Lysosomal acid lipase deficiency

Synonyms

1

Overview

Lysosomal acid lipase deficiency (or LAL deficiency) happens when the body does not produce enough (or none) lysosomal acid lipase (LAL or LIPA) enzyme. This enzyme plays an important role in breaking down fatty material (cholesteryl esters and triglycerides) in the body. Infants, children and adults that suffer from LAL Deficiency experience a range of serious health problems. The lack of the LAL enzyme can lead to a build-up of toxic fatty substances in the body's cells and tissues.

Two rare conditions may result from this deficiency (likely representing two ends of a clinical spectrum): Wolman disease and cholesterol ester storage disease. These conditions are caused by mutations in the LIPA gene and are inherited in an autosomal recessive manner. Enzyme replacement therapy for both Wolman disease and cholesteryl ester storage disease is currently approved for use.

Symptoms

Some symptoms may include:

  • Abdominal pain 
  • Cognitive impairment
  • Hepatic failure (liver cirrhosis or fibrosis)
  • Hepatomegaly (fatty liver)
  • Swelling of the spleen (splenomegaly)
  • Ascites (accumulation of liquids in the peritoneal area causing abdominal swelling)
  • Hyperkeratosis
  • Malabsorption
  • Nausea and vomiting
  • Weight loss
  • Anemia
  • Atherosclerosis

Causes

Lysosomal acid lipase deficiencies occur when a person has defects (mutations) in both copies of the LIPA gene. Each parent of a person with LAL deficiency carries one copy of the defective LIPA gene. With every pregnancy, parents with a son or daughter affected by LAL deficiency have a 1 in 4 (25%) chance of having another affected child. A person born with defects in both LIPA genes is not able to produce adequate amounts of the LAL enzyme.

Prevention

Genetic testing for family members and genetic prenatal diagnosis of pregnancies for women who are at increased risk are possible if family members carrying pathological mutations have been identified.

Diagnosis

LAL Deficiency is so rare that many physicians have not had any previous experience with this condition. The diagnosis of LAL Deficiency by your physician begins with an examination, interview, history and preliminary lab tests. The physician makes observations about the symptoms and other risk factors to identify a suspected diagnosis.

Abnormalities that a person may have, and would make the doctor think of late onset LAL Deficiency (Cholesteryl Ester Storage Disease) include:

  • A high cholesterol and high triglyceride level
  • A high 'bad' cholesterol (Low-density lipoprotein, or LDL)
  • A very low (<10mgdl) 'good' cholesterol (HDL)
  • Unexplained hepatomegaly (liver enlargement)
  • Elevated liver enzymes (a marker of liver damage)
  • Unexplained fat or lipid material in the liver
  • Unexplained chronic liver disease that may be getting worse over time

Abnormalities that a child may have and that would make a doctor think of early onset LAL Deficiency (Wolman Disease) include:

  • Feeding difficulties with frequent vomiting
  • Diarrhea (loose frequent stools)
  • Swelling of the abdomen (abdominal distention)
  • Enlargement of the liver and spleen (hepatosplenomegaly)
  • Failure to gain weight or sometimes weight loss

Once the physician thinks about the possibility of LAL Deficiency as a cause of the medical problems, he or she may order a confirmatory test such as an enzyme assay that measures the level and activity of the enzyme or a genetic sequencing analysis.

Prognosis

Infants with LAL deficiencies typically show signs of disease in the first weeks of life and if untreated, die within 6–12 months due to multiple-organ failure. Older children or adults with LAL-D may remain undiagnosed or be misdiagnosed until they die early from a heart attack or stroke or die suddenly of liver failure. The first enzyme replacement therapy was approved in 2015. In those clinical trials nine infants were followed for one year; 6 of them lived beyond one year. Older children and adults were followed for 36 weeks.

Treatment

Sebelipase alfa (Kanuma) is approved in the US and EU for the treatment of human LAL enzyme deficiency. 

It has been granted orphan designation by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Ministry of Health, Labour and Welfare. Sebelipase alfa received Fast Track designation by the U.S. FDA, and Breakthrough Therapy designation by the U.S. FDA for LAL D presenting in infants.