Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare, inherited metabolic disorder that impacts the body’s ability to convert specific types of fat into usable energy. It belongs to a group of conditions known as fatty acid oxidation disorders, which prevent the normal breakdown of long-chain fatty acids. This inability to process fat efficiently leads to both an energy deficit and a dangerous accumulation of toxic byproducts within the body’s cells. LCHAD deficiency is typically identified early in life through comprehensive public health screening programs because of its potentially severe consequences.
How LCHAD Deficiency Affects Metabolism
The disorder stems from a defect in the mitochondrial trifunctional protein (MTP), an enzyme complex located within the mitochondria. This complex is responsible for the last three steps of the \(\beta\)-oxidation pathway for long-chain fatty acids. Specifically, LCHAD deficiency involves an isolated reduction in the activity of one part of this complex, the long-chain 3-hydroxyacyl-CoA dehydrogenase enzyme.
When the LCHAD enzyme is deficient, the body cannot properly break down long-chain fatty acids. During periods when the body relies on fat for fuel, such as fasting, illness, or prolonged exercise, this metabolic block causes a severe energy shortage. Simultaneously, partially processed long-chain fatty acids and their byproducts build up to toxic levels. This accumulation of toxic intermediates, like long-chain 3-hydroxyacyl-CoAs, can damage organs that rely heavily on fat for energy, including the heart, liver, and muscles.
LCHAD deficiency is an autosomal recessive inherited disorder, meaning an individual must inherit a mutated copy of the responsible gene from both parents. The gene involved is the HADHA gene, which provides the instructions for making the alpha subunit of the mitochondrial trifunctional protein. Variants in this gene disrupt the function of the LCHAD enzyme, creating the block in the fatty acid oxidation pathway.
Symptoms and the Diagnostic Process
Symptoms often appear in infancy or early childhood, though severity and timing vary widely. The condition frequently presents with acute symptoms triggered by catabolic stress, such as illness or fasting. Initial signs include lethargy, poor feeding, weak muscle tone (hypotonia), and episodes of low blood sugar (hypoglycemia). This hypoglycemia is typically hypoketotic, meaning the body cannot produce ketone bodies to compensate for the low sugar.
If not diagnosed quickly, the condition can progress to serious complications, including liver enlargement (hepatomegaly), heart muscle weakness (cardiomyopathy), and muscle tissue breakdown (rhabdomyolysis). Most cases are identified before symptoms manifest through Newborn Screening (NBS) programs. Newborn screening involves analyzing a small blood sample collected from a heel stick shortly after birth.
The screening measures levels of specific acylcarnitines in the baby’s blood, particularly C16OH, which is often elevated. An out-of-range screen does not confirm the disorder but necessitates immediate follow-up testing. Confirmatory diagnostic tests include quantification of acylcarnitines and other metabolites in blood and urine, along with molecular genetic testing of the HADHA gene.
Treatment through Dietary and Acute Care
Treatment relies on a strict dietary regimen that prevents the body from needing to rely on long-chain fatty acids for energy. The primary goal is to avoid fasting by ensuring regular, frequent meals and snacks, often requiring supplemental overnight feedings for infants and young children. The diet must significantly restrict long-chain fat intake, typically limiting it to about 10% of total energy intake.
Dietary therapy includes supplementation with Medium-Chain Triglyceride (MCT) oil. Unlike long-chain fatty acids, medium-chain triglycerides do not require the LCHAD enzyme and can be metabolized for energy, providing a safe fat source. For infants and toddlers, a dosage of 1.0 to 1.5 grams of MCT oil per kilogram of body weight is often recommended for additional calories. The remainder of the diet is rich in carbohydrates to provide the body with its preferred energy source.
Acute care, known as “sick-day rules,” is a protocol for managing metabolic crises triggered by illness, fever, or vomiting. Any illness or stressor that reduces food intake or increases energy demands puts the child at high risk for metabolic decompensation. During these periods, the child must immediately increase their intake of simple carbohydrates, such as sugary drinks, to prevent the body from entering a fat-burning state.
If a child with LCHAD deficiency is unable to tolerate oral intake due to vomiting or lethargy, immediate hospitalization is required. Intravenous (IV) glucose must be administered without delay to provide a continuous, high-dose source of energy. This IV glucose, typically a 10% dextrose solution, stops the body’s catabolic state, preventing the use of stored long-chain fats and halting the buildup of toxic byproducts.
Living with LCHAD Deficiency and Prognosis
When LCHAD deficiency is diagnosed early and managed with strict adherence to dietary and emergency protocols, the prognosis is significantly improved, allowing children to lead healthy lives. However, even with diligent management, individuals with the condition face the risk of developing chronic, long-term complications. These complications are often linked to the repeated or lingering effects of toxic intermediate buildup, especially in sensitive tissues.
Two specific long-term issues are progressive pigmentary retinopathy and cardiomyopathy. Retinopathy involves changes to the light-sensitive tissue at the back of the eye, leading to impaired vision, including difficulty seeing in low light. This eye complication is more common in LCHAD deficiency than in other related fatty acid oxidation disorders, and its progression correlates with metabolic decompensations.
Cardiomyopathy (weakening of the heart muscle) is a significant risk, alongside peripheral neuropathy (loss of sensation in the arms and legs). Individuals with LCHAD deficiency require regular, specialized monitoring by a multidisciplinary medical team. This team typically includes a metabolic specialist, a cardiologist for heart function checks, and an ophthalmologist for annual eye examinations to track and manage potential complications.