Alternative titles; symbols
SNOMEDCT: 724175002; ORPHA: 98955; DO: 0060450;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.2 | Lisch epithelial corneal dystrophy | 620763 | Autosomal dominant | 3 | MCOLN1 | 605248 |
A number sign (#) is used with this entry because of evidence that Lisch epithelial corneal dystrophy (LECD) is caused by heterozygous mutation in the MCOLN1 gene (605248) on chromosome 19p13.
Lisch epithelial corneal dystrophy (LECD) is characterized by corneal bands of whorled, feathery, gray opacities of varying widths. The opaque bands consist of clear, densely crowded, intraepithelial blisters. Vision may be impaired if the bands involve the central cornea (Lisch et al., 1992; Lisch et al., 2000).
Reviews
Lisch and Weiss (2019) provided a clinical and genetic update of the corneal dystrophies. They noted that LECD shows slow progression, and may result in blurred vision if the pupillary axis is involved. Indirect illumination focusing on the corneal epithelium reveals crowded clear microcysts, which are the clinical hallmark of LECD.
Lisch et al. (1992) described 5 members of a German family and 3 unrelated patients (4 males, 4 females), aged 23 to 71 years, with bilateral or unilateral, gray, band-shaped, and feathery opacities that sometimes appeared in whorled patterns. Retroillumination showed that the opacities consisted of intraepithelial, densely crowded, clear microcysts. Light and electron microscopy disclosed diffuse vacuolization of the cytoplasm of epithelial cells in the affected area. Visual acuity was so reduced in 3 patients that abrasion of the corneal epithelium was performed. The corneal abnormalities recurred within months, with the same reduction in visual acuity as before. Onset occurred in childhood; similar amounts of opacities were observed in men and women. Immunohistochemistry showed scattered staining on Ki67, indicating no evidence of increased mitotic activity.
Patterson et al. (2024) reported 23 patients from 13 families, including the German pedigree originally described by Lisch et al. (1992), with LECD and mutation in the MCOLN1 gene. Clinical data was retrieved by retrospective review of medical records. Age at diagnosis ranged from the second to ninth decades of life. Approximately three-quarters of patients were bilaterally affected, and visual acuity was unimpaired in most patients. The authors noted that the clinical features were consistent with less than 10% of stem cells in the corneoscleral limbus expressing the disease, with affected cells moving toward the center of the cornea as part of the normal epithelial cell migration; however, it was unclear why LECD involves only isolated portions of the corneoscleral limbus and corneal epithelium.
The transmission pattern of LECD in the families reported by Patterson et al. (2024) was consistent with autosomal dominant inheritance.
Lisch et al. (2000) established that Lisch and Meesmann (see 122100) epithelial corneal dystrophies are genetically distinct. They examined 48 members of an expanded 8-generation pedigree of the German family originally reported by Lisch et al. (1992). A total of 19 trait carriers were identified in 6 generations. No hereditary transmission from father to son was observed. Multipoint linkage analysis revealed linkage with a maximum lod score of 2.93 between markers DXYS233 and DXYS228X in the pseudoautosomal region at Xp22.3. Linkage was excluded for Xp22.2-qter.
Patterson et al. (2024) analyzed exome data generated for the expanded pedigree of the German family originally reported by Lisch et al. (1992) (family LECD1) and another 3-generation family (LECD2) but identified no candidate variants within the putative linkage interval at Xp22.3.
By genome sequencing in an expanded pedigree of the German family originally reported by Lisch et al. (1992) (family LECD1) and in another 3-generation family (LECD2), Patterson et al. (2024) identified heterozygosity for nonsense mutations in the MCOLN1 gene: a C192X substitution in 7 affected members over 2 generations of family LECD1 (605248.0010), and an R172X substitution in 4 affected members over 2 generations of family LECD2 (605248.0011). The mutations segregated with disease in both families and neither was found in the gnomAD database. However, in family LECD1, a 64-year-old carrier of the C192X substitution did not show signs of LECD, suggesting incomplete penetrance. Analysis of another 16 LECD patients from 15 families revealed heterozygosity for mutations in MCOLN1 in 12 of them, including 7 who were heterozygous for variants previously reported to cause mucolipidosis IV (ML4; 252650) in the biallelic state (see, e.g., 605248.0001). In 1 family (LECD3), there was father-to-son transmission of a missense mutation (L259P) that was not found in the gnomAD database, but the variant was designated as being of unknown significance by ACMG classification. The authors also reviewed the ophthalmic reports from 6 heterozygous carrier parents from 3 ML4 families, but did not find any evidence of LECD (see, e.g., 605248.0007). Patterson et al. (2024) concluded that heterozygous MCOLN1 variants can be associated with incomplete penetrance of LECD, and estimated a penetrance of 0.2% for MCOLN1 loss-of-function variants based on the gnomAD database population sample. They suggested that such a low penetrance might support the hypothesis that LECD opacities are localized areas of cells with ML4 due to a somatic 'second hit' to the second MCOLN1 gene copy in those cells, which would be consistent with observed unilateral and sporadic cases.
Lisch, W., Buttner, A., Oeffner, F., Boddeker, I., Engel, H., Lisch, C., Ziegler, A., Grzeschik, K.-H. Lisch corneal dystrophy is genetically distinct from Meesmann corneal dystrophy and maps to Xp22.3. Am. J. Ophthal. 130: 461-468, 2000. [PubMed: 11024418] [Full Text: https://doi.org/10.1016/s0002-9394(00)00494-3]
Lisch, W., Steuhl, K. P., Lisch, C., Weidle, E. G., Emmig, C. T., Cohen, K. L., Perry, H. D. A new, band-shaped and whorled microcystic dystrophy of the corneal epithelium. Am. J. Ophthal. 114: 35-44, 1992. [PubMed: 1621784] [Full Text: https://doi.org/10.1016/s0002-9394(14)77410-0]
Lisch, W., Weiss, J. S. Clinical and genetic update of corneal dystrophies. Exp. Eye Res. 186: 107715, 2019. Note: Erratum: Exp. Eye Res. 192: 107929, 2020. [PubMed: 31301286] [Full Text: https://doi.org/10.1016/j.exer.2019.107715]
Patterson, K., Chong, J. X., Chung, D. D., Lisch, W., Karp, C. L., Dreisler, E., Lockington, D., Rohrbach, J. M., Garczarczyk-Asim, D., Muller, T., Tuft, S. J., Skalicka, P., and 9 others. Lisch epithelial corneal dystrophy is caused by heterozygous loss-of-function variants in MCOLN1. Am. J. Ophthal. 258: 183-195, 2024. [PubMed: 37972748] [Full Text: https://doi.org/10.1016/j.ajo.2023.10.011]