Lysosomal Acid Lipase Deficiency (LAL-D)

What is LAL-D?

Lysosomal Acid Lipase Deficiency (LAL-D) is a rare genetic disorder caused by mutations in the LIPA gene, which is responsible for producing an enzyme called lysosomal acid lipase (LAL). A deficiency in this enzyme prevents the body from breaking down certain fats, leading to a buildup in the liver and other organs. This accumulation can cause a variety of health issues, ranging from liver disease to elevated blood fat levels. An estimated 1 in 40,000 to 300,000 people are affected worldwide. However, due to the rarity of the disease and non-specific symptoms, LAL-D may be underdiagnosed.

The disease presents in various forms, depending on the age of onset and the severity of enzyme deficiency. There are two main types of LAL-D. The first type, known as Wolman disease, is very severe and appears in infancy. The condition is characterized by vomiting, diarrhea, poor weight gain, and an enlarged liver. If untreated, it leads to liver failure and death within the first year of life. The second type, known as Cholesteryl Ester Storage Disease (CESD), is less severe and appears in older children and adults. Individuals with this condition often develop an enlarged liver and high cholesterol levels. If untreated, significant liver damage can develop over time, leading to liver failure and early death.

Diagnosis of LAL-D is challenging because it is a rare condition and its features overlap with more common conditions such as Familial Hypercholesterolemia (FH), metabolic dysfunction-associated liver disease (MASLD), and metabolic syndrome.

Treatment with a special enzyme replacement therapy called sebelipase alfa has been shown to reduce liver size, improve liver function, and reduce cholesterol levels in affected individuals. Understanding LAL-D is important because early diagnosis and treatment can significantly improve the quality of life and survival for those affected by this disease.
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Criteria for Diagnosis of LAL-D

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:

  1. 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.
  2. Enzyme activity testing: Dried blood spot test to measure LAL enzyme activity. Low activity suggests LAL-D might be the problem.
  3. Genetic testing: Check the LIPA gene for mutations that cause LAL-D.

What Does a Diagnosis of LAL-D Mean for an Infant, Child, or Adult?

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.

Lifestyle Recommendations for Individuals with LAL-D

Dietary Adjustment: Adhering to a low-fat diet is crucial to help manage symptoms, support liver health, and prevent fat accumulation. This dietary regimen involves reducing the overall intake of fats, particularly saturated fats and cholesterol, to minimize accumulation in the liver and other organs. Patients are advised to work with a dietitian to ensure they receive a balanced nutrition while addressing the low-fat dietary requirements. Regular follow-up with healthcare providers is also necessary to monitor the effectiveness of dietary management.

Key components of a low-fat diet for LAL-D patients include:

  • Choosing lean proteins: Preference for lean cuts of meat, such as poultry without skin, and fish. Incorporating plant-based protein sources like beans, lentils, and tofu is also beneficial.
  • Limiting saturated fats: Avoid high-fat dairy products, fatty cuts of meat, and processed foods that often contain hidden saturated fats.
  • Incorporating healthy fats: While overall fat intake should be reduced, including sources of healthy unsaturated fats can be beneficial. These are found in foods like avocados, nuts, seeds, and olive oil.
  • Focusing on whole grains: Replace refined grains with whole grains, which are more nutritious and have a lower impact on blood fat levels.
  • Increasing fruits and vegetables: These are naturally low in fat and contain fiber, vitamins, and minerals that are essential for maintaining health.

Regular Physical Activity: Engaging in moderate physical activity can help improve cardiovascular health and manage blood fat levels. However, the intensity and type of exercise should be adjusted based on individual tolerance and health status.

Avoidance of Alcohol: Alcohol can exacerbate liver conditions, so it is advised that individuals with LAL-D avoid alcohol to prevent further liver damage.

 

 

Treatment Options for Individuals with LAL-D

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.

Patient Support

There are several support organizations available for patients and families diagnosed with LAL-D, which can be found at https://laldsource.com/.

LAL-D Aware ( https://www.laldaware.org/), formally known as SOLACE organization (Support Organization for LAL Deficiency – Advocacy, Care and Expertise), provides support for children and adults with LAL-D, including Wolman disease and cholesteryl ester storage disease (CESD). This organization offers a community for patients and families to connect, sharing experiences, knowledge and compassion.

Connect with patients with LAL-D

Finding a Specialist

The management of LAL-D typically involves a multidisciplinary team of healthcare providers due to the complexity and range of symptoms associated with the disorder. The key specialists involved include:

  • Geneticists: Medical geneticists play a crucial role in diagnosing genetic conditions like LAL-D and guiding the genetic counseling for patients and their families.
  • Pediatricians or Pediatric Endocrinologists: For children, pediatricians, especially those specializing in metabolic disorders or endocrinology, are crucial in managing the disease from infancy through adolescence.
  • Gastroenterologists or Hepatologists: These specialists are essential for managing liver-related symptoms of LAL-D, as the disease often leads to significant liver dysfunction.
  • Cardiologists: Since LAL-D can impact cardiovascular health due to lipid abnormalities, cardiologists may be involved to manage and monitor heart-related issues.
  • Endocrinologists: These specialists may be involved due to the metabolic nature of LAL-D and its effects on cholesterol and triglyceride levels.
  • Dietitians: Registered dietitians help devise appropriate dietary plans that support liver health and overall nutrition, particularly focusing on low-fat diets necessary for managing LAL-D.

Clinical Trials




References:

  1. Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency—an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30. doi:10.1016/j.atherosclerosis.2014.04.003.
  2. Francis GA, Baker CJ, Szamosi JC, et al. A216 Clinical Manifestations and Management Challenges of Lysosomal Acid Lipase Deficiency. J Clin Lipidol. 2021;15(4):e24. doi:10.1016/j.jacl.2021.05.080.
  3. Bashir A, Duseja A, Kaur R, et al. Lysosomal acid lipase deficiency: A treatable cause of dyslipidemia and cirrhosis in adults. Indian J Gastroenterol. 2021;40(2):182-185. doi:10.1007/s12664-021-01148-6.
  4. Maciejko JJ. Lysosomal acid lipase deficiency: diagnosis and treatment of Wolman and Cholesteryl Ester Storage Diseases. Pediatr Endocrinol Rev. 2017;15(Suppl 1):159-168.
  5. Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58(6):1230-1243. doi:10.1016/j.jhep.2013.02.014.
  6. Grabowski GA, Du H, Charnas L. Dietary and medical management of LAL deficiency. Prog Pediatr Cardiol. 2016;41:51-56. doi:10.1016/j.ppedcard.2016.04.004.
  7. Di Rocco M, Pisciotta L, Madeo A, et al. Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency. Orphanet J Rare Dis. 2018;13(1):24. doi:10.1186/s13023-018-0768-8.