Lysosomal Acid Lipase Deficiency (LAL-D) Disease Information

Lysosomal Acid Lipase Deficiency (LAL-D):

What is LAL-D?
LAL-D is also called Cholesteryl Ester Storage Disease (CESD) or Wolman Disease for the most severe, infantile onset form.  Both CESD and Wolman disease are caused by an inherited deficiency in the enzyme called lysosomal acid lipase, so now both CESD and Wolman disease are also called LAL-D. LAL-D is caused by inheriting two non-working copies of a gene called LIPA.

Genetics of LAL-D

LAL-D is an inherited (genetic) disorder which means that it is passed down within a family. Genes are the instructions for making proteins that carry out the functions of the body and its development. Genes come in pairs. We inherit one copy of every gene from our mother and the other copy from our father. When both copies of a gene are not working and cause a disease, it's called autosomal recessive inheritance. In autosomal recessive inheritance, a person with one working copy of a gene and one non-working copy is a carrier and has no symptoms.  Only people who inherit two non-working copies inherit the disease, so a mutation can be passed from generation to generation with no one affected until a carrier has a child with another mutation carrier. When both parents are mutation carriers  there is a 1 in 4 chance for each child to inherit two non-working genes and be affected.  LIPA gene mutations result in deficiency of the enzyme lysosomal acid lipase.  Lysosomal acid lipase is an enzyme that is responsible for breaking down fats in a part of the cell called the lysosome. If the LAL enzyme is not working, fats build up in many cells which primarily lead to liver disease, high bad cholesterol and low good cholesterol. LAL D sometimes leads to death before a baby’s first birthday because they are unable to absorb nutrients. Most of the people that have LAL D are children and adults.

Recognizing Lysosomal Acid Lipase Deficiency (LAL D) 
Lysosomal Acid Lipase Deficiency (LAL D) in children and adults may often go undiagnosed because signs and symptoms may not be obvious and overlap with many common conditions. Also many doctors are not familiar with LAL-D (CESD or Wolman disease) because it is rare, so only a handful of doctors have seen a patient with LAL-D. (Click on the LAL-D Treatment Centers tab at the top of he page to locate a physician with LAL-D expertise).

Babies with LAL-D (Wolman disease) have severe, life threatening symptoms and die in the first year of life if untreated. Infantile Wolman disease is the most rare form of LAL-D, so even though the symptoms are evident, the diagnosis can still be missed. The exact prevalence is unknown, but t is estimated that only about one in 60,000 to one in 190,000 people have LAL-D. People of Iranian Jewish ancestry or Jewish people from Uzbekistan (Bukharan) are at much higher risk (about 1 in 3600) to have a child with LAL-D, specifically the infantile lethal form. 

LAL-D Signs and Symptoms

Signs of the disease typically include enlarged fatty liver and possibly enlarged spleen, often causing a big belly, even in an underweight child, high bad cholesterol (LDL), low good cholesterol (HDL), and elevated liver enzymes (AST and ALT) with no known cause (i.e. poor diet, obesity or alcohol use).  Enlarged liver and spleen may be missed on physical exam or only evident on imaging studies (MRI or CT scan).

Children and Adults (CESD)

o People with LAL-D may have total cholesterol higher than 240 mg/dL

o People with LAL-D may have LDL-cholesterol higher than 160 mg/dL

o People with LAL D usually have HDL-cholesterol lower than 40 or 50 mg/dL

· Liver enzymes may be referred to as liver transaminases or “ALT” and “AST”

o Higher than normal liver transaminases may indicate liver injury

· A large liver can be described in medical terminology as "hepatomegaly"

· A large spleen can be described in medical terminology as "splenomegaly"

Infantile Lethal LAL-D (Wolman disease)

Infants with LAL-D 

  • Extremely enlarged belly 
  • Adrenal enlargement and adrenal spots called calcifications (in about 50%)
  • Poor growth and poor weight gain often called failure to thrive
  • Severe, chronic watery yellow diarrhea
  • Severe chronic vomiting
  • Inability to absorb nutrients (malabsorption)
  • Agressive liver disease
  • Bleeding
  • Severe anemia requiring blood transfusions
  • An abnormality of immune cells in the blood called hemophagocytic lymphohistiocytosis

LAL D affects people differently. In many children and adults with LAL D, the result of the deficiency is severe liver disease (liver fibrosis, cirrhosis and liver failure) and a build-up of fat in artery walls(called atherosclerosis) which can lead to heart failure, stroke and other cardiovascular related disease at varying ages. Liver disease in LAL-D is progressive and there is a high risk of developing liver failure requiring liver transplant or causing death if untreated.

LAL D in infants is the most severe form of the disorder often called Wolman disease. Babies die within the first 6 months to one year of life if untreated. Infantile lethal LAL-D is very rare in comparison with LAL-D in children and adults. About 1 – 2 babies are born per 1 million births with this severe form of the disease, except for among people of Mizrahi Jewish ancestry. (About 1 in 3600 Iranian and Bukharan Jewish babies are born with LAL-D. It is believed that the primary reason that LAL-D affects these infants differently is that these babies have no LAL enzyme. LAL-D in children and adults is likely due to the ability of these people to produce some (even a very little amount) of LAL enzyme.

· The infants that die generally have almost 0% of normal LAL enzyme activity

· Children and adults generally have 1% to 10% of normal LAL enzyme activity

LAL-D Treatment

Enzyme replacement therapy (ERT) for LAL-D called Kanuma was FDA approved in 2015. Kanuma ERT replaces the non-working lysosomal acid lipase enzyme with a man-made version of the enzyme. ERT is giving by intravenous infusion twice a month or weekly for severe infantile patients.  This is the only treatment that addresses the underlying disease. ERT should be initiated immediately as soon as the LAL-D diagnosis is made, since it can be life saving. ERT is safe and efficacious. With any medication there is a risk of hypersensitivity reactions, for which ERT patients should be monitored.

Other LAL-D interventions may be helpful, though they do not address the underlying cause of the disease.

Statins may help to lower some kinds of cholesterol in the blood, but does not prevent liver disease in LAL-D. No clinical trials have been published on their efficacy in treating LAL-D. There are several reports of LAL-D patients receiving statins who progressed to liver failure.

Bile acids or bile acid sequestrants have also been tried in patients with LAL-D. No clinical trials have been published on their efficacy in treating LAL-D. There are several reports of  LAL-D patients receiving bile acid sequestrants who progressed to liver failure.

Ezetimibe is a cholesterol lowering medication that has been reported to have been used in a few LAL-D patients, but there is no long term follow-up available at this time.

Cholesterol lowering medications and bile acid sequestrants may be helpful if enzyme replacement therapy is not available, but these will not address the underlying cause of LAL-D or stop its progression.  

Liver Tranplant-  Liver transplant requires life long immunosuppressant drugs with a high long-term risk of life threatening conditions, including organ rejection/graft vs host disease, solid tumor and blood cancers, renal failure, adrenal insufficiency sepsis and death.

Stem Cell Transplant HSCT (hematopoietic stem cell transplant)or BMT (bone marrow transplant)-    Stem cell transplant has been attempted for babies and children with LAL-D. In a report of 10 patients with LAL-D treated with HSCT all patients died within 1-3 years of being treated. Seven patients died by 9 months of age, one baby dies at age 3.8 years and and other at 3 years of age.

Infants with LAL-D should receive IV feeding called total parenteral nutrition because the intestines are blocked and cannot absorb nutrients. 

Babies and children with LAL-D who are able to receive formula feeding may benefit from medium chain triglyceride formulas.

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