Clinical and genetic characteristics and natural history of Finnish families with familial exudative vitreoretinopathy due to pathogenic FZD4 variants.

PURPOSE: To report clinical and genetic characteristics of familial exudative vitreoretinopathy (FEVR) in the Finnish population. METHODS: Detailed clinical and genetic data of 35 individuals with heterozygous pathogenic variants in FZD4 were gathered and analysed. RESULTS: Thirty-two individuals with FZD4 c.313A>G variant and three individuals with FZD4 c.40_49del were included in the study. The clinical phenotype was variable even among family members with the same FZD4 variant. Only 34% (N = 12/35) of variant-positive individuals had been clinically diagnosed with FEVR. The median age of the onset of symptoms was 2.3 years, ranging between 0 to 25 years. Median visual acuity was 0.1 logMAR (0.8 Snellen decimal), ranging between light perception and -0.1 logMAR (1.25 Snellen decimal). Most (N = 33/35, 94%) were classified as not visually impaired. Despite unilateral visual loss present in some, they did not meet the criteria of visual impairment according to the WHO classification. Two study patients (N = 2/35, 6%) had severe visual impairment. The most common FEVR stage in study patient's eyes (N = 28/70 eyes, 40%) was FEVR stage 1, that is, avascular periphery or abnormal vascularisation. Most of FZD4-variant-positive study patient's eyes (N = 31/50 eyes, 62%) were myopic. Two individuals presented with persistent hyperplastic primary vitreous expanding the phenotypic spectrum of FEVR. Shared haplotypes extending approximately 0.9 Mb around the recurrent FZD4 c.313A>G variant were identified. CONCLUSION: Most study patients were unaffected or had mild clinical manifestations by FEVR. Myopia seemed to be overly common in FZD4-variant-positive individuals.

A novel frameshift variant in CEP78 associated with nonsyndromic retinitis pigmentosa, and a review of CEP78-related phenotypes.

BACKGROUND: Pathogenic variants in the CEP78 gene can present as atypical Usher syndrome or as retinitis pigmentosa. Here, we present a review of all reported cases of CEP78 variants in the literature to date and present a novel variant of CEP78, c.1261_1262delinsA, in a consanguineous northern Finnish family with two individuals. MATERIALS AND METHODS: Our patients were first discovered in a registry-based study. Later, they gave their written consent for this study. In order to describe the genotype and phenotype, their historic clinical patient data and genetic data were gathered, and a clinical ophthalmic examination and an audiogram were performed. For this review, a PubMed search using the keyword CEP78 was carried out. The first article on CEP78 was published in the year 2007, and the publications from the years 2007-2021 were included. RESULTS: A large gene panel identified a homozygous CEP78 c.1261_1262delinsA variant in two affected siblings. In addition to the classical signs of retinitis pigmentosa, both siblings had large round atrophic spots in the mid periphery, and hyperautofluorescence of the macula. Patient 1 had age-related hearing impairment; patient 2 had normal hearing. In total, 20 articles have been published about CEP78. Eight of these papers report patient data with the affected individuals typically having retinal dystrophy combined with sensorineural hearing impairment, classified as atypical Usher syndrome. CONCLUSIONS: Here, we present a comprehensive review of CEP78 and expand the knowledge of pathogenic CEP78 variants and the phenotypic variety.

MULTIMODAL IMAGING DURING THE EVOLUTION OF BLOOD-BRAIN BARRIER DISRUPTION MACULOPATHY.

PURPOSE: To highlight the course of blood-brain barrier disruption maculopathy in a patient with successfully managed relapsed central nervous system lymphoma. METHODS: Case report with fundus autofluorescence and optical coherence tomography imaging, and literature review. RESULTS: A 57-year-old patient diagnosed with central nervous system large B-cell lymphoma had a normal ophthalmic evaluation on his first visit. Subsequently, when his malignancy recurred locally, he was started on blood-brain barrier disruption therapy and intraarterial methotrexate. During the course of the therapy, he developed bilateral retinal pigment epithelial abnormalities located in the foveal and perifoveal zones. The changes were first mildly progressive and then marginally regressive in nature with minimal eventual loss of visual acuity to 20/32 and 20/25 in his right and left eye, respectively. CONCLUSION: Maculopathy is a known complication in patients with central nervous system malignancies undergoing blood-brain barrier disruption. A detailed clinical evaluation using fundus autofluorescence and high-definition optical coherence tomography are informative in managing such patients.

Prevalence of diabetic retinopathy in young adults with type 1 diabetes since childhood: the Oulu cohort study of diabetic retinopathy.

PURPOSE: To evaluate the prevalence and stage of diabetic retinopathy (DR) in a population-based cohort of young Finnish adults who have had type 1 diabetes (T1D) since childhood. MATERIAL AND METHODS: The cohort includes all 5- to 16-year-old patients with T1D who lived in the Northern Ostrobothnia Hospital District of Finland, in 1989 (n = 216). DR was evaluated from fundus photographs taken in 1989-1990 and again in 2007. The patients were 7 ± 4 years age (range 0-15 years) at the time of diagnosis of T1D, and the average duration of diabetes at the re-evaluation was 23 ± 4 years (range 17-32 years). RESULTS: The prevalence of DR was analysed in 172 patients (80% of the original cohort) at 22-35 years. Proliferative DR (PDR) was observed in 35% (60/172) and non-proliferative DR in 59% (101/172), with no signs of DR being present in the remaining 6% (11/172) of the subjects. The prevalence of DR did not differ by gender (p = 0.356). CONCLUSIONS: After the 18-year follow-up, a high prevalence of DR and PDR (94% and 35%, respectively) was found in patients who have had T1D since childhood, with no difference between the genders.

Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration.

