Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: Year of the Zebra

Long-chain 3-hydroxyacyl-CoA dehydrogenase, or LCHAD, deficiency is a rare disorder of fatty acid metabolism that prevents the body from metabolizing certain types of fat.

Normally, the primary source of energy in the body is glucose. However, when glucose levels are 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-, and long-chain fatty acids based on their size and length.

When the body needs extra energy, fatty acids are mobilized from fat stores and broken down, or oxidized, in the mitochondria of cells.

Fatty acid oxidation results in the formation of acetyl-CoA, which can be further metabolized to obtain more energy; or sent to the liver to get converted into ketone bodies.

Ketone bodies are important because they are the brain’s alternate source of energy when there’s no glucose available.Now, in LCHAD deficiency, a genetic mutation in the HADHA gene results in a deficiency in an enzyme called long-chain 3-hydroxyacyl-CoA dehydrogenase, which is one of the enzymes involved in the oxidation of long-chain fatty acids.

This deficiency leads to long-chain fatty acids that cannot be broken down, so they end up accumulating in cells. LCHAD deficiency is an autosomal recessive disorder, meaning an individual must inherit two copies of the mutated gene to develop the disorder.Alright, now LCHAD deficiency usually first manifests in infants or young children as hypoketotic hypoglycemia, which is an episode of low blood sugar that can’t be compensated for by producing ketone bodies to obtain energy.

Symptoms of hypoketotic hypoglycemia are often precipitated by fasting, strenuous exercise, or viral infections like gastroenteritis or influenza; and can include lack of energy, nausea and vomiting, seizures, altered mental status, and even coma.

Since fatty acid oxidation primarily takes place in the mitochondria of heart, skeletal muscle, and liver cells, individuals with LCHAD deficiency can develop dilated cardiomyopathy, or an enlarged heart; skeletal muscle hypotonia, or decreased muscle tone; and hepatomegaly, or an enlarged liver.

Finally, LCHAD deficiency can result in damage to the peripheral nerves, causing symptoms like a decrease in sensation in certain parts of the body; or damage to the retina of the eye, leading to visual impairment.Now, testing for LCHAD deficiency is typically done as part of routine newborn screening.

Laboratory tests typically show low blood levels of glucose and ketone bodies, but the most important findings are high levels of medium- to long-chain fatty acids called acyl-carnitines.

Diagnosis of LCHAD can be confirmed with genetic testing identifying mutations in the HADHA gene. Treatment of LCHAD deficiency involves avoiding fasting and prolonged exercise, as well as maintaining a low-fat, high-carbohydrate diet and eating frequent meals.

Additionally, individuals may be recommended dietary supplementation with triheptanoin, a synthetic form of fat that provides an alternate source of fuel that bypasses the deficient enzyme.

Triheptanoin has to be taken with every meal and can be mixed with soft foods and drinks to prevent gastrointestinal upset.

Alright, as a quick recap… Long-chain 3-hydroxyacyl-CoA dehydrogenase, or LCHAD, deficiency is a rare genetic disorder that prevents the body from converting long-chain fatty acids into energy.

Symptoms are usually triggered by prolonged fasting, exercise, or viral infections; and can include lack of energy; vomiting; seizures; enlargement of the heart and liver; and skeletal problems.

Diagnosis is confirmed by genetic testing, and treatment involves avoiding prolonged fasting periods; following a low-fat