Severe Reduction Of Visual Acuity Research Articles

Case Series: Avoidable Blindness after Inappropriate Ophthalmic Self-medication in Ghana.

Inappropriate ophthalmic self-medication continues to plague Sub-Saharan Africa because of lack of public health education and inaccessibility to eye care services. This case series describes three cases of blindness (two monocular, one binocular) in Ghana, because of self-treatment of ocular conditions using improper drugs or homemade herbal mixtures. The article highlights the consequences of misinterpretation of symptoms and use of traditional home remedies, leading to delayed professional eye care and avoidable blindness. This case series aims to report three separate cases of avoidable blindness after inappropriate ophthalmic self-medication to draw attention to the need for intense public health education in Ghana. Three men aged 25, 79, and 35 years, respectively, reported severe reduction in visual acuity in one eye for two cases and both eyes for one case. All patients reported ophthalmic self-medication either with an inappropriate drug bought from the drug store or a homemade herbal mixture made from leaves assumed to treat eye infections. Professional care did not yield any improvement in visual acuity because their corneas were already decompensated at the onset of management. The eye of one patient had to be enucleated. These cases highlight the importance of eye health promotion and education. It is recommended that intense sensitization is carried out at all levels.

Treatment of a full-thickness macular hole and retinal detachment secondary to toxoplasma chorioretinitis that developed shortly after COVID-19: A case report

Although ocular toxoplasmosis is usually a self-limiting infection, it can lead to severe reduction in visual acuity due to intense vitreous inflammation or involvement of posterior segment structures. Depending on the severity of intraocular inflammation, serious complications, including epiretinal membrane or retinal detachment may develop. In this paper, we aim to present a case that complicated by both a full-thickness macular hole and retinal detachment secondary to toxoplasmosis chorioretinitis that developed shortly after the novel coronavirus disease (COVID-19) and discuss our treatment approach. After the patient was diagnosed based on a routine ophthalmological examination, fundus imaging, and serological examination, functional and anatomical recovery was achieved through systemic antibiotherapy and vitreoretinal surgery. Full-thickness macular hole and retinal detachment are rare complications of ocular toxoplasmosis. However, there are only few publications in the literature concerning these complications and their surgical treatment. In this case report, we demonstrated the success of vitreoretinal surgery combined with antibiotic therapy on the posterior segment complications of ocular toxoplasmosis.

Clinical and Optic Disc Characteristics of Patients Showing Visual Recovery in Leber Hereditary Optic Neuropathy.

The visual prognosis in Leber hereditary optic neuropathy (LHON) is generally poor. However, some individuals can have spontaneous visual recovery (VR) in one or both eyes by a mechanism that is not yet clearly understood. The purpose of this study was to determine whether certain clinical and optic disc features are associated with VR in patients with LHON. We retrospectively examined 80 eyes of 40 patients with LHON using clinical databases, fundus photographs, and high-definition spectral-domain optical coherence tomography (OCT) images. VR was defined as a gain of 3 or more lines of logarithm of the minimum angle of resolution (logMAR)-scaled visual acuity from nadir; this represents a doubling of the visual angle. Patients were divided into VR and nonrecovery (NR) groups. Using fundus photographs, we measured optic disc size and evaluated for the presence of optic disc features, including peripapillary telangiectasia, disc hyperemia, and swelling. We also measured the disc area, cup-to-disc ratio, and rim area of the optic disc using OCT. Twenty-one of 80 eyes (26%) had a VR. The VR occurred within 2 years after onset in 81% of cases. The VR group showed younger age at onset (21 vs 29 years, P = 0.017) and better visual acuity at the nadir (1.39 vs 2.16 logMAR, P < 0.001) compared with the NR group. Optic disc features, particularly peripapillary telangiectasia (P = 0.027) and disc hyperemia (P = 0.006), were more prominent in the NR group. The cup-to-disc ratio was significantly smaller (0.64 vs 0.71, P = 0.004) and the rim area was significantly greater (1.17 vs 0.85 mm, P < 0.001) in the VR group compared with the NR group. A younger age at onset and a less severe reduction of visual acuity at the nadir were associated with a higher probability of VR. Presence of peripapillary telangiectasia and optic disc hyperemia may serve as predictive factors for poor visual prognosis in patients with LHON.

