LIPA Gene Sequence and LAL Dry Blood Spot Genetic Confirmation

Clinical Background

Wolman disease is a rare inherited condition involving the breakdown and use of fats and cholesterol in the body (lipid metabolism). In affected individuals, harmful amounts of lipids accumulate in the spleen, liver, bone marrow, small intestine, small hormone-producing glands on top of each kidney (adrenal glands), and lymph nodes. In addition to fat deposits, calcium deposits in the adrenal glands are also seen.

Infants with Wolman disease are healthy and active at birth but soon develop signs and symptoms of the disorder. These may include an enlarged liver and spleen (hepatosplenomegaly), poor weight gain, low muscle tone, a yellow tint to the skin and the whites of the eyes (jaundice), vomiting, diarrhea, developmental delay, low amounts of iron in the blood (anemia), and poor absorption of nutrients from food. Children affected by this condition develop severe malnutrition and generally do not survive past early childhood. Other names used to describe this disorder include:

  1. Acid lipase deficiency
  2. Familial Xanthomatosis
  3. LAL deficiency
  4. LIPA deficiency
  5. Liposomal Acid Lipase Deficiency, Wolman Type
  6. Lysosomal acid lipase deficiency

For more information, review OMIM (see reference bottom of page)

Wolman disease was first reported in 1961 in infants of Persian-Jewish descent. Following the Iranian revolution of 1979, an estimated 40,000 Iranian-Jews migrated to Los Angeles area. Although worldwide Wolman disease is believed to affect 1/350,000 infants, in the Iranian-Jewish population in Los Angeles several cases have been noted (unpublished data) that may indicated higher prevalence than the general world population.

People of Iranian-Jewish descent seem to have the founder mutation p.G87V (ggc>gtc). This mutation is also reported as p.G66V due to post-translational cleavage of signal peptide (Anderson, et al 1991).

A rapid diagnostic test described by Hamilton(1) reports the measurement of lysosomal acid lipase (LAL) in dried blood spots (DBS) is done using a fluorimetric substrate, 4-methylumbelliferyl palmitate (4mU palmitate), with cardiolipin present as an activator of LAL. The presence of other forms of lipase in whole blood will interfere with the measurement of LAL. Since Lalistat 2 is a specific inhibitor of LAL, measuring the total lipase activity and lipase activity in the presence of Lalistat 2 will allow for determination of LAL in DBS.

Specimen Requirements

Requisition form.

Specimen and Volume: Buccal epithelial cells collected on standard cotton tip swabs. The cotton must be only on one side of the swab stick. Alternative acceptable specimen include whole blood- Collect 0.3-5 cc of blood in EDTA or ACD BD Vacutainer tubes guidessue. Dry blood spot DBS.

Container: Depends on specimen. Vacutainer tubes must be shipped in a padded secure container or shipping pack.

Temperature: Specimen can be at room temperature and needs to be at the laboratory no more than 72hrs after collection. Do not freeze whole blood .

Turn around time: 5-7 days

Policy: General rejection criteria for specimens received at the laboratory may be developed. Additionally, each test may have specific requirements and shall have specific rejection criteria under the Specimen Requirements of the NCCLS formatted description of the test.

Procedure: Below are general rejection criteria. If the specimen must be rejected based on the following criteria, or specific criteria for the requested test, follow instructions under Disposal of Unacceptable Specimens (4.3.9):

  1. The test requisition form has missing information. Requisition must contain the required information including:
    • Requesting party and referring authority, usually a healthcare professional.
    • Patient identifying information - Name or alias if anonymous;
    • Test requested, Clinical indication for testing;
    • Date and time of specimen collection;
    • Type of sample (e.g. whole blood or epithelial cells obtained by buccal swab);
    • All other identifying information (e.g. social security number, telephone number, hospital ID, sex … etc.) is optional, but useful for accurate differentiating between patients with similar names.
  2. Label is unclear;
  3. Blood specimen is from a recipient of bone marrow transplant;
  4. Specimen is inappropriate for test requested;
  5. Blood sample is clotted or hemolyzed;
  6. Incorrect container or Vacutainer used;
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