In classical human genetics, females with a gene for a recessive disease or trait on only 1 X chromosome should have no manifestations of the defect. However, ophthalmic examples of structural and functional abnormalities in females heterozygous for supposedly recessive X-linked traits abound. Such carrier states, usually mild but occasionally severe, have been described in carriers of such diseases as
X-linked ocular albinism, or ocular albinism type 1 (also called Nettleship-Falls ocular albinism)
X-linked sutural cataracts
color vision defects of the protan and deutan types
See Figure 6-8 and Table 6-7.
Detection of these carrier states of the X-linked traits is clinically relevant, especially for sisters and maternal aunts of affected males. In 1961, geneticist Mary Lyon advanced an explanation for the unanticipated or partial expression of a trait by a heterozygous female. Briefly, in lyonization (X-chromosome inactivation), every somatic cell of a female has only 1 X chromosome that is actively functioning. The second X chromosome is inactive and forms a densely staining marginal nuclear structure demonstrated as a Barr body in a buccal smear or in “drumsticks,” pedunculated lobules of the nucleus identified in about 5% of the leukocytes of the unaffected female. Inactivation of 1 X chromosome occurs randomly in early embryogenesis. The same X chromosome will be irreversibly inactive in every daughter cell of each of these “committed” primordial cells. The active gene is dominant at a cellular level. Thus, a heterozygous female for an X-linked disease will have 2 clonal cell populations (mosaic phenotype), 1 with normal activity for the gene in question and the other with mutant activity.
The proportion of mutant to normal X chromosomes inactivated usually follows a normal distribution, because presumably the inactivation in various cells is a random event. Thus, an average of 50% of paternal X chromosomes and 50% of maternal X chromosomes are inactivated. It is conceivable, however, that in some cases the mutant X is active in almost all cells; in other cases, the mutant X is inactivated in nearly all cells. By this mechanism, a female may express an X-linked disorder; and rare cases are known of women who have a classic color deficiency or X-linked ocular albinism, X-linked RP, or choroideremia.
Carriers of X-linked ocular albinism may have a mottled mosaic fundus: in the pigmented retinal epithelial cells, the normal X chromosome is active; in the nonpigmented cells, the mutant X is active. However, these distinguishing features of the carrier state are not always present. The possibility that the patient is a carrier cannot be entirely eliminated if a given sign is not present because in a female, chance inactivation of the mutant X chromosome may have occurred in most of her primordial cells, which evolved into the specific tissue observed and may appear phenotypically normal. This subtlety is even more important in the evaluation of family members with X-linked disease if the phenotypic carrier state is age dependent; thus, even in obligate carrier females for Lowe syndrome, lenticular cortical opacities are not necessarily present before the third decade of life.
A, Yellow, “gold-dust” tapetal-like reflex in the left retina of a carrier for X-linked retinitis pigmentosa (RP). B, Nasal midperipheral retina in the left eye of a carrier for X-linked RP, showing patchy bone spicule–like pigment clumping. C, Peripheral retina from the left eye of a carrier of choroideremia, showing a “moth-eaten” fundus appearance from areas of hypopigmentation and hyperpigmentation. D, Wide-field fundus photograph, right eye, from a carrier for ocular albinism, showing a chocolate-brown pigmentation from areas of apparently enhanced pigmentation and clusters of hypopigmentation. E, Fundus autofluorescence image, right eye, from the same patient as in part D, showing mottled autofluorescence consistent with lyonization.
(Parts D and E courtesy of Elias Traboulsi, MD.)
Table 6-7 Ocular Findings in Carriers of X-Linked Disorders
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.