Sociodemographic Factors in Neovascular Age-Related Macular Degeneration

‬‬‬‬Abstract‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬ In 3205 patients with newly diagnosed neovascular age-related macular degeneration (nAMD), older age, non-white race, and decreased regional average adjusted gross income were associated with a severe reduction in visual acuity at initial nAMD

Overexpression of the gene product of ocular albinism 1 (GPR143/OA1) but not its mutant forms inhibits neurite outgrowth in PC12 cells

Neurite outgrowth is a complex differentiation process regulated by external and/or internal mechanisms. Among external mechanisms, G-protein coupled receptors (GPCRs) have been implicated in this process, but the pathways involved are not fully understood. L-3,4-dihydroxyphenylalanine (l-DOPA) is considered to be inert by itself, and to relieve Parkinson's disease through its conversion to dopamine. We have proposed that l-DOPA acts as a neurotransmitter. GPR143, the gene product of ocular albinism 1 (OA1), was identified as a receptor for l-DOPA. OA1 is an X-linked disorder characterized by all typical visual anomalies associated with hypopigmentation and optic misrouting, resulting in severe reduction of visual acuity. However, the molecular basis for this phenotype remains unknown. To study the function of GPR143, we investigated the phenotypic effect of overexpression of GPR143 in pheochromocytoma (PC12) cells treated with nerve growth factor. Overexpression of mouse GPR143 inhibited neurite outgrowth, and the effect was mitigated by l-DOPA cyclohexylester, an antagonist for l-DOPA. Furthermore, knockdown of G-protein Gα13 attenuated mouse GPR143 induced inhibition of neurite outgrowth. Human wild-type (wt) GPR143 also inhibited neurite outgrowth, but its mutants did not mimic the effect of wt GPR143. Our results provide a mechanism for axon guidance phenotype in ocular albinism 1.

Socio-economic status and outcomes for patients with age-related macular degeneration.

To explore disparities in severity of baseline disease, treatment completion, and treatment outcomes among patients with wet age-related macular degeneration (AMD) receiving anti-vascular endothelial growth factor therapy by socio-economic status (SES) and distance from home to hospital. Retrospective cohort study. Data from clinic records of 756 wet AMD patients receiving treatment for wet AMD with aflibercept between May 2013 and Jan 2017 were obtained. Area SES (using Index of Multiple Deprivation (IMD) 2015) and distance from hospital (dichotomized > = 10 vs. <10 km) were derived from anonymized postcodes. Univariate and multivariable logistic regression models were used to identify associations of area deprivation and distance from hospital at baseline-with visual acuity (VA) at baseline-treatment completion, and treatment outcome. Living in the most deprived compared with less deprived areas was associated with a significantly higher risk of presenting with severe reduction in VA (OR = 3.59; 95% CI = 1.39-9.27; P = .01). This association was maintained after adjustment for age, gender, and distance from hospital. On univariate analysis, delayed treatment completion was more likely in those living in most deprived areas (OR = 2.80; 95% CI = 1.21-6.47; P = .04), though this association was attenuated after adjustment for age, gender, and distance from hospital. No association was observed between SES and treatment outcomes or between distance from hospital and baseline VA, treatment completion or treatment outcome. This study found poorer baseline VA among people with wet AMD from more deprived areas. This work suggests a need for earlier identification of AMD among more deprived populations.

Unfavorable Structural and Functional Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis.