BACKGROUND: Variants in the complement cascade genes and the LOC387715/HTRA1, have been widely reported to associate with age-related macular degeneration (AMD), the most common cause of visual impairment in industrialized countries. METHODS/PRINCIPAL FINDINGS: We investigated the association between the LOC387715 A69S and complement component C3 R102G risk alleles in the Finnish case-control material and found a significant association with both variants (OR 2.98, p = 3.75 x 10(-9); non-AMD controls and OR 2.79, p = 2.78 x 10(-19), blood donor controls and OR 1.83, p = 0.008; non-AMD controls and OR 1.39, p = 0.039; blood donor controls), respectively. Previously, we have shown a strong association between complement factor H (CFH) Y402H and AMD in the Finnish population. A carrier of at least one risk allele in each of the three susceptibility loci (LOC387715, C3, CFH) had an 18-fold risk of AMD when compared to a non-carrier homozygote in all three loci. A tentative gene-gene interaction between the two major AMD-associated loci, LOC387715 and CFH, was found in this study using a multiplicative (logistic regression) model, a synergy index (departure-from-additivity model) and the mutual information method (MI), suggesting that a common causative pathway may exist for these genes. Smoking (ever vs. never) exerted an extra risk for AMD, but somewhat surprisingly, only in connection with other factors such as sex and the C3 genotype. Population attributable risks (PAR) for the CFH, LOC387715 and C3 variants were 58.2%, 51.4% and 5.8%, respectively, the summary PAR for the three variants being 65.4%. CONCLUSIONS/SIGNIFICANCE: Evidence for gene-gene interaction between two major AMD associated loci CFH and LOC387715 was obtained using three methods, logistic regression, a synergy index and the mutual information (MI) index.

Photodynamic therapy with verteporfin to induce regression of aggressive retinal astrocytomas.

PURPOSE: To evaluate the effect of photodynamic therapy (PDT) with verteporfin on symptomatic, aggressive retinal astrocytomas. METHODS: A prospective, interventional study in a tertiary referral centre. Two patients were treated with a single session of PDT using the standard parameters of the Verteporfin in Photodynamic Therapy (VIP) study: a 34-year-old man whose previously stationary juxtapapillary retinal astrocytoma, secondary to tuberous sclerosis, progressed within 7 months to involve the foveola; and a 68-year-old man whose acquired retinal astrocytoma progressed over 18 months in spite of standard photocoagulation. Both tumours were vascularized and had caused secondary lipid exudation and an exudative retinal detachment. Outcome measures were visual acuity, resorption of subretinal fluid, tumour height and fluorescein angiography. RESULTS: The progressing, vascularized part of both retinal astrocytomas regressed, with little change in the poorly vascularized, stationary part of the congenital hamartoma. Visual acuity improved in the first patient and was unchanged in the second by 3 months, with stable vision in both and no sign of recurrence at 2 years. The exudative retinal detachments resolved completely. Tumour height reduced a median of 30%. Regression was associated with obliteration of tumour vessels within the progressing part of the lesion, with closure of some of the dilated retinal capillaries over the tumour. Intraretinal microvascular abnormalities and scattered haemorrhages appeared outside the treated area in the first patient. CONCLUSION: PDT with verteporfin can induce regression of progressive, vascularized, aggressive retinal astrocytomas and may prevent typical progression to total retinal detachment and enucleation, whether the astrocytoma is associated with tuberous sclerosis or not. PDT may be considered a first-line treatment for aggressive retinal astrocytomas.

Analysis of variants in the complement factor H, the elongation of very long chain fatty acids-like 4 and the hemicentin 1 genes of age-related macular degeneration in the Finnish population.

PURPOSE: A strong association of a Tyr402His polymorphism in the complement factor H (CFH) gene and a Met299Val polymorphism in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene with age-related macular degeneration (AMD) has been identified in Caucasian populations in the United States. Earlier a Gln5345Arg variant in the hemicentin 1 (HMCN1) gene was reported in a large AMD family in the United States. We wanted to investigate whether the polymorphisms of the CFH and the ELOVL4 genes or the mutation of the HMCN1 gene are associated with AMD in patients originating from the Finnish population with characteristics of a genetic isolate. METHODS: The material consisted of familial (n=181) and sporadic cases (n=154) with AMD, a control group with no AMD (non-AMD controls, n=105), and a control group of anonymous blood donors (blood donor controls, n =350). The DNA of the subjects was sequenced to analyze the variants of the three genes. RESULTS: We detected a strong association between the C/C-genotype compared to the T/T-genotype of Tyr402His polymorphism (first base of the Tyr-codon changes) of the CFH gene and AMD in the AMD cases compared to the non-AMD (p=8.86x10(-12)) or to blood donor controls (p=2.02x10(-13)). The frequency of the C/C genotype was significantly increased in both familial cases compared to non-AMD controls with non-adjusted odds ratio (OR) 10.1 (confidence intervals [CI] 95% 4.64-22.2) or compared to blood donor controls with non-adjusted OR 5.50 (CI 95% 3.17-9.55) and in sporadic cases with non-adjusted OR 9.33 (CI 95% 4.10-21.3; non-AMD-controls), OR 5.06 (CI 95% 2.75-9.28; blood donor controls). Frequency of C allele differed significantly between cases and controls (p=1.32x10(-11); non-AMD-controls and p=3.94x10(-14); blood donor controls). No association with AMD was detected with Met299Val polymorphism in the ELOVL4 gene in the familial or sporadic cases compared to non-AMD or blood donor controls. None of our subjects (258 AMD cases, 72 non-AMD controls) had the Gln5345Arg variant in the HMCN1 gene. CONCLUSIONS: The CFH gene polymorphism seems to be an important etiologic factor for AMD also in the isolated Finnish population.