LAL Deficiency
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Mucopolysaccharidosis (MPS) IIIB

Synageva BioPharma Corp. is recruiting patients to participate in global clinical trials that evaluate sebelipase alfa (SBC-102) as an enzyme replacement therapy for Lysosomal Acid Lipase (LAL) Deficiency. For more information, please visit, or click here if you would like to contact Synageva regarding LAL Deficiency.

Lysosomal Acid Lipase (LAL) Deficiency

Causes of LAL Deficiency and Rationale for Use of sebelipase alfa

Lysosomal Acid Lipase (LAL) Deficiency is a rare autosomal recessive lysosomal storage disorder (LSD) that is caused by a marked decrease or almost complete absence of the lysosomal enzyme, lysosomal acid lipase (LAL). Sebelipase alfa, Synageva’s recombinant form of the human LAL enzyme (rhLAL) is being evaluated in clinical trials as an enzyme replacement therapy (ERT) for LAL Deficiency. Sebelipase alfa demonstrates efficacy in a highly relevant in vivo disease model.  In addition, the medical value and long term safety of enzyme replacement therapy as previously established for Cerezyme in Gaucher disease has now been extended to a broader range of disorders, including Pompe Disease, Fabry disease, Mucopolysaccharidosis I and Mucopolysaccharidosis II.

LAL Deficiency Background 

The clinical manifestations of LAL Deficiency span a wide spectrum of severity and broadly correlate with a patient’s residual LAL levels. Although a single disease, LAL Deficiency presents as a clinical continuum with two major phenotypes, late onset LAL Deficiency, frequently referred to as Cholesteryl Ester Storage Disease (CESD), and early onset LAL Deficiency, frequently referred to as Wolman disease. The marked reduction or almost complete absence of LAL in patients with LAL Deficiency leads to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various tissues and cell types, particularly the liver leading to hepatomegaly, liver dysfunction, and hepatic failure, and in the small intestinal macrophages leading to severe malabsorption. Early onset LAL Deficiency is characterized by profound malabsorption, growth failure, and hepatic failure and is usually fatal within the first year of life. In late onset LAL Deficiency, liver complications and type II hyperlipidemia (high cholesterol and triglyceride levels) dominate the clinical picture. 

Late Onset LAL Deficiency

This is the more common form of LAL Deficiency and is associated with predominant liver involvement and type II hyperlipidemia. The liver is most severely affected with marked hepatomegaly, elevation of transaminases and liver fibrosis, and the cardiovascular involvement is characterized by dyslipidemia (high cholesterol, high triglyceride and low HDL) and accelerated atherosclerosis. In addition, chronic liver disease (cirrhosis) can develop resulting in liver failure. An accumulation of fatty deposits on the artery walls (atherosclerosis) is sometimes described early in life. The presentation of late onset LAL Deficiency is highly variable with some patients going undiagnosed until complications manifest in late adulthood, while others can present with liver dysfunction in early childhood. Late onset LAL Deficiency is associated with significant ill health, and although the natural history of late onset LAL Deficiency is not well described, there is evidence that life expectancy is reduced with premature death due to liver complications, cardiac dysfunction or stroke.

Based on a review of medical literature related to late onset LAL Deficiency (also known as Cholesteryl Ester Storage Disease or CESD), patients are often diagnosed during the childhood years. Common clinical findings include hepatomegaly (enlarged liver), abnormal liver function tests, and splenomegaly (enlarged spleen). In approximately 25 percent of cases, death, liver transplant, and/or advanced liver disease (e.g., cirrhosis and/or clinical evidence liver failure/fibrosis) was reported. Furthermore, the age at death was early (7-56 years of age) as was the age at the time of liver transplant (7-12 years of age), all of which serve to underscore the significant morbidity and mortality associated with the disease.

No approved therapies are available for treatment of this form of LAL Deficiency, but palliative therapies may be used in an attempt to mitigate some of the symptoms of the disease. Current treatment options are focused on control of blood lipid levels through a diet that excludes foods rich in cholesterol and triglycerides and suppression of cholesterol synthesis and apolipoprotein B production through administration of statins and other lipid lowering therapies. Although some clinical improvement may be seen, the underlying disease manifestations persist and disease progression continues. As liver function deteriorates, liver transplantation may be required. There is limited information at present on the long-term outcomes of liver transplantation in late onset LAL Deficiency patients.

If you know of or have a patient with LAL Deficiency, Synageva BioPharma Corp. is recruiting patients to participate in a clinical trial that evaluates sebelipase alfa as an enzyme replacement therapy of Lysosomal Acid Lipase (LAL) Deficiency. For more information, please visit, or click here if you would like to contact Synageva regarding LAL Deficiency. 