Recurrent optic neuritis (rON) associated with myelin oligodendrocyte glycoprotein (MOG)-specific antibodies has been initially reported to show a better clinical outcome than aquaporin-4 (AQP4)-seropositive ON in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterize clinical and neuroimaging findings in severe cases of MOG antibody-positive and AQP4 antibody-negative bilateral rON. Three male adults with rON (ages 18, 44, and 63 years) were evaluated with optical coherence tomography (OCT), MRI, cerebrospinal fluid (CSF), and serological studies. All patients experienced >7 relapses of ON with severe reduction of visual acuity and partial response to steroid treatment. Optic nerves were affected bilaterally, although unilateral relapses were more frequent than simultaneous bilateral recurrences. Patients were MOG-seropositive but repeatedly tested negative for AQP4 antibodies. OCT showed severe thinning of the peripapillary retinal nerve fiber layer. On MRI, contrast-enhancing lesions extended over more than half the length of the optic nerve. CSF analyses during ON episodes were normal. Severe visual deficits accumulated over time in 2 of 3 patients, despite immunosuppressive therapy. MOG-seropositive and AQP4-seronegative rON may be associated with an aggressive disease course and poor functional and structural outcomes. In contrast to previous reports, the severity and pattern of retinal and optic nerve damage closely resembled phenotypes commonly observed in AQP4-seropositive rON without fulfilling current diagnostic criteria for NMOSD.

Visual prognosis better in eyes with less severe reduction of visual acuity one year after onset of Leber hereditary optic neuropathy caused by the 11,778 mutation

BackgroundPatients with Leber hereditary optic neuropathy (LHON) have a progressive decrease of their visual acuity which can deteriorate to <0.1. Some patients can have a partial recovery of their vision in one or both eyes. One prognostic factor associated with a recovery of vision is an early-age onset. The purpose of this study was to determine other clinical factors that are predictive of a good visual recovery.MethodsSixty-one Japanese LHON patients, with the 11,778 mutation and a mean age of 23.1 ± 12.1 years at the onset, were studied. All patients were initially examined at an acute stage of LHON and were followed for 3 to 10 years. At 1 year after the onset, the lowest visual acuity was <0.1 in all eyes. We studied the following parameters of patients with/without a final visual acuity of ≥ 0.2: sex; heavy consumption of cigarettes and alcohol; taking idebenone; mean age at onset; mean lowest visual acuity; and distribution of the lowest and the final visual acuity.ResultsFifteen (24.6%) of the 61 patients or 25 (20.5%) of the 122 eyes had a recovery of their visual acuity to ≥ 0.2. The mean age at onset of these 15 patients with visual recovery to ≥ 0.2 was 17.5 ± 7.7 years, and that of the 46 patients without visual recovery to ≥ 0.2 was 25.0 ± 12.8 years (P = 0.02, Mann-Whitney U test). The mean lowest visual acuity of the 25 eyes with visual recovery ≥ 0.2 was 0.04, and that of the 97 eyes without visual recovery to ≥ 0.2 was 0.015 (P < 0.001, Mann-Whitney U test). Fifty percent (15/30) of the eyes whose lowest visual acuity was ≥ 0.04 during 1 year after the onset had a visual recovery to ≥ 0.2, while 11% (10/92) of the eyes whose the lowest visual acuity was ≤ 0.03 had a visual recovery to ≥ 0.2 (P < 0.001, χ2 test). There were no significant differences in the other clinical factors.ConclusionA final visual acuity of ≥ 0.2 was associated with a less severe reduction of the visual acuity at 1 year after the onset. Our findings can be used to predict the visual prognosis in LHON patients.

Management of Keratoconus: Recent Trends

Keratoconus is a bilateral, progressive disease characterised by corneal thinning, ectasia, variable degree of irregular astigmatism and resultant mild to severe reduction in visual acuity. Multiple advances in corneal imaging and topographic mapping have led to a better understanding of the disease and its progression. Traditionally, use of spectacles and rigid contact lenses has been the primary mode of treatment in early KC while keratoplasty has been the treatment of choice in advanced cases. However, development of an array of therapeutic options over the last decade has revolutionized the approach to this disease. The preferred treatment for progressive KC has shown a paradigm shift from contact lens fitting for as long as tolerated, followed by Penetrating Keratoplasty (PK) or Deep anterior lamellar keratoplasty (DALK), to Ultraviolet-A (UV-A) induced collagen cross-linking (CXL) to stabilize corneal ectasia in the long term. Recently, use of Intrastromal Corneal Ring Segments, Phakic IOLs, application of excimer laser and use of combination techniques have all made significant contribution in providing options for effective management of different stages of this disease. Bowman layer (BL) transplantation is a new technique that has recently been introduced as an alternative to PK/ DALK in eyes with advanced KC, unsuitable for either UV-CXL or ICRS. By means of this article, we aim to provide a summary of these recent trends in therapeutic options for the optimal management of keratoconus.

