Disorders of fatty acid metabolism: Pathology review

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Case Study0:00–0:59

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.

Physiology0:59–4:18

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.

Pathology4:18–4:41

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 def.4:41–8:24

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.
And since long chain fatty acids can’t be used up, they end up accumulating in cells; so over time, affected individuals can develop dilated cardiomyopathy or an enlarged heart, skeletal hypotonia or decreased muscle tone, and hepatomegaly or an enlarged liver.
Finally, some individuals may develop encephalopathy or brain damage. On the other hand, secondary carnitine deficiency occurs due to an underlying cause or condition, which usually manifests later in life, and so it tends to be milder than primary carnitine deficiency.
A high yield cause is inadequate dietary intake of carnitine, which is mainly found in meat and animal products like milk.
So in a test question, an important clue would be that the individual is a vegan or undergoing total parenteral nutrition.
Another cause is having a gastrointestinal condition that doesn’t allow proper absorption of nutrients, such as short bowel syndrome.
Now, since carnitine is mainly produced by the liver and kidney cells, individuals with liver or kidney disease may also develop carnitine deficiency.
Finally, one last important cause of secondary carnitine deficiency is taking certain medications, such as valproate, that may interfere with carnitine production.
Diagnosis of systemic carnitine deficiency is usually made with newborn screening blood tests showing hypoglycemia, hypoketonemia or low blood ketones, and most importantly, very low carnitine levels.
At the same time, urine tests will reveal increased carnitine levels. Diagnosis can be confirmed with genetic testing to look for the mutated SLC22A5 gene.
Treatment of systemic carnitine deficiency involves carnitine supplementation. For your exams, remember that these individuals also need to avoid fasting to prevent hypoglycemia.Moving on, there’s medium chain acyl-CoA dehydrogenase deficiency, or MCADD for short.

MCADD8:24–10:41

This is caused by a mutation in the ACADM gene, which codes for the enzyme medium chain acyl-CoA dehydrogenase. For your exams, remember that this is also an autosomal recessive disease.
Now, medium chain acyl-CoA dehydrogenase is the enzyme that’s specifically in charge of breaking down medium chain fatty acids into acetyl-CoA.
As a result, fatty acid oxidation is interrupted, which ultimately leads to accumulation of fatty acyl-carnitine that leaks into the blood.Symptoms of MCADD usually first manifest in infants or young children as hypoketotic hypoglycemia, which is associated with lethargy or lack of energy, vomiting, seizures, and even coma.
Keep in mind that these symptoms can often be precipitated by prolonged fasting, strenuous exercise, or diseases like gastroenteritis or the flu, which may cause appetite loss and vomiting.
Over time, many individuals develop liver dysfunction. And since the liver is normally in charge of removing toxic compounds like ammonia from the body, this can result in hyperammonemia or high ammonia levels in blood.
And ultimately, liver dysfunction may cause severe complications like cerebral edema and death. And sadly, MCADD is also associated with sudden infant death syndrome, which is when a child younger than 1 year of age has a sudden and unexplained death.Diagnosis of MCADD also relies on newborn screening blood tests, which has helped greatly reduce the incidence of sudden infant death syndrome.
These tests show hypoglycemia and hypoketonemia, but the most important finding here are the high levels of fatty acyl-carnitine.
Finally, diagnosis can be confirmed with genetic testing to look for the mutated ACADM gene. Treatment of MCADD involves avoiding fasting and prolonged exercise, as well as maintaining a low-fat, high-carbohydrate diet and eating frequent meals.
All right, as a quick recap…Systemic carnitine deficiency can be primary or secondary. Systemic primary carnitine deficiency is caused by an autosomal recessive mutation in the SLC22A5 gene, which codes for the carnitine transporter OCTN2.

Review10:41–13:01

As a result, carnitine is excreted in urine, and can’t be transported inside cells. This often manifests early as fatigue, weakness, irritability, feeding difficulty, and hypoketotic hypoglycemia.
In addition, long chain fatty acids end up accumulating in cells, causing dilated cardiomyopathy, skeletal hypotonia, and hepatomegaly, and some may develop encephalopathy.
On the other hand, secondary carnitine deficiency is caused by inadequate dietary intake, gastrointestinal conditions, liver or kidney disease, and taking certain medications.
This usually manifests later in life, and is milder. Diagnosis of systemic carnitine deficiency mainly involves blood tests showing very low carnitine levels.
Treatment involves carnitine supplementation. Next, medium chain acyl-CoA dehydrogenase deficiency or MCADD is caused by an autosomal recessive mutation in the ACADM gene, which codes for medium chain acyl-CoA dehydrogenase that breaks down medium chain fatty acids into acetyl-CoA.
As a result, fatty acid oxidation is interrupted, which ultimately leads to accumulation of fatty acyl-carnitine in blood.
Symptoms of MCADD usually manifest early as hypoketotic hypoglycemia, lethargy, vomiting, seizures, and coma. Symptoms are precipitated by prolonged fasting, strenuous exercise, or diseases that cause appetite loss and vomiting.
Over time, individuals can develop liver dysfunction, hyperammonemia, cerebral edema, and death. And sadly, MCADD may also cause sudden infant death syndrome.
Diagnosis mainly involves blood tests showing high levels of fatty acyl-carnitine. Treatment involves maintaining a low-fat, high-carbohydrate diet.
Okay, back to our cases. Dalia is a 2 year old girl that presents with fatigue, weakness, and feeding difficulties.

Summary13:01–14:09

This presentation is probably associated with the hypoketotic hypoglycemia revealed via blood tests. The most important clue though, is that her carnitine levels are really low.
All of this, combined with her hepatomegaly, points to systemic carnitine deficiency. And because she’s so young, it’s probably primary.
Diagnosis is confirmed by genetic testing, revealing a mutation in the SLC22A5 gene, so you put Dalia on carnitine supplementation.
After Dalia, you see Luca, a 3 year old boy who had a brief seizure. This was probably precipitated by the fact that he’s been vomiting and fasting for the past few days.
Now, Luca also has hypoketotic hypoglycemia. However, unlike Dalia, he has elevated fatty acyl-carnitine in blood, and this should immediately make you think of medium-chain acyl-CoA dehydrogenase deficiency.
Genetic testing confirms the mutated ACADM gene, so you instruct Luca’s mother to make sure that he
Disorders of fatty acid metabolism: Video | Osmosis