Defects in certain enzymes called metabolic myopathies can prevent prevent the proper metabolism of fatty acids. These can lead to death at an early age. Less serve forms manifest in adults as muscle weakness, cramps, and heart failure.
Carnitine is made in the liver or obtained from our diet, mainly meat. Genetic defects of the OCTN2–the carnitine transporter–prevent the transport of carnitine into several tissues (cardiac and skeletal muscles).
Another cause is a low-level of carnitine synthesis in the liver.
Consequences: acylcarnitines are not made, thus fatty acids cannot enter the matrix to be oxidized. This leads to an increase of lipid storage in muscle and liver due to the imbalance between storage and breakdown. This is a common feature of metabolic myopathies.
Patients have to take oral carnitine supplements for the rest of their lives. Often defective transporters are not completely dysfunctional. An increase in supply (plasma level) can compensate for the lower level of transport.
Fibrates can also help. These activate a family of transcription factors (PPAR) and which trigger the expression of genes implicated in BA. This leads to a boost of FA Oxidation.
A mutation in CPT2 (see previous lecture).
Consequences: exercise intolerance, cramps, muscle weakness, appearing early in adult life. Exacerbated by exercise, fasting, infection (challenges to the body’s metabolism).
The deficiency prevents the conversion of acetylcarnitine to Acetyl-CoA in the matrix. Long acid chain acylcarnitines accumulate and can cause irregular heart beats.
Patients should avoid triggers such as prolonged exercise and fasting. They can adopt high carb diet which minimizes the dependency on lipid metabolism. Fibrates are also an option.
Acyl-CoA Dehydrogenase Defects
Used in step one of Beta Oxidiation. There are in fact variations in this enzyme based on the length of the chain:
- SCAD: C6, C8
- MCAD: C14, C12, C10, C8
- VLCAD: C18, C16
VL: very long; M: medium: S: short
Defects in VLCAD dehydrogenase affect the oxidation of very long chain FAs.
Similar symptoms to CPT2 deficiency. Diagnosed by increased concentration. of long-chain acylcarnitines in the blood and urine.
Defects in MCAD dehydrogenase.
One of the most frequent forms of disease associated with the types of defects. Diagnosed by increased concentration. of medium-chain acylcarnitines, which have a neurotoxic effect.
Defects in SCAD dehydrogenase.
This prevents the final rounds of Beta Oxidation. It’s less severe than the others since some Acetyl-CoA has already been produced. Diagnosis is by detecting increased concentration of 4-carbon acylcarnitines. A related molecule called thematic acid is produced and accumulates in urine causing aciduria, a decrease in urine pH.
Acyl-CoA Dehydrogenase Treatment
The treatment is often simple: eat frequent carb-rich meals and avoid fasting. The goal is to maintain on high levels of muscle/liver glycogen, reducing the dependency on fatty acid oxidations.
Patients with VLCAD deficiencies in particular should have a diet low in very long chain fatty acids. They also supplement their diet with triheptanoin, a TAG with medium length chains and an odd number of carbons. These medium length fatty acids bypass the VLCAD enzyme, while the odd number of carbons provide both acetyl-CoA and propionyl-CoA, a precursor of oxaloacetate, helping the citric acid cycle continue to operate when only fats, and not carbs, are available.
CONGRATULATIONS this concludes the course. Now, re-start from the top.