Clinical and pathological features of acute optic neuritis in Chinese patients

Background The incentives and the factors that affect the onset and outcome of optic neuritis (ON) are not very clear. The aim of this study is to define and get a comprehensive understanding of the clinical profile of ON, and to identify the factors that were related to the prognosis of the patients. Methods Medical records of patients with diagnosis of ON at Huashan Hospital, Fudan University between March 2008 and June 2011 were reviewed. Clinical features, ophthalmologic and neurologic assessments, neuroimaging studies, laboratory examinations, visual recovery, and final outcome of the patients were evaluated by the authors. Results Records of 50 patients (32 females and 18 males), aged 15-56 years, were reviewed, in which 22% patients had a previous onset of ON. Maximal visual deficit was severe in 72.5% (&lt;20/200). Abnormal rates of hormone levels and rheumatoid indicators were found in 54.2% and 25.0%. ANA test returned positive in 40%, oligoclonal banding (OCB) was identified in 31.3%, and Serum neuromyelitis optica (NMO)-IgG studies were abnormal in 25% of the patients. Neuroimaging abnormalities associated with ON were documented in six patients. Three of the 50 patients have been diagnosed with multiple sclerosis, and two with NMO. Visual acuity was 20/20 or better in 26.1% and 20/100 or worse in 39.1% affected eyes at the last visit. Poor visual acuity at onset is the main factor that would affect the final outcome of vision (P &lt;0.05). Conclusions Vision defects of this group of patients were severe. Females had a higher incidence of ON than males. Hormone levels, rheumatoid indicators and immune parameters may be related to the onset of ON. The severe reduction of visual acuity at onset may be related to the poor outcome of vision in ON patients.

Bevacizumab for the Treatment of Corneal Neovascularization

Corneal neovascularization (NV) is a severe complication associated with inflammatory or infectious disorders of the cornea. NV may lead to severe reduction in visual acuity and poor prognosis for corneal transplantation and excimer laser refractive surgery. Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to play a major role in the pathogenesis of corneal NV. Use of an anti-VEGF antibody would seem a theoretically plausible means for treating corneal NV. Recently, bevacizumab, a humanized monoclonal antibody against VEGF, has been reported significantly to inhibit choroidoretinal NV. Several animal and human studies have also reported beneficial effects of bevacizumab against corneal NV; both topical and subconjunctival application were effective. Nonetheless, optimal dosage, route of administration, and possible complications are yet to be fully characterized. This review summarizes the relevant literature and formulates several key questions to guide future use of bevacizumab in the treatment of corneal NV.

Eight previously unidentified mutations found in the OA1ocular albinism gene

BackgroundOcular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene.MethodsThe ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments.ResultsWe sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found.ConclusionThe identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand.

Successful use of recombinant activated factor VII in the treatment of vitreous haemorrhage: a report of seven cases

Vitreous haemorrhage poses a serious threat to vision if untreated. Therapeutic options remain scarce and surgical intervention to resolve persistent bleeding is associated with risks that may further compromise vision. We report the use of recombinant activated factor VII (rFVIIa) in seven patients (six men, one woman; age, 30-65 years) with vitreous haemorrhage and severe reduction in visual acuity caused by trauma (n = 4) or proliferative diabetic retinopathy (n = 3). Initial doses ranged from 60 to 140 microg/kg; most patients received maintenance therapy with 20-60 microg/kg for at least 3 days. One patient received rFVIIa treatment for only 24 h and suffered a re-bleed, controlled successfully with further rFVIIa therapy. Five patients responded well to rFVIIa treatment, with reduced symptoms and improvements in visual acuity. Late presentation several days after trauma or symptom onset may have contributed to poor outcomes in the two patients who failed to respond to rFVIIa therapy. No adverse events were observed. An initial dose of rFVIIa 60-140 microg/kg, followed by 20-60 microg/kg repeated at 8-h intervals for 3-5 days, appears to be an effective therapeutic option for vitreous haemorrhage. However, further studies of rFVIIa use in this indication are warranted.

