novel type 2

  • OCTN2 is highly expressed in the heart, muscle, kidneys, and other tissues

• defective fatty acid oxidation pathway

What are the biochemical values of dysfunctional OCTN2?

• urinary carnitine wasting

• low serum and intracellular carnitine levels

What is the clinical presentation of CUD?

• defective fatty acid oxidation results in:

  • hypoglycemia due to excessive glucose consumption

  • ectopic fat accumulation in the liver, skeletal muscles, and heart

    • causes … steatosis, myopathy, and cardiomyopathy

How is CUD diagnosed?

• reduced free and total carnitine

• genetic testing