Glaucoma


BACKGROUND:

Primary open angle glaucoma is now the most common molecularly recognizable form of blindness in the U.S., especially among African-Americans, and the second leading cause overall. Nearly 2% of the total population over age 40 are affected with the disease and the disorder blinds 12,000 people annually. Dysgenesis of the iris, iridocorneal angle and elevated ocular pressure are early indications of the disease. Subsequent optic nerve damage results in gradual painless loss of peripheral vision and eventual blindness. The juvenile form of the disease (approximately 1% of all cases) is inherited as a highly penetrant autosomal dominant trait that has been mapped to chromosome 1q21. The gene at this locus called GLC1A has recently been identified and its protein product found to be a trabecular meshwork component called TIGR (trabecular meshwork inducible glucocorticoid response protein). The trabecular meshwork regulates the outflow of intraocular fluid from the eye and thus ocular pressure. Affected individuals in five families linked to the 1q21 locus all carried one of three mutations of the GLC1A gene ( Gly357Val, Gln361STOP, Tyr430His), providing strong evidence that defects of this gene are responsible for the disease. This includes one family in which all affected members have adult onset glaucoma. When 227 unrelated adult glaucoma patients having at least one living first degree relative with a documented history of the disease were tested, 4.4% of them carried one of these mutations. Therefore, the gene=s effects are not limited to juvenile onset families. In fact, 3 of 103 unrelated randomly chosen adult patients presenting with open angle glaucoma at the University of Iowa glaucoma clinic carried the Gln361STOP mutation. In sum, these data indicate that 3% of all glaucoma cases can be recognized by screening for these three GLC1A mutations.

Presymptomatic screening with a simple genetic test can identify 100,000 people in the U.S. who have the glaucoma gene and do not know it. Interventions to preclude intraocular hypertension in these individuals could greatly decrease the burden of glaucoma. Also, since clinical determination of glaucoma is difficult in the early stages of the disease, confirmation of the diagnosis by molecular analysis in cases where glaucoma is already suspected would be extremely beneficial.

INDICATIONS FOR TESTING:

  • Confirmation of a clinical diagnosis of glaucoma.

  • Identification of presymptomatic individuals at high risk for developing glaucoma, especially those with a family history of the disease.

  • Individual with confirmed glaucoma who wishes hereditary information for other family members

SAMPLE REQUIREMENTS:

Blood: Two 5 ml purple top (EDTA) vacutainers of whole blood inverted several times to mix. Forward within 48 hours at room temperature.

INTERPRETATION:

PCR based assays are used to detect three mutations in the GLC1A gene (Gly357Val, Gln351STOP, Tyr430His).

Report will include assay results, background information, and a calculation of residual risk if results are negative.

COUNSELING ISSUES:

  1. The absence of a detectible GLC1A mutation does not exclude a diagnosis of glaucoma, since only 3% of all cases are detected in this assay.

  2. Detection of a GLC1A mutation indicates that the individual is at high risk for developing glaucoma. The phenotype is highly penetrant in people with a family history of disease, although the age of onset can be quite variable. The penetrance in nonsymptomatic individuals without a family history is not yet known.

 

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