Occult macular dystrophy
Occult macular dystrophy (OMD) is a rare inherited retinal degeneration that causes a slowly progressive central visual decline despite an essentially normal appearing fundus. First described in 1989, this disease has become increasingly recognized.  The preponderance of literature has been published out of East Asia and it has been hypothesized to be more common in those of East Asian decent; however, due to the rarity of this disease and possible under-recognition, the epidemiology remains unknown.
OMD is an autosomal dominant disease caused by a mutation in the retinitis pigmentosa 1-like 1 (RP1L1) gene. 
The RP1L1 gene has been found in both rods and cones. The precise function remains unknown, but based on the structural and electrophysiological characteristics in affected patients, it would seem logical the encoded protein is involved in the function and/or structure of outer photoreceptor segments. Cones seem to be affected earlier in the course of disease or in less severe cases, and in more advanced cases rod function in the macula is also affected. It remains unknown why the disease primarily affects the fovea and why a more generalized cone dysfunction isn't present. RP1L1 mutations have also been associated autosomal recessive retinitis pigmentosa and cone dystrophy.
OMD is diagnosed by clinical history, with the aid of ancillary retinal imaging and electrophysiologic studies.
Patients present with a gradual visual acuity decline or a central scotoma. Symptom onset is variaible, with a reported mean age of 25-30 and a range from 2 to 74. Approximately 50% of patients will experience photophobia at some point during the course of their disease, while only a small minority experience light sensitivity at presentation.
Visual acuity measurements are variable and likely depend on the stage or severity of disease. In the largest series published, the mean visual acuity was 20/80, with 20% having 20/30 or better vision and approximately 10% measuring 20/200 or worse. Anterior and posterior segment exams are normal by definition.
OCT reveals a blurring of the ellipsoid zone (EZ) and loss of the interdigitation zones (IZ) in the central macula (Figure 1), thinning of the outer nuclear layers in patients with severe disease and a preservation of the retinal pigment epithelium. The EZ can also appear thickened, blurred and dome-shaped in some patients. Asymptomatic patients may show mild parafoveal abnormalities of the IZ and EZ.
Electroretinography demonstrates normal full-field cone and rod responses with local depression on macular or multifocal ERGs.
Visual fields can reveal a central scotoma.
Fluorescein angiography is typically normal and some patients may have mild foveal hyperautofluorescence.
Genetic testing for known RP1L1 mutations can confirm the diagnosis and be helpful in ambiguous cases.
OMD can be classified into RP1L1-associated OMD (Miyake disease), other hereditary OMD caused by non-RP1L1 mutations and nonhereditary OMD. There are subtle phenotypic differences between these groups, in particular nonhereditary OMD cases may not have involvement of both EZ and IZ. These phenotypic differences are suggestive of a possible differing mechanisms of photoreceptor injury and vision loss.
For patients with a normal appearing fundus and a vision decline, the differential diagnosis includes other retinal degenerations (such as cone dystrophy and early ABCA4-associated retinopathy), optic neuropathy, amblyopia, cortical vision loss and functional vision loss. Macular OCT, macular ERG or multifocal ERG in patients with unexplained visual acuity loss should be considered and can help in identifying patients with OMD.
Currently no treatment is available for patients with OMD. Two major challenges in developing gene therapy for OMD, among many other challenges, are the rarity of disease and the unknown function of the RP1L1 gene. However, as gene therapy improves for other pathologies, OMD may eventually be a reasonable target because, unlike in many other inherited retinal degenerations, patients with OMD often present in adulthood, don't have amblyopia and appear have a large window of therapeutic intervention due to the slow predictable progression of disease.
The visual acuity for most patients appears to slowly worsen over a 10 to 15 year period and then remain stable. However, significant variability exists between patients, and larger, long-term studies are needed to better counsel patients on their individual prognosis.
Open access articles with examples of ERGs and additional OCT images can be found here:
- Miyake Y, Ichikawa K, Shiose Y, Kawase Y. Hereditary macular dystrophy without visible fundus abnormality. Am J Ophthalmol. 1989;108(3):292-299. doi:10.1016/0002-9394(89)90120-7
- Fujinami K, Yang L, Joo K, et al. Clinical and Genetic Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake Disease): East Asia Occult Macular Dystrophy Studies Report Number 1. Ophthalmology. 2019;126(10):1432-1444. doi:10.1016/j.ophtha.2019.04.032
- Akahori M, Tsunoda K, Miyake Y, et al. Dominant mutations in RP1L1 are responsible for occult macular dystrophy. Am J Hum Genet. 2010;87(3):424-429. doi:10.1016/j.ajhg.2010.08.009
- Miyake Y, Tsunoda K. Occult macular dystrophy. Jpn J Ophthalmol. 2015;59(2):71-80. doi:10.1007/s10384-015-0371-7
- Zobor D, Zobor G, Hipp S, et al. Phenotype Variations Caused by Mutations in the RP1L1 Gene in a Large Mainly German Cohort. Invest Ophthalmol Vis Sci. 2018;59(7):3041-3052. doi:10.1167/iovs.18-24033
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- Kikuchi S, Kameya S, Gocho K, et al. Cone dystrophy in patient with homozygous RP1L1 mutation. Biomed Res Int. 2015; 2015: 545243.
- Nakamura N, Tsunoda K, Mizuno Y, et al. Clinical Stages of Occult Macular Dystrophy Based on Optical Coherence Tomographic Findings. Invest Ophthalmol Vis Sci. 2019;60(14):4691-4700. doi:10.1167/iovs.19-27486
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- Koizumi H, Maguire JI, Spaide RF. Spectral domain optical coherence tomographic findings of occult macular dystrophy. Ophthalmic Surg Lasers Imaging. 2009;40(2):174-176. doi:10.3928/15428877-20090301-13
- Kato Y, Hanazono G, Fujinami K, et al. Parafoveal Photoreceptor Abnormalities in Asymptomatic Patients With RP1L1 Mutations in Families With Occult Macular Dystrophy. Invest Ophthalmol Vis Sci. 2017;58(14):6020-6029. doi:10.1167/iovs.17-21969
- Fujinami K, Tsunoda K, Hanazono G, Shinoda K, Ohde H, Miyake Y. Fundus autofluorescence in autosomal dominant occult macular dystrophy. Arch Ophthalmol. 2011;129(5):597-602. doi:10.1001/archophthalmol.2011.96
- Fujinami K, Kameya S, Kikuchi S, et al. Novel RP1L1 variants and genotype-photoreceptor microstructural phenotype associations in cohort of Japanese patients with occult macular dystrophy. Invest Ophthalmol Vis Sci. 2016; 57: 4837–4846.
- Tsunoda K, Usui T, Hatase T, Yamai S, Fujinami K, Hanazono G, et al. Clinical characteristics of occult macular dystrophy in family with mutation of Rp1l1 gene. Retina-J Retinal Vitreous Dis. 2012;32:1135–47