The ocular albinism type 1 (OA1) protein and the evidence for an intracellular signal transduction system involved in melanosome biogenesis

Ocular albinism type 1 is an X-linked disorder characterized by severe reduction of visual acuity, retinal hypopigmentation, foveal hypoplasia, optic misrouting and the presence of giant melanosomes (macromelanosomes) in skin melanocytes and retinal pigment epithelium. The protein product of the OA1 gene is a pigment cell specific membrane glycoprotein, displaying structural and functional features of G protein-coupled receptors (GPCRs). However, in contrast to all other previously characterized GPCRs, OA1 is not localized to the plasma membrane, but is targeted to intracellular organelles, namely late endosomes/lysosomes and melanosomes. These unique characteristics suggest that OA1 represents the first example described so far of an exclusively intracellular GPCR and regulates melanosome biogenesis by transducing signals from the organelle lumen to the cytosol. These findings support previous hypotheses that GPCR-mediated signaling might also operate at the internal membranes in mammalian cells.

Mutational analysis of the OA1 gene in ocular albinism

Ocular albinism type 1 (OA1) is an X-linked disorder, mainly characterized by a severe reduction in visual acuity, foveal hypoplasia, nystagmus, hypopigmentation of the retina, the presence of macromelanosomes in the skin and eyes, and the misrouting of optic pathways, resulting in the loss of stereoscopic vision. We screened the OA1 gene for mutations in three unrelated Canadian and French families and in two isolated patients with OA1. We found three different missense mutations and two different nonsense mutations, three of which were novel. To date, 41 mutations (including missense mutations, insertions, and deletions) have been reported in the OA1 gene. Mutation and polymorphism data for this gene are available from the international albinism center albinism database website: http://www.cbc.umn.edu/tad/oa1map.htm.

Vitreous Surgery for Bilateral Bullous Retinal Detachment in Vogt-Koyanagi-Harada Syndrome

A successful surgical treatment (vitrectomy) for bilateral bullous retinal detachment in a patient with Vogt-Koyanagi-Harada (VKH) disease is reported. A 78-year-old woman had severe reduction of visual acuity in both eyes because of an extremely bullous nonrhegmatogenous retinal detachment accompanied by VKH disease. We performed lens extraction and vitrectomy on both eyes combined with systemic and topical corticosteroid therapy. The retina was reattached immediately after the surgery and her visual acuity promptly improved in both eyes. She had no recurrence of retinal detachment even after tapering the dose of corticosteroid. We suggest that vitrectomy may be an effective therapeutic option in the treatment for severe bullous retinal detachment associated with VKH disease.

Effective retrovirus-mediated gene transfer in normal and mutant human melanocytes.

Melanocytes represent the second most important cell type in the skin and are primarily responsible for the pigmentation of skin, hair, and eyes. Their function may be affected in a number of inherited and acquired disorders, characterized by hyperpigmentation or hypopigmentation, consequent aesthetic problems, and increased susceptibility to sun-mediated skin damage and photocarcinogenesis. Nevertheless, the possibility of genetically manipulating human melanocytes has been hampered so far by a number of limitations, including their resistance to retroviral infection. To address the problem of human melanocyte transduction, we generated a melanocyte culture from a patient affected with ocular albinism type 1 (OA1), an X-linked pigmentation disorder, characterized by severe reduction of visual acuity, retinal hypopigmentation, and the presence of macromelanosomes in skin melanocytes and retinal pigment epithelium (RPE). The cultured patient melanocytes displayed a significant impairment in replication ability and showed complete absence of endogenous OA1 protein, thus representing a suitable model for setting up an efficient gene transfer procedure. To correct the genetic defect in these cells, we used a retroviral vector carrying the OA1 cDNA and exploited a melanocyte-keratinocyte coculturing approach. Despite their lower replication rate with respect to wildtype cells, the patient melanocytes were efficiently transduced and readily selected in vitro, and were found to express, process, and properly sort large amounts of recombinant OA1 protein. These results indicate the feasibility of efficiently and stably transducing in vitro not only normal neonatal, but also mutant adult, human melanocytes with nonmitogenic genes.

