Content Reviewers:Antonia Syrnioti, MD
Two kids are brought to the clinic by their mothers. The first one’s Dalia, a 2 year old girl. Her mother is concerned because Dalia always seems to be tired and weak, and in general doesn’t eat much. On physical examination of the abdomen, you palpate an enlarged liver. You decide to run a blood test, which reveals that her blood glucose and ketone bodies are decreased, but what really stands out to you is that her carnitine levels are also really low.
After Dalia, you see Luca, a 3 year old boy who had a brief seizure earlier that day. Luca’s mother tells you that he’s had gastroenteritis for the past few days, so he’s been vomiting and not eating much. You decide to run a blood test, which also reveals low blood glucose and ketone bodies, but unlike Dalia, he has high levels of fatty acyl-carnitine.
Based on the initial presentation, both Dalia and Luca seem to have some fatty acid metabolism disorder. Now, let’s review fatty acid metabolism real quick. Normally, the body's main source of energy is the glucose we get from food. When glucose is running low, like with prolonged fasting or exercise, the body is able to obtain energy from stored fats.
The simplest form of fats are fatty acids, which are grouped by length into short, medium, long, and very long chain fatty acids. Short and medium chain fatty acids are primarily obtained from the diet, while long and very long chain fatty acids can be synthesized from acetyl-CoA by the liver and fat cells.
Now, keep in mind that acetyl-CoA is usually found in the mitochondrial matrix, whereas the enzymes required for fatty acid synthesis are all in the cytoplasm. For acetyl-CoA to cross the mitochondrial membranes and get to the cytoplasm, it first needs to combine with oxaloacetate to form citrate. Once in the cytoplasm, an enzyme called citrate lyase leaves citrate back into acetyl-CoA and oxaloacetate. This whole process is called the citrate shuttle.
Now, when the body needs some extra energy, fatty acids can be broken down by the acyl-CoA dehydrogenases into smaller chain fatty acids to ultimately obtain acetyl-CoA. This process is called fatty acid or beta oxidation. To do this, fatty acids need to leave the fat cells, and enter the bloodstream, where they bind to a protein called albumin.
Albumin carries the fatty acids to the heart, skeletal muscle, and liver cells, which is where fatty acid oxidation mainly takes place. Once inside these cells, a cytosolic enzyme called fatty acyl-CoA synthetase adds a coenzyme A or CoA molecule to the end of the fatty acid, turning it into a fatty acyl-CoA.
Now, oxidation of very long chain fatty acyl-CoAs takes place in the peroxisomes, and that’s another topic; on the other hand, oxidation of short, medium, and long chain fatty acyl-CoAs takes place in the mitochondrial matrix. What’s important here is that short and medium chain fatty acyl-coAs can freely cross the mitochondrial membranes, while the long chain fatty acyl-CoAs can’t.
To get around this problem, an enzyme within the outer mitochondrial membrane called carnitine palmitoyltransferase 1 or CPT1 replaces the CoA with a carnitine, making fatty acyl-carnitine and a free CoA, both of which can easily cross the inner mitochondrial membrane. Then, along the inner mitochondrial membrane, another enzyme called carnitine palmitoyltransferase 2 or CPT2 substitutes carnitine and CoA back, therefore regenerating fatty acyl-CoA and free carnitine within the mitochondrial matrix. This whole process is called the carnitine shuttle, and it’s very high yield.
With prolonged starvation, fatty acid oxidation ramps up, and the excess acetyl-CoA is sent to the liver to get converted into ketone bodies. These ketone bodies are then released into the bloodstream, so that they can reach the rest of the body and be used to obtain energy.
Now, fatty acid metabolism disorders result from a defect of an enzyme involved in obtaining energy sources like acetyl-CoA and ketone bodies from fatty acids. For your exams, the two most high yield fatty acid metabolism disorders are systemic carnitine deficiency and medium chain acyl-CoA dehydrogenase deficiency.
Let’s begin with systemic carnitine deficiency, in which there’s not enough carnitine available to assist in the carnitine shuttle. Systemic carnitine deficiency can be primary or secondary. Systemic primary carnitine deficiency, or SPCD for short, is caused by a mutation in the SLC22A5 gene, which codes for the organic cation transporter protein OCTN2.
For your exams, remember that this is an autosomal recessive disease, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition. Now, OCTN2 is a carnitine transporter that would normally help reabsorb carnitine in kidneys, as well as transport carnitine inside cells capable of fatty acid oxidation.
As a result, in primary carnitine deficiency, most of the carnitine ends up being excreted in urine, leading to a carnitine shortage in the body. And even that little carnitine available can’t be transported inside the cells to be used in the carnitine shuttle. As a result, long chain fatty acids can’t get into the mitochondria, so fatty acid oxidation is impaired.
Systemic primary carnitine deficiency often first manifests in infants or young children as fatigue and weakness. In addition, the child may show irritability and feeding difficulties. What’s most important for your exams is that, during fasting, individuals may experience hypoketotic hypoglycemia, which is basically an episode of low blood sugar that can’t be compensated by producing ketone bodies to obtain energy.
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