Occult macular dystrophy is characterized by progressive decline of visual acuity in both eyes, associated with a normal fundus and normal fluorescein angiography. Patients have normal full-field electroretinograms (ERGs) but severely reduced focal macular ERGs, as recorded by ... Occult macular dystrophy is characterized by progressive decline of visual acuity in both eyes, associated with a normal fundus and normal fluorescein angiography. Patients have normal full-field electroretinograms (ERGs) but severely reduced focal macular ERGs, as recorded by conventional techniques using small stimuli under background illumination. OCMD patients are believed to have localized retinal dysfunction distal to the ganglion cells in the central retina (summary by Piao et al., 2000).
Miyake et al. (1989) reported a family in which a sister and brother and their father displayed an unusual form of macular dystrophy. Both sibs reported noticing reduced visual acuity around 13 years of age, with acuity measurements ... Miyake et al. (1989) reported a family in which a sister and brother and their father displayed an unusual form of macular dystrophy. Both sibs reported noticing reduced visual acuity around 13 years of age, with acuity measurements of 20/20 to 20/25 at that time; their visual acuity progressively worsened to 20/100 by 29 years and 19 years of age, respectively. Both sibs also had mild disturbances of color vision, with both red-green and yellow-blue defects. Their 55-year-old father had no severe visual complaints, but had noticed some progressive visual disturbance over the past 20 years. His best-corrected visual acuity was 20/20, and he had a mild red-green color vision defect bilaterally. Despite the patients' poor visual acuity and the advanced age of the father, their maculas appeared normal by ophthalmoscopy, with good ring and foveal reflexes, and fluorescein angiography was also normal. Results of full-field electroretinograms were normal in both cone and rod components, but the focal macular ERG results were severely affected: the central fovea was most impaired and the parafovea and perifovea were relatively spared in the sibs, whereas the reverse was true in their father, findings that were consistent with the sibs' poor visual acuity and their father's good visual acuity. Examination of the mother and an unaffected brother revealed normal visual acuity, color vision, fundi, full-field ERGs, and focal macular ERGs. Miyake et al. (1996) examined 13 patients with occult macular dystrophy from 8 families, including 3 patients from the family previously studied by Miyake et al. (1989). The fundi of 12 of the patients showed normal findings on ophthalmoscopy and fluorescein angiography, but the oldest patient (aged 65 years) had bull's eye maculopathy bilaterally. Electroretinograms in all 12 patients showed cone sensitivity loss only in the macular area; in addition, 6 older patients showed borderline or abnormal rod sensitivity in the macular area, whereas 6 relatively young patients had normal rod sensitivity. Miyake et al. (1996) suggested that the most suitable name for the disorder might be central cone dystrophy. Piao et al. (2000) examined 8 patients with OCMD, 5 of whom were previously studied by Miyake et al. (1996). Three patients were considered to represent autosomal dominant inheritance, and the other 5 patients were classified as sporadic. The diagnosis of OCMD was made based on bilateral involvement, normal ophthalmoscopic findings, normal fluorescein angiography, decreased visual acuity, normal full-field ERGs for both rod and cone components, and decreased focal macular cone ERGs. Corrected visual acuities ranged from 20/200 (0.1) to 20/50 (0.4), and light-adapted perimetry showed abnormally elevated cone thresholds within the central 10 degrees in all patients. Multifocal ERGs were performed in the 8 patients and 20 age-matched controls with normal visual acuity and color vision and normal full-field ERGs. OCMD patients had severely depressed responses from the central retina, with all patients having reduced amplitudes within 7 degrees of the fovea, although a large variation in amplitude was observed among the patients. Responses were relatively well-preserved peripherally, with differences in ERG amplitude between patients and controls becoming smaller towards the peripheral retina. In addition, most OCMD patients had slight but significantly delayed implicit times across the whole testing field, and the differences between patients and controls did not change with retinal eccentricity. Piao et al. (2000) stated that their results supported the concept of localized retinal dysfunction distal to the ganglion cells in the central retina in OCMD, and that the delayed implicit times across the whole test field suggested that the retinal dysfunction is more widespread than expected by ERG amplitudes and psychophysical perimetric results. Wildberger et al. (2003) studied an Italian family segregating autosomal dominant OCMD, in which affected individuals reported reduced visual acuity beginning in early childhood. The fundus in the 3 examined patients appeared normal, with no signs of maculopathy even in the oldest, at age 53 years. Multifocal ERGs demonstrated a marked depression of signal amplitudes in the macular region, whereas the retinal near-periphery was less disturbed. Wildberger et al. (2003) noted that amplitude values in these patients were depressed to an extent similar to that of patients reported previously by Piao et al. (2000); implicit times, however, were less prolonged than in the previous report, perhaps due to the higher mean age of patients in the earlier study. Brockhurst and Sandberg (2007) used optical coherence tomography (OCT) to evaluate foveal structure in 8 patients with OCMD who had corrected visual acuities ranging from 20/25 to count fingers. All reported slowly progressive vision loss, and all had normal pupillary responses, full peripheral fields, normal slit-lamp and ophthalmoscopic examinations, and normal