Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy

Abstract

DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). Patient 1 was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. Patients 2 and 3 were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel DRAM2 variants were identified. TEM of the lymphocytes of Patients 1 and 2 showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the DRAM2-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of DRAM2 mutations may be compensable and have variations.

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

“…Their genotypes were p.Trp3del homozygous (Patient 3) and p.Val16Ala; p.Gly95Val (Patient 4). Although nyctalopia is often observed in patients with CRD, it is not expected to be the first symptom [16,23]. Patient 4 had reduced dark-adapted and light-adapted responses, whereas Patient 3 had ERG findings in the pattern of RCD.…”

“…The search in the previously published cases of retinopathy caused by biallelic variants in DRAM2 identified 6 reports with overall 24 cases from 14 families [12][13][14][15][16][17]. The genetic and clinical findings of these cases including ours are summarized in Tables 2 and 3, respectively.…”

“…Based on the review all (N = 25) DRAM2 patients with clinical data, the first symptoms most often appear in the third decade [12][13][14][15][16], although the onset varies from teenage years to the sixth decade of life (Figure 5). The earliest reported onset was by Patient 18 at the age of 16 [12], whereas the Slovenian Patient 2 had the latest onset so far, at the age of 59 years (Figure 5).…”

“…It is suggested that light hypersensitivity occurs due to impairment of either S-cones in the parafoveal region, rods, and/or photosensitive retinal ganglion cells, but the mechanism is not fully understood [22]. Interestingly, a subset of DRAM2 patients (12%; 3/24) described difficulty seeing in dark environments and dark adaption difficulties as their initial symptoms, suggesting an early rod impairment [14,16]. Their genotypes were p.Trp3del homozygous (Patient 3) and p.Val16Ala; p.Gly95Val (Patient 4).…”

“…Immunohistochemical analysis of the retina revealed that DRAM2 localizes to the inner segments of the photoreceptors and the apical surface of the RPE cells [12]. Since the first description of DRAM2 retinopathy in 2015 [12], fewer than 30 patients [12][13][14][15][16][17] have been reported with DRAM2 retinopathy, and the disease is still not well understood [12][13][14][15][16].…”