Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency

Introduction

Long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency is a rare metabolic disorder that prevents the conversion of certain fats into energy. Glucose is the primary source of energy in the body. During fasting, the body initially tries to compensate for the glucose deficiency by relying on the stored form-glycogen from the liver and the skeletal muscles. Depleting glycogen content makes the body tap into the fat reserves to fulfill the energy requirements. During such dire needs, an LCHAD deficiency results in energy shortage and weakness.

Who Is Susceptible to LCHAD Deficiency?

The exact global incidence of LCHAD deficiency is still unknown, but a Finnish study estimates the incidence of one in 62,000 individuals in their population. The condition-relevant mutations were found in 100 percent of the alleles in the Ukrainian patients, where the frequency was found to be one in 329,968 individuals, which places the incidence 2.1 times lower than the average European incidence. The condition was also seen in significantly higher numbers in the adult Kashubian population (in north Poland), Silesian population (in south Poland), and Austria. The condition is reported in all ethnic groups with no gender predilection. The deficiency presents clinical features around six months, with just a minority of patients (15 percent) presenting with neonatal development.

What Causes LCHAD Deficiency?

LCHAD deficiency is caused due to a molecular defect that leads to mitochondrial trifunctional protein (MTP) dysfunction. Molecular defects affecting MTP function cause two types of problems-LCHAD deficiency and MTP deficiency.

Primarily, a mutation in the HADHA gene is the cause of LCHAD deficiency. The HADHA gene is present on the short arm of chromosome 2. Being autosomal recessive in inheritance, LCHAD deficiency can affect an individual if the person receives both the mutated gene variants in their genome from either parent (affected or carrier). The presence of one copy of the wild gene in the genome typically does not prop up any characteristic LCHAD deficiency symptoms.

What Is the Pathophysiology of LCHAD Deficiency?

LCHAD deficiency is caused due to the presence of mutant HADHA genes in the genome. These genes are responsible for building a part of the enzyme complex known as mitochondrial trifunctional protein. This enzyme is intimately involved with fat metabolism within the mitochondria. Since the deficiency involves a malfunctioning enzyme complex, it is evident that each of the three segments within the complex is responsible for a different function in mitochondrial long-chain lipid metabolism. As a result of mutant enzyme complexes, fats are not adequately broken down into ATP (adenosine triphosphate-unit of energy), leading to a state of weakness, lethargy, and hypoglycemia in the body.

The severity of the deficiency can also be adjudged by the number of enzymatic aberrations (out of three present in the complex). Additionally, the lack of long-chain fatty acid breakdown leads to the accumulation of these fats. Such abnormal fatty deposition can cause extensive damage to the liver, heart, muscles, and retina.

What Are the Signs and Symptoms of LCHAD Deficiency?

LCAHD deficiency usually presents with recurrent episodes of hypoketotic hypoglycemia, often caused secondary to fasting or illness. Other clinical features of the condition are:

• Liver dysfunction.

• Cardiomyopathy.

• Skeletal myopathy.

• Peripheral neuropathy.

• Retinopathy.

Early Onset

The neonatal onset of the deficiency is often severe, with cardiac manifestations. The signs are:

• Metabolic Decompensation: Encephalopathy, hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, hepatosteatosis, lactic acidosis, and hyperammonemia.

• Neurologic Manifestations: Encephalopathy, lethargy, poor feeding, seizures, apnea, or coma.

• Cardiac Manifestations: progressive dilated cardiomyopathy, arrhythmias, and cardiac failure.

Infantile Onset

Infantile onset shows intermediate severity with primarily hepatic manifestations.

• Hypoketotic hypoglycemia.

• Lactic acidosis.

• Elevated liver enzymes.

• High creatine kinase.

• Vomiting.

• Lethargy.

• Poor feeding.

• Hepatomegaly.

• Weakness.

• Feeding difficulties.

• Hypotonia.

• Cardiomyopathy.

• Long QT intervals.

• Liver cirrhosis.

• Cholestasis.

• Developmental delays.