Ocular albinism type 1: more than meets the eye.

Ocular albinism type 1 (OA1) is an X-linked recessive disorder characterized by a severe reduction of visual acuity, and hypopigmentation of the retina that leads to nystagmus, strabismus, and photophobia/photodysphoria. Microscopic examination of both retinal pigment epithelium and skin melanocytes in OA1 reveals the presence of macrome-lanosomes, suggesting that the OA1 gene product plays a role in melanosome biogenesis. Studies of mutations identified from OA1 patients and an Oa1 knock-out mouse model further implicate OA1 protein function in the late stage of melanosome development. Because its effects are primarily limited to the eye, OA1 represents an ideal model system to study the relationship between pigmentation and visual development. Based upon sequence homology and biochemical studies, OA1 may represent a novel intracellular G-protein coupled receptor. Understanding the function of OA1 will contribute greatly to our understanding of melanosome biogenesis and the role of pigmentation in visual development.

Diverse prevalence of large deletions within the OA1 gene in ocular albinism type 1 patients from Europe and North America.

Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by congenital nystagmus and photodysphoria, moderate to severe reduction of visual acuity, hypopigmentation of the retina, and the presence of macromelanosomes in the skin and eyes. We have previously isolated the gene for OA1 and characterized its protein product as melanosomal membrane glycoprotein displaying structural and functional features of G protein-coupled receptors. We and others have identified mutations of various types within the OA1 gene in patients with this disorder, including deletions and splice site, frameshift, nonsense, and missense mutations. However, different prevalences of large intragenic deletions have been reported, ranging from 10% to 50% in independent studies. To determine whether these differences might be related to the geographic origin of the OA1 families tested, we performed a further extensive mutation analysis study leading to the identification of pathogenic mutations in 30 unrelated OA1 patients mainly from Europe and North America. These results, together with our earlier mutation reports on OA1, allow us to resolve the apparent discrepancies between previous studies and point to a substantial difference in the frequency of large intragenic deletions in European (<10%) compared with North American (>50%) OA1 families. These observations and our overall refinement of point mutation distribution within the OA1 gene have important implications for the molecular diagnosis of OA1 and for the establishment of any mutation detection program for this disorder.

Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1.

Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina and the presence of macromelanosomes in the skin and eyes. Various types of mutation have been identified within the OA1 gene in patients with the disorder, including several missense mutations of unknown functional significance. In order to shed light into the molecular pathogenesis of ocular albinism and possibly define critical functional domains within the OA1 protein, we characterized 19 independent missense mutations with respect to processing and subcellular distribution on expression in COS-7 cells. Our analysis indicates the presence of at least two distinct biochemical defects associated with the different missense mutations. Eleven of the nineteen OA1 mutants (approximately 60%) were retained in the endoplasmic reticulum, showing defecNStive intracellular transport and glycosylation, consistent with protein misfolding. The remaining eight of the nineteen OA1 mutants (approximately 40%) displayed sorting and processing behaviours indistinguishable from those of the wild-type protein. Consistent with our recent findings that OA1 represents a novel type of intracellular G protein-coupled receptor (GPCR), we found that most of these latter mutations cluster within the second and third cytosolic loops, two regions that in canonical GPCRs are known to be critical for their downstream signaling, including G protein-coupling and effector activation. The biochemical analysis of OA1 mutations performed in this study provides important insights into the structure-function relationships of the OA1 protein and implies protein misfolding as a major pathogenic mechanism in OA1.