Early Onset LAL Deficiency

Early onset LAL Deficiency presents shortly after birth with predominant gastrointestinal and liver involvement.  This form of the disease is the most rapidly fatal presentation of LAL Deficiency and is characterized by growth failure, malabsorption, steatorrhea, profound weight loss, and hepatomegaly.  Early onset LAL Deficiency is rapidly progressive and fatal, usually within the first year of life.  Growth failure is the predominant clinical feature and is the key contributor to the early mortality.  Hepatic involvement, as evidenced by liver enlargement and elevation of transaminases, is also common and is very similar to that described in other patients across the LAL Deficiency continuum. 

Interim data from our on-going natural history study for early onset LAL Deficiency were presented at the Congress of Lysosomal Diseases held in Northern Cyprus in April 2012. The study, based on retrospective data collected on 19 patients with growth failure at six months, showed:

  • Symptom onset occurred generally 1 month after birth
  • Patients were diagnosed at approximately two months of age
  • Patients succumbed to the disease at approximately 3-4 months after birth

    Watch the video to hear the perspective from two mothers who lost children to early onset LAL Deficiency. (Having trouble viewing the video: click here.

    There are no therapies approved by regulatory authorities for the treatment of patients with early onset LAL Deficiency. A variety of supportive therapies are used in an attempt to mitigate some of the effects of this rapidly fatal disease. Although some stabilization of the clinical condition has been described with nutritional support, these interventions are not believed to substantially modify the outcome in affected patients. As there has been no effective treatment, patients with early onset LAL Deficiency are sometimes offered experimental therapy with hematopoietic stem cell transplantation (HSCT). Based on the currently available information, early onset LAL Deficiency remains almost universally fatal.

    Synageva BioPharma Corp. is recruiting patients to participate in a clinical trial that evaluates sebelipase alfa as an enzyme replacement therapy of Lysosomal Acid Lipase (LAL) Deficiency. For more information, please visit, or click here if you would like to contact Synageva regarding LAL Deficiency.

    Summary Points 

    Disease Risk in Families

    • Autosomal recessive disorder, LAL deficiency is carried on chromosome 10
    • Parents with an affected son or daughter have a 1 in 4 chance of having another affected child

    Diagnosing Late Onset LAL Deficiency (CESD)

    Clinical diagnosis is based upon presentation of signs, symptoms and laboratory abnormalities (lipids, liver transaminases) and may be confirmed by enzyme assay (blood test) detecting low or absent levels of lysosomal acid lipase or in relatives of affected patients by mutation linkage analysis (blood test). Genetic sequencing analysis may be warranted to confirm presence of a genetic mutation.

    Patients with LAL Deficiency typically have elevated cholesterol and triglyceride levels (type II hyperlipidemia) and may present at an early age with the following liver abnormalities:

    • Unexplained hepatomegaly
    • Elevated transaminases
    • Unexplained fatty liver
    • Progressive and/or unexplained chronic liver disease

    Type II hyperlipidemia in association with unexplained fatty liver or elevated transaminases in more than one sibling in a family would warrant consideration of a diagnosis of LAL Deficiency.

    Late onset LAL Deficiency patients are typically investigated for infectious, metabolic and autoimmune liver disease. Imaging may suggest hepatic steatosis, and liver biopsies when performed show accumulation of fat in hepatocytes and Kupffer cells. Periportal fibrosis and cirrhosis is not uncommon. Descriptive terms including sea blue Histiocytosis may be applied to the liver abnormalities.

    Click here to download a physician brochure regarding LAL Deficiency.

    Useful Diagnostic Clues:

    • Low normal HDL, especially very low HDL
    • Excessive hepatomegaly and/or transaminase increase for a given BMI
    • Unusual coexisting lymphadenopathy or enlarged lymph nodes
    • Onset of liver abnormalities in childhood
    • Clinical suspicion of visceral Niemann Pick not confirmed by enzyme analysis
    • An enlarged spleen that is disproportionate in size to the degree of liver involvement/disease
    • Short stature
    • Premature cardiac disease
    • Premature stroke 

    Delayed diagnosis may be the result of disease under-recognition and/or symptoms being mistaken for those of other disorders, such as:

    • Non Alcoholic Fatty Liver Disease (NAFLD)
    • Non Alcoholic Steatohepatitis (NASH)
    • Alcoholic Liver Disease
    • Cryptogenic Cirrhosis

    Labs That Support Testing for LAL Deficiency

    The following web sites provide information regarding labs that provide diagnostic support for LAL Deficiency: (search using, “cholesterol ester storage disorder” in disease field)

    http://www.or (search using, “cholesterol ester storage disorder)