Later Onset

The late onset of LCHAD deficiencies is often mild in their presentation, primarily neuromyopathic manifestations.

• Skeletal Manifestations: Weakness, exercise intolerance, hypotonia, rhabdomyolysis, diffuse muscle pain, myoglobinuria, and elevations of serum CK (creatine kinase), aldolase, aspartate aminotransferase, and alanine transaminase enzymes.

• Neuropathies: Progressive peripheral neuropathy (similar to axonal Charcot-Marie-Tooth disease).

How to Diagnose LCHAD Deficiency?

Symptomatic individuals present to the primary physician with characteristic clinical features. Upon recognizing the symptoms, laboratory tests are ordered to look for supportive findings of LCHAD deficiency.

Non-specific Laboratory Report:

• Hypoglycemia.

• Absence of ketones in urine even with hypoglycemia.

• Metabolic acidosis.

• Lactic acidosis.

• Hyperammonemia.

• Elevated liver transaminases (AST, ALT).

• Elevated creatine kinase.

Specific Laboratory Report:

• Plasma Acylcarnitine Profile: Elevation of 3-hydroxy derivatives.

• Urine Organic Acid Analysis: Elevations of 3-hydroxy-dicarboxylic acids and lactic acid.

An absolute diagnosis is possible only through molecular genetic testing, either through single or multi-gene panels, or comprehensive genetic testing, which detects the mutations in the HADHA gene.

Histopathological evaluation reveals microvesicular and macrovesicular fat accumulation in skeletal muscle fibers, heart, and liver. Necrotic myopathy, degeneration of muscle fibers, and hepatic cirrhosis have been observed. Under an electron microscope, mitochondria appear swollen and in greater numbers. Mitochondrial matric condensation and irregular cristae are also observed.

How to Treat LCHAD Deficiency?

Following the initial diagnosis, the patients might need immediate treatment protocol for managing the presenting symptoms, which should then be followed by management protocols.

Management protocols involve-

• Frequent feeding.

• Avoiding fasting.

• Low-fat diet.

• Triheptanoin supplementation.

A team of specialists should be involved to treat various systemic manifestations in their specific specialties, including ophthalmic, cardiac, neural, and pediatric specialists. Manifestations like fever and vomiting can be managed with Acetaminophen and antiemetics, respectively.

Hypoglycemia can be managed by glucose infusion, metabolic acidosis by a bicarbonate dose, hyperammonemia by sodium benzoate with sodium phenylacetate and glucose and insulin infusion, and rhabdomyolysis by dextrose and electrolyte infusions.

What Is the Prognosis of LCHAD Deficiency?

Acute symptoms of LCHAD deficiency are difficult to manage, with potentially high mortality due to acute liver failure, rapidly progressing cardiomyopathy, or hypoketotic hypoglycemic encephalopathy. Acute stages show resistance to therapeutic management regimens. However, treatment can improve the long-term prognosis. Standard therapeutic protocols targeted against specific systems may not be sufficient, yet early diagnosis plays a major role in prognosis determination and avoiding future complications.

What Is the Differential Diagnosis of LCHAD Deficiency?

• Acute hypoglycemia.

• Carnitine deficiency.

• Pediatric dilated cardiomyopathy.

• Pediatric metabolic acidosis.

What Are the Complications of LCHAD Deficiency?

• Peripheral neuropathy.

• Psychomotor retardation.

• Seizures.

• Permanent hypotonia.

• Delayed motor development.

• Hepatic necrosis.

• Peripheral neuropathy.

• Pigmentary retinopathy.

• HELLP syndrome.

• Acute fatty liver of pregnancy.

• Neonatal respiratory distress syndrome.

• Necrotizing enterocolitis.

Conclusion:

LCHAD deficiency is a potentially fatal disorder, but FDA approved the usage of a drug in 2020, which has improved the outcomes in the patients. The patients require regular monitoring for multi-system complications. Dietary modifications along with supplementation go a long way in managing the symptoms and preventing progression to life-threatening intricacies.