Lysosomal Acid Lipase Deficiency (LAL)

LIPA gene

Also known as: cholesteryl ester storage disease (CESD); LIPA deficiency; LAL deficiency; Cholesterol ester hydrolase deficiency; Wolman disease

OMIM#2278000 https://omim.org/entry/278000

1. The disease

The phenotypic spectrum of lysosomal acid lipase (LAL) deficiency ranges from the infantile-onset form (Wolman disease) to later-onset forms collectively known as cholesterol ester storage disease (CESD). Infants can be initially asymptomatic at birth.

2. The symptoms

Wolman disease is characterized by infantile-onset malabsorption that results in malnutrition, storage of cholesterol esters and triglycerides in hepatic macrophages that results in hepatomegaly and liver disease, and adrenal gland calcification that results in adrenal cortical insufficiency. Unless successfully treated with hematopoietic stem cell transplantation (HSCT), infants with classic Wolman disease do not survive beyond age one year.

CESD may present in childhood in a manner like Wolman disease or later in life with such findings as serum lipid abnormalities, hepatosplenomegaly, and/or elevated liver enzymes long before a diagnosis is made. The morbidity of late-onset CESD results from atherosclerosis (coronary artery disease, stroke), liver disease (e.g., altered liver function ± jaundice, steatosis, fibrosis, cirrhosis, and related complications of oesophageal varices, and/or liver failure), complications of secondary hypersplenism (i.e., anaemia and/or thrombocytopenia), and/or malabsorption. Individuals with CESD may have a normal life span depending on the severity of disease manifestations. Lack of early signs or symptoms does not exclude the diagnosis.

3. Actions to take in case of early diagnosis

Infants with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the LIPA gene) should continue breastfeeding.
Biochemical correlation is essential for confirming diagnosis with LAL enzyme activity in peripheral blood leukocytes, fibroblasts, or dried blood spots. Can also be present elevated transaminases, and a typical serum lipid profile – high total serum concentrations of cholesterol, low-density lipoprotein, and triglycerides; and low serum concentration of high-density lipoprotein
LAL deficiency is a lifelong disease that requires lifetime management and regular follow-up with a paediatric gastroenterologist physician and a multidisciplinary approach to care.
Enzyme replacement therapy (ERT) with sebelipase alfa was recently approved by the FDA and is administered at a dose of 1 mg/kg body weight every other week; this treatment can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have CESD.
Successful hematopoietic stem cell transplantation can correct the metabolic defect.
Consider referral to a liver specialist. Liver transplantation may be indicated when liver disease progresses to cirrhosis and liver failure.
Consultation with a nutrition team to limit malnutrition if possible, including use of parenteral nutrition, corticosteroid, and mineralocorticoid replacement in the presence of adrenal insufficiency.
Reduce cholesterol using statins, cholestyramine, and a diet low in cholesterol and triglycerides. Aggressive reduction of additional cardiovascular risk factors and lipophilic vitamins may also be beneficial.
Prevention of secondary complications: Use nonspecific beta-blockers in those with esophageal varices to reduce the risk of bleeding.
Genetic counselling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

3. For more information

Orphanet: