Lysosomal Acid Lipase Deficiency

 Lysosomal Acid Lipase Deficiency

Overview

Lysosomal acid lipase deficiency is a subset of lysosomal acid lipase deficiency (LALD). There are two types of this disease, infantile LALD and late-onset LALD.

Infantile LALD presents early in infancy and is less common and more severe than late-onset LALD.

Late-onset LALD generally presents in mid-childhood.

Both conditions are characterized by a deficiency in a specific enzyme, which results in problems with lipid metabolism, or the body’s ability to properly break down and utilize certain fats. When these fats are not broken down and utilized, they accumulate in many of the body’s cells, tissues, and organs — eventually leading to signs of disease. LALD is one of about 50 diseases classified as lysosomal storage disorders (LSD).

Lysosomes contain specific proteins (enzymes) that are responsible for breaking down and recycling molecules such as fats and sugars. Individuals with a lysosomal storage disorder lack one of these necessary enzymes or do not have one of these enzymes in sufficient quantities to break down molecules for proper cell function

Symptoms

Children with infantile-onset LALD generally begin exhibiting signs of the disease shortly after birth as fat molecules begin to accumulate throughout the body.

Symptoms may include:

Enlargement of the liver and spleen (hepatosplenomegaly)

Yellowing of the skin and whites of the eyes (jaundice)

Developmental delay

Poor feeding

Fatty stools (steatorrhea)

Vomiting

Diarrhea

Poor weight and height gain (failure to thrive)

Low iron (anemia)

Children with late-onset LALD show great variation in their symptoms and the age at which signs of the disease begin to show. While many have their first symptoms in mid-childhood, some first develop symptoms in adolescence or even adulthood.

Symptoms and complications may include:

Enlargement of the liver and spleen (hepatosplenomegaly)

Fatty stools (steatorrhea)

Vomiting

Diarrhea

High cholesterol (hypercholesteremia)

Liver disease

Fatty deposits in the arteries (atherosclerosis)

Causes

LALD is caused by mutations in the LIPA gene, which contains instructions for the production of an enzyme known as lysosomal acid lipase. This enzyme normally functions in the lysosomes of cells to break down various types of fats. Mutations in the LIPA gene result in a deficiency of this critical enzyme, resulting in an accumulation of fat molecules in the body, which eventually leads to dysfunction.

This genetic condition is inherited in an autosomal recessive pattern, which means that an affected child has received one defective copy of the LIPA gene from each of their parents.

The severity of LALD depends on the degree of deficiency of lysosomal acid lipase in the body’s cells. Children with infantile-onset LALD often have no lysosomal acid lipase and thus have a severe form of the disease. Children with late-onset LALD often have low levels of lysosomal acid lipase, which allows for the breakdown of some fat molecules, but not to the degree necessary for proper cellular function. Because of this, the disease is typically less severe.

Diagnosis

Testing for LAL-D begins with identifying signs that raise suspicion for the disease, including an enlarged liver (hepatomegaly), higher than normal liver enzymes, and high levels of fat in the blood (dyslipidemia).

LAL-D is diagnosed by measuring LAL enzyme activity followed by genetic testing for known LIPA gene mutations. A simple dried blood spot test can measure the activity of the LAL enzyme and suggest LAL-D if enzyme levels are low. Molecular genetic testing can then identify specific mutations in the LIPA gene that are known to cause LAL-D.

The diagnosis of LAL-D can be summarized below:

Suspicion for LAL-D: Development of enlarged liver, elevated liver enzymes, high cholesterol levels, especially if usual treatments aren’t working or there’s no clear reason for these issues.

Enzyme activity testing: Dried blood spot test to measure LAL enzyme activity. Low activity suggests LAL-D might be the problem.

Genetic testing: Check the LIPA gene for mutations that cause LAL-D.

A diagnosis of LAL-D requires lifelong monitoring and management. It affects infants, children, and adults differently, impacting their day-to-day life in significant ways:

Infants: Infants diagnosed with LAL-D usually present the most severe form, known as Wolman disease. They experience rapid health decline, with symptoms appearing within the first few weeks of life. Common issues include severe digestive problems, malnutrition, and liver failure. Without timely intervention, typically through enzyme replacement therapy, survival beyond the first year is rare. Daily life for these infants involves intensive enzyme replacement therapy and frequent hospital visits.

Children: Children with LAL-D may not exhibit symptoms as early or as severely as infants but often face significant health challenges. They may experience chronic liver disease, elevated cholesterol levels, and growth delays. Daily management includes regular medical checkups, dietary restrictions, and enzyme replacement therapy to manage symptoms and prevent severe liver damage.

Adults: Adults with LAL-D often experience a milder form of the disease, which can still significantly impact daily life. They may experience fatigue, liver disease, and cardiovascular problems due to elevated cholesterol levels. Like children, adults must undergo regular health monitoring, adhere to strict dietary guidelines, and receive enzyme replacement therapy.

For all age groups, the psychological and emotional toll of managing a chronic, life-threatening condition can affect daily life, necessitating ongoing support from medical professionals, family, and support groups.

Additionally, a diagnosis of LAL-D can have implications for family members since the condition is genetic. Siblings and parents may also need to be tested to ensure they receive appropriate care if affected. Understanding and managing LAL-D is a lifelong process. However, routine follow up with multidisciplinary healthcare teams can lead to a functional and active life.

Treatment

The treatment for LAL-D primarily involves enzyme replacement therapy with sebelipase alfa, which works by breaking down accumulated fats within the liver and other organs. Clinical trials have shown that this medication improves liver function, blood fat levels, and overall survival. Sebelipase alfa is typically a lifelong treatment. The therapy is administered through intravenous infusions and is generally well-tolerated. Regular infusions maintain the enzyme levels needed to prevent accumulation of fats and progression of the disease. However, the dosing regimen varies according to patient age and disease severity. Regular monitoring of liver function and blood fat levels is essential to assess treatment effectiveness and make necessary adjustments.

Infants: For infants diagnosed with rapidly progressive LAL-D, manifesting as Wolman disease, the recommended starting dose of sebelipase alfa is 1 mg/kg body weight administered once weekly as an intravenous infusion. This dosing can be adjusted based on clinical response and tolerability, with some cases requiring increases to 3 mg/kg or even 5 mg/kg weekly, especially in the presence of insufficient response or severe symptoms.

Children and Adults: For older children and adults diagnosed with less severe variants of LAL-D, the recommended starting dose of sebelipase alfa is generally 1 mg/kg every other week as an intravenous infusion.

Supportive care may be necessary for managing symptoms and complications associated with LAL-D, such as malnutrition and liver disease. This comprehensive approach aims to improve quality of life and reduce disease-related complications.

Given the lifelong nature of LAL-D, psychological support for the patient and family is recommended to help manage the mental health challenges associated with chronic disease.

Regular follow-up with healthcare providers is crucial to monitor therapy effectiveness and side effects, and in turn, adjust treatment plans as needed. Improvement in liver function tests, blood fat levels, and liver imaging results are key indicators of treatment success.

Type of Doctor Department :Hepatologist or Gastroenterologist