Uncovering complexity of MAC disease

Take-Home

Genetic discoveries enable identification of carriers of MAC disease and have provided information about vitamin A supplementation that may help prevent ocular malformations.

By Lynda Charters; Reviewed by Christine C. Nelson, MD, FACS

Ann Arbor, MI-Microphthalmic, anophthalmia, and coloboma are devastating inherited ocular diseases.

The most recent developments in the genetic study of this disease were presented by Christine C. Nelson, MD, FACS, professor of ophthalmology and visual sciences, Kellogg Eye Center, University of Michigan, Ann Arbor. She discussed the components of MAC disease (Microphthalmic, Anophthalmia, Coloboma), a congenital eye disease spectrum that occurs in 1 in 10,000 children, presented the genetic findings, and offered possible new options for treating these children with this devastating congenital disorders.

MAC disease is characterized by great heterogeneity of the phenotypes and the genotypes. Dr. Nelson explained that MAC disease can be isolated, occur with other systemic anomalies, or be part of a well-defined syndrome; it can occur unilaterally or bilaterally.

Some gene mutations associated with MAC disease have been identified; SOX2, for example, is found in about 10% of patients with bilateral anophthalmia, according to Dr. Nelson.

Family study

Dr. Nelson and colleagues have uncovered a wealth of information based on the study of a family with many members who were blind or had varying degrees of abnormal ocular structures.

She explained that more than 25 genes for anophthalmia were found in many different locations in the genome.

During the course of this family study, Dr. Nelson and colleagues identified novel RBP4 gene mutations that cause MAC disease. RBP4 mutations in the mother and fetus plus normal vitamin A in pregnancy can cause MAC disease in the baby. In patients with the mutation, vitamin A transportation was affected, causing levels to decrease to too low in the mothers. Administration of increased vitamin A before pregnancy and during the first trimester boosts the available retinoids above the level of vitamin A deficiency. Vitamin A supplementation is critical during the period before conception and during the early first trimester of pregnancy.

Dr. Nelson and colleagues have developed a strategy by which they will screen mothers with a family history of MAC for fasting vitamin A levels or RBP4 mutations before they become pregnant. Vitamin A supplementation can then be provided to these women along with the usual prenatal vitamins.

“This supplementation will keep the vitamin A levels above the critical threshold,” she said.

Future directions

Dr. Nelson and her team have developed a three-pronged approach to treat these patients. Families will be counseled about the risk for MAC when the RBP4 gene is inherited from the mother, which constitutes about 75% of the cases. Carrier women who have a family history of MAC have a 35% to 40% chance of having a child with ocular malformations.

The investigators will also help develop a formal clinical test for the mutant allele in other family members. Finally, patients are being treated with additional vitamin A during the period before conception and early during the first trimester.

“By implementing these strategies, we can expect a range of outcomes,” Dr. Nelson said. “We hope to change from bilateral anophthalmia in children to those with two beautiful eyes.”

Christine C. Nelson, MD, FACS

E: cnelson@umich.edu

Dr. Nelson has no financial interest in the subject matter. This article was adapted from Dr. Nelson’s presentation of the 2012 Wendell L. Hughes Lecture, entitled “From Bench to Bedside: Genetics of Congenital Anophthalmia,” at the 2012 meeting of the American Academy of Ophthalmology.