Genetic mutations are alterations in an organism’s DNA sequence. While many have no noticeable effect, some can alter gene products or prevent genes from functioning correctly, potentially leading to various health conditions.
What the LAL-PG Mutation Is
The LAL-PG mutation refers to a change within the LIPA gene. This gene provides instructions for making an enzyme called lysosomal acid lipase (LAL). The LAL enzyme functions within lysosomes, which are cellular compartments responsible for breaking down waste products.
Within lysosomes, LAL is responsible for breaking down cholesteryl esters and triglycerides. These lipids are delivered to the lysosome for processing. When the LIPA gene has a mutation like LAL-PG, the LAL enzyme’s function becomes impaired or is eliminated, preventing the proper breakdown of these lipids. This dysfunction leads to an accumulation of cholesteryl esters and triglycerides inside cells, leading to an abnormality in splicing and a non-functional LAL protein.
How the Mutation Affects Health
The impaired function of the LAL enzyme due to the LAL-PG mutation results in the accumulation of lipids in various organs, leading to two distinct conditions: Wolman disease and Cholesteryl Ester Storage Disease (CESD). Wolman disease is the more severe, early-onset form, typically manifesting in infancy due to a near-complete loss of LAL activity. Infants with Wolman disease often experience severe symptoms such as an enlarged liver and spleen (hepatosplenomegaly), poor weight gain, vomiting, diarrhea, and malabsorption of nutrients. Adrenal glands can also become calcified, and affected infants often face multiple organ failure and severe malnutrition, leading to a high mortality rate, often within the first year of life if untreated.
Cholesteryl Ester Storage Disease (CESD) is a less severe form, with later onset that can range from childhood into adulthood. Individuals with CESD retain some residual LAL enzyme activity, which distinguishes it from Wolman disease. Symptoms in CESD often include an enlarged liver and spleen, liver dysfunction, and elevated liver enzymes. Individuals may also experience dyslipidemia, characterized by elevated levels of LDL cholesterol and triglycerides, and reduced HDL cholesterol, which can contribute to premature hardening of the arteries.
Inheritance Patterns and Diagnosis
The LAL-PG mutation, and the conditions it causes, follow an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of the mutated LIPA gene—one from each parent—to develop Wolman disease or CESD. Parents who carry one copy of the mutated gene are typically asymptomatic and are referred to as carriers. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two copies of the mutated gene and develop the condition.
Diagnosis of LAL deficiency, whether Wolman disease or CESD, involves assessing LAL enzyme activity and genetic testing. Enzyme activity can be measured in various samples, including peripheral blood leukocytes, cultured fibroblasts, or dried blood spots. Genetic testing directly identifies specific mutations in the LIPA gene. Early diagnosis is important for timely intervention and management.
Treatment and Management
Treatment for conditions caused by the LAL-PG mutation primarily involves enzyme replacement therapy (ERT). This therapy delivers a manufactured version of the LAL enzyme to the body, replacing the deficient natural enzyme. Sebelipase alfa, a recombinant human LAL, was approved in 2015 for treating LAL deficiency.
Sebelipase alfa is typically administered intravenously every other week. Studies have shown that ERT can lead to significant improvements in lipid parameters and liver enzymes, contributing to better patient outcomes and prolonged survival, particularly in severe cases like Wolman disease. Supportive care measures are also part of managing the condition, which may include nutritional support to address malabsorption, monitoring organ function, and managing specific symptoms. For instance, individuals with Wolman disease may require parenteral nutrition and corticosteroid replacement for adrenal insufficiency, while those with CESD might benefit from lipid-lowering medications and dietary modifications.