full-field ERGs. Fluorescein angiography, performed in 3 of the patients, was also normal. OCT in 7 of the patients showed reduced foveal thickness associated with thinning of the outer nuclear layer, and the degree of visual impairment could be predicted from the OCT because visual acuity was proportional to central foveal thickness (p = 0.005). The eighth patient, whose visual acuity was reduced to counting fingers, had normal tomograms but reduced foveal ERGs, indicating that foveal malfunction rather than photoreceptor loss resulted in her visual acuity impairment. Park et al. (2010) used spectral-domain (SD)-OCT to investigate photoreceptor status in 8 sporadic OCMD patients and 1 patient with autosomal dominant OCMD. The decline in visual acuity was bilateral and symmetric in 4 patients, whereas 5 had unilateral deterioration of vision. Conventional time-domain OCT showed reduced foveal thickness in these patients, but revealed no other retinal layer abnormality. However, in 15 eyes of 8 patients, SD-OCT demonstrated a well-defined disruption of the inner segment-outer segment (IS-OS) junction of the photoreceptors and of the Verhoeff membrane (cone outer segment tips). Degrees of abnormality in the photoreceptor layer varied and correlated with the severity of vision deterioration and duration of symptoms. Park et al. (2010) noted that there was no correlation between multifocal ERG amplitudes and the severity of photoreceptor disruption, which they suggested might be due to technical difficulties in performing multifocal ERGs. No morphologic abnormality could be demonstrated in the photoreceptors of 1 patient. The other retinal layers, including the outer nuclear layer and the retinal pigment epithelium, were normal in all patients. SD-OCT also showed that 3 of 5 patients with presumed unilateral OCMD had bilateral OCMD after initial or follow-up examinations. Kim et al. (2011) studied 5 patients with OCMD. Color vision testing in 4 of the patients showed total dyschromatopsia in 3 and strong red-green color defect in 1. Visual field testing demonstrated central scotomata in all 5 patients, and all had decreased amplitude in the first ring on multifocal ERGs. SD-OCT showed decreased bowing of the IS-OS boundary of the photoreceptors in all patients, with disruption of the IS-OS boundary in 5 of 9 eyes and interruption of the external limiting membrane in 3 of 9 eyes. Tsunoda et al. (2012) examined 14 mutation-positive members of a large 5-generation Japanese family with RP1L1 (608581)-associated OCMD, previously studied by Akahori et al. (2010). All of the affected individuals had a similar phenotype, consisting of bilateral slowly progressive visual disturbances with a normal-appearing fundus, normal fluorescein angiography and full-field ERGs over the entire course of the disease, selective dysfunction of the macula detected by focal macular and multifactorial ERGs, selective abnormality of the photoreceptor layer in the macular on OCT, and a final best-corrected visual acuity (BCVA) not poorer than 20/200 (0.1). However, age at onset of OCMD was very variable among family members and ranged from 6 years to 50 years. Tsunoda et al. (2012) stated that their findings in this family confirmed that there are patients with OCMD who have normal visual acuity and no subjective visual disturbances until the disease has progressed to a more advanced stage; in addition, once the BCVA is reduced to 20/100 (0.2) to 20/200, the disease becomes stationary and both subjective and objective visual functions do not deteriorate thereafter. One family member, a 60-year-old woman, carried the mutation but had no subjective or objective signs of macular dysfunction. Because OCT examination of 2 OCMD patients who were negative for mutation in the RP1L1 gene showed dissimilar findings, Tsunoda et al. (2012) suggested that OCMD may represent different disease entities with similar retinal dysfunction.
In a large 5-generation Japanese pedigree with occult macular dystrophy mapping to chromosome 8p23-p22, Akahori et al. (2010) identified a heterozygous missense mutation in the candidate gene RP1L1 (R45W; 608581.0001) that segregated with the disease. The authors analyzed ... In a large 5-generation Japanese pedigree with occult macular dystrophy mapping to chromosome 8p23-p22, Akahori et al. (2010) identified a heterozygous missense mutation in the candidate gene RP1L1 (R45W; 608581.0001) that segregated with the disease. The authors analyzed RP1L1 in 3 additional Japanese families with OCMD and detected R45W in affected members of 2 of the families and a different heterozygous mutation (W960R; 608581.0002) in the third family. Neither mutation was found in 876 Japanese controls. There were 3 apparently unaffected individuals from 2 families who carried the R45W mutation, suggesting either reduced penetrance of the mutation or possibly a later onset of disease for these individuals, who were 55, 58, and 60 years old. Akahori et al. (2010) noted that 4 of the 8 OCMD patients described by Brockhurst and Sandberg (2007) had onset of disease at over 65 years of age, and that an elderly patient in the 5-generation Japanese pedigree had no symptoms in one of her eyes even at 81 years of age. Davidson et al. (2013) sequenced the coding region and intron-exon boundaries of the RP1L1 gene in 28 probands with clinical and electrophysiologic findings of OCMD similar to those previously reported by Akahori et al. (2010). Heterozygosity for the R45W variant was identified in 5 probands, but 8 unaffected family members, including an asymptomatic 90-year-old woman, were also found to carry R45W, for a penetrance of only 38%. Four of the asymptomatic carriers, including 3 who were over 55 years of age, underwent detailed phenotypic assessment and no signs of OCMD were detected. Davidson et al. (2013) concluded that the R45W variant represents a risk factor for OCMD rather than a causative mutation. They also identified heterozygosity for a different RP1L1 missense mutation, P110L, in 1 OCMD proband.