Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Lysosomal Acid Lipase Deficiency

This illness is also known as Wolman disease.

What is Lysosomal Acid Lipase Deficiency?

• Lysosomal acid lipase deficiency (LAL-D) is a rare, inherited, genetic condition that causes improper cholesterol processing because of a lack of a functioning enzyme called LAL which stands for lysosomal acid lipase.
• In affected individuals, harmful amounts of fats (lipids) accumulate in cells and tissues throughout the body, which typically causes liver disease. There are two forms of the condition. The most severe and rarest form begins in infancy. The less severe form can begin from childhood to late adulthood.​
• Depending on the amount of LAL enzyme activity loss of function, LAL-D can be severe with infantile onset and life threating symptoms, or milder with slower progression, depending on the changes in the DNA.​
• Lysosomal acid lipase deficiency is estimated to occur in 1 in 40,000 to 300,000 individuals, varying by population. ​
• The later-onset form is more common than the early-onset form.​
• LAL-D is rare. Only about 1 in 40,000 to <1/100,000 people have LAL-D. Severe infantile LAL-D is more common among people of Iranian Jewish or Bukharan Jewish ancestry. ​
• About 1 in 32 Iranian Jewish or Bukharan Jewish people carry a LIPA gene mutation called G87V (also called G66V), and about 1 in 4000 Iranian Jewish or Bukharan Jewish babies are born with infantile LAL-D. Carrier screening is recommended, ideally before pregnancy is conceived.
• Because some of the signs and symptoms associated with LALD are similar to those of other more common disorders, it may take months or even years for people with LALD to get an accurate diagnosis.​​​

How Do You Get It?

• If a relative was diagnosed with LAL-D, or is a known carrier, the risk for family members to be a carrier is significantly greater.
• Lysosomal acid lipase deficiency is a genetic disease that is autosomal recessive
• The LIPA gene encodes the instructions for making lysosomal acid lipase (LAL), an enzyme that helps process cholesterol. ​
• Without LAL enzyme, dangerous amounts of cholesterol build up in the liver, digestive tract and many cells of the body.​
• LALD is caused by a deficiency of an enzyme called lysosomal acid lipase (LAL). ​
• The LAL enzyme plays a major role in the control of lipid particles known as low density lipoproteins (LDL), a type of cholesterol referred to as “bad cholesterol” which can be linked to cardiovascular disease. ​
• Without this enzyme, harmful amounts of various lipid particles build up in a part of the cell known as the lysosome. This fat accumulation, can lead to significant health consequences including damage to the liver and other organs.​

What Are The Symptoms?

• In the early onset form symptoms appear in infancy and can include:
  • Adrenal calcifications on imaging studies
  • Watery diarrhea
  • Low blood cell counts (anemia)
  • Large belly size
  • Weight loss, or abnormally poor weight gain
  • Frequent vomiting
  • Enlarged spleen and liver
• In the later onset form that appears in childhood or adulthood, symptoms include:
  • Poor cholesterol numbers (high overall, low HDL, high LDL)
  • Frequent diarrhea
  • Increased risk of stroke and heart disease
  • Poor weight gain (in children)
  • Fatty liver disease
    • May lead to fibrosis, cirrhosis, and liver failure
  • Delayed puberty
  • Short stature compared to relatives
• In the later-onset form of lysosomal acid lipase deficiency, signs and symptoms vary and usually begin in mid-childhood, although they can appear anytime up to late adulthood.​
• Nearly all affected individuals develop an enlarged liver (hepatomegaly); an enlarged spleen (splenomegaly) may also occur.
• Individuals with this form of lysosomal acid lipase deficiency may have increased liver enzymes and high cholesterol levels, which can be detected with blood tests.​
• About two-thirds of individuals have liver fibrosis, eventually leading to cirrhosis. Approximately one-third of individuals with the later-onset form have malabsorption, diarrhea, vomiting, and steatorrhea.​

How Is It Treated?

• A mixture of steroids and nutritional therapies have been administered to those afflicted with LAL-D to alleviate symptoms​
• Statins and fibrates might also be prescribed.​
• In 2015 a breakthrough in enzyme replacement therapy improved quality of life and life expectancy for people with the disease. Sebelipase alfa, a form of recombinant lysosomal acid lipase that is injected into the spinal canal, was approved in the USA, EU and Japan.​
• Haemopoietic (blood-forming) stem cell transplants have shown some success in treating patients although more data needs to be obtained and long-term follow ups conducted.​
• Gene therapy is currently being investigated
• CESD stands for cholesteryl ester storage disease, which describes LAL-D patients who survive past infancy but still may have severe, life threating symptoms or milder symptoms with slower progression. 
• Without treatment, the infantile form is lethal within a year. Older patients may be at risk as well due to difficulties with diagnosis, and therefore may die from stroke, heart attack, or liver failure if they do not receive appropriate treatment.​

Where Can I Learn More???

• Check out our cornerstone on this disease here.
• Learn more about this illness from LAL-D Aware.