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.
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. 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. The most severe form of LAL-D was historically called Wolman disease. In this form, untreated patients do not survive past the first year of life.
Wolman disease and CESD are both caused by inherited variants in the LIPA gene resulting in insufficient LAL enzyme activity. They describe the spectrum of disease severity, but are the same condition, LAL-D.
Infantile Rapidly Progressive LAL-D (Wolman Disease)
LAL-D symptoms beginning soon after birth include:
- Watery diarrhea
- Large belly size
- Enlarged liver and spleen size
- Frequent vomiting
- Poor weight gain or weight loss
- Low blood counts
- Adrenal calcifications on imaging studies
Childhood and Adult LAL-D (CESD)
LAL-D symptoms for children and adults include:
- High total cholesterol, high LDL (bad) cholesterol and low HDL (good) cholesterol
- Frequent diarrhea
- Poor weight gain
- Shorter stature than family members
- Delayed puberty
- Fatty liver disease leading to liver fibrosis and cirrhosis and risk for liver failure
- Increased risk of heart problems and stroke
Some babies with LAL-D have benign, hardened spots called adrenal calcifications that can be seen on the adrenal glands, above the kidneys on MRI, X-ray or ultrasound imaging from birth or sometimes even during pregnancy. Fewer than 50% of babies with LAL-D have adrenal calcifications. If present, LAL-D is likely, since they not seen in other conditions.
What Causes LAL-D?
Genes are the Instructions for Making Proteins
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.
The Genetics of LAL-D (CESD and Wolman disease)
Genes are made of DNA. Variants, also called mutations, are errors in the spelling of the DNA. LAL-D is caused by inheriting two LIPA gene variants, one in each copy of the gene.
- Genes come in pairs. One copy of each gene is inherited from each parent.
- LIPA mutation carriers have one working gene and one non-working copy.
- Carriers do not have symptoms. They make enough LAL enzyme to stay healthy, but can pass on the nonworking gene to their children.
- If a child inherits two nonworking LIPA genes, they cannot make enough working LAL enzyme to process cholesterol. The severity of the mutations determines if a baby will have the rapidly progressive infantile lethal form or more slowly progressive LAL-D.
- If both parents are LIPA mutation carriers, there is a one in four chance (25%) for each of their pregnancies to be affected with LAL-D.
- There is a one in two (50%) likelihood that each child will be a mutation carrier, with no symptoms.
- There is a one in four (25%) chance for each child to inherit two working LIPA genes and be unaffected.
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.
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.
Prenatal and Preconception Testing
If both members of a couple are LIPA mutation carriers, an appointment with a genetic counselor is recommended. To find a genetic counselor near you visit www.NSGC.org
Amniocentesis or CVS (chorionic villus sampling) are options to test a pregnancy for LAL-D.
- Amniocentesis tests fetal cells from the amniotic fluid at 15 weeks to 18 weeks of gestation.
- CVS tests cells from a part of the placenta, and can be done as early as 10 weeks into the pregnancy.
If the fetus is affected, the parents must decide whether or not to continue the pregnancy or prepare for having a baby with LAL-D. The option to terminate a pregnancy is possible until 24 weeks of gestation in most states in the USA.
- Preimplantation genetic diagnosis (PGD) is available before a pregnancy is established at specialized fertility centers. PGD utilizes in vitro fertilization, in which fertilization takes place in a petri dish. Cells from the embryos are tested for the parents’ LIPA mutations. Only unaffected embryos are implanted into the mother’s womb, almost eliminating the possibility of having a baby with LAL-D.
If an individual has symptoms of LAL-D, testing through a simple blood test should be done immediately, since early interventions may be life saving. Enzyme replacement therapy should be initiated at once when the diagnosis is confirmed.
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