Leberin perinnöllinen näköhermonsurkastuma - katse kohti hoitoa

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Natural history and biomarkers of retinal dystrophy caused by the biallelic TULP1 variant c.148delG

Purpose To report clinical features and potential disease markers of inherited retinal dystrophy (IRD) caused by the biallelic c.148delG variant in the tubby-like protein 1 (TULP1) gene. Methods A retrospective observational study of 16 IRD patients carrying a homozygous pathogenic TULP1 c.148delG variant. Clinical data including fundus spectral-domain optical coherence tomography (SD-OCT) were assessed. A meta-analysis of visual acuity of previously reported other pathogenic TULP1 variants was performed for reference. Results The biallelic TULP1 variant c.148delG was associated with infantile and early childhood onset IRD. Retinal ophthalmoscopy was primarily normal converting to peripheral pigmentary retinopathy and maculopathy characterized by progressive extra-foveal loss of the ellipsoid zone (EZ), the outer plexiform layer (OPL), and the outer nuclear layer (ONL) bands in the SD-OCT images. The horizontal width of the foveal EZ showed significant regression with the best-corrected visual acuity (BCVA) of the eye (p < 0.0001, R-2 = 0.541, F = 26.0), the age of the patient (p < 0.0001, R-2 = 0.433, F = 16.8), and mild correlation with the foveal OPL-ONL thickness (p = 0.014, R-2 = 0.245, F = 7.2). Modelling of the BCVA data suggested a mean annual loss of logMAR 0.027. The level of visual loss was similar to that previously reported in patients carrying other truncating TULP1 variants. Conclusions This study describes the progression of TULP1 IRD suggesting a potential time window for therapeutic interventions. The width of the foveal EZ and the thickness of the foveal OPL-ONL layers could serve as biomarkers of the disease stage.Peer reviewe

Keratoendotheliitis Fugax Hereditaria : A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene

PURPOSE: To describe the phenotype and the genetic defect in keratoendotheliitis fugax hereditaria, an autosomal dominant keratitis that periodically affects the corneal endothelium and stroma, leading in some patients to opacities and decreased visual acuity. DESIGN: Cross-sectional, hospital-based study. METHODS: PATIENT POPULATION: Thirty affected and 7 unaffected subjects from 7 families, and 4 sporadic patients from Finland. OBSERVATION PROCEDURES: Ophthalmic examination and photography, corneal topography, specular microscopy, and optical coherence tomography in 34 patients, whole exome sequencing in 10 patients, and Sanger sequencing in 34 patients. MAIN OUTCOME MEASURES: Clinical phenotype, disease causing genetic variants. RESULTS: Unilateral attacks of keratoendotheliitis typically occurred 1-6 times a year (median, 2.5), starting at a median age of 11 years (range, 5-28 years), and lasted for 1-2 days. The attacks were characterized by cornea pseudoguttata and haze in the posterior corneal stroma, sometimes with a mild anterior chamber reaction, and got milder and less frequent in middle age. Seventeen (50%) patients had bilateral stroma! opacities. The disease was inherited as an autosomal dominant trait. A likely pathogenic variant c.61G > C in the NLRP3 gene, encoding cryopyrin, was detected in all 34 tested patients and segregated with the disease. This variant is present in both Finnish and non-Finnish European populations at a frequency of about 0.02% and 0.01%, respectively. CONCLUSION: Keratoendotheliitis fugax hereditaria is an autoinflammatory cryopyrin-associated periodic syndrome caused by a missense mutation c.61G > C in exon 1 of NLRP3 in Finnish patients. It is additionally expected to occur in other populations of European descent. ((c) 2018 The Author(s). Published by Elsevier Inc.Peer reviewe

Clinical Spectrum and Geographic Distribution of Keratitis Fugax Hereditaria Caused by the Pathogenic Variant c.61G>C in NLRP3

Publisher Copyright: © 2021 The Author(s)PURPOSE: To chart clinical findings in individuals with keratitis fugax hereditaria (KFH) and the geographic distribution of their ancestors. DESIGN: A prospective cross-sectional study. METHODS: This study took place in a tertiary referral center with a cohort of 84 Finnish patients (55% female) from 25 families with the pathogenic nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) variant c.61G>C. Observation procedures and main outcome measures were Sanger sequencing, clinical examination, corneal imaging, and a questionnaire regarding symptoms, quality of life, treatment, and comorbidities. RESULTS: The oldest members in each family were born in Ostrobothnia in Western Finland or in Southwestern Finland with historical ties to Sweden. One carrier was asymptomatic. Most (77%, 46/60) experienced their first attack between age 6 and 20 years. Three-quarters had unilateral attacks 3 to 5 times annually, primarily triggered by cold wind or air, or stress. Eighty percent (48/60) reported ocular pain (median, 7 on scale 1-10), conjunctival injection, photophobia, foreign body sensation, and tearing during attacks. Visual blur occurred in 75% (45/60) and 91% (55/60) during and after the attack, respectively, for a median of 10 days (range, 1 day-2 months). Forty-seven percent (39/60) had corneal oval opacities with irregular tomography patterns and mild to moderate decrease (20/60 or better) in best-corrected visual acuity that improved with scleral contact lenses. Except for headache in 40%, systemic symptoms were absent during the attacks. CONCLUSIONS: Symptoms and signs of KFH are restricted to the anterior segment of the eye and vary widely between individuals. We recommend scleral contact lenses as the first-line treatment for reduced vision. Allele frequencies suggest that KFH goes unrecognized in Sweden and populations with Scandinavian heritage.Peer reviewe

Childhood-onset Leber hereditary optic neuropathy

Background The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Methods Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m. 3460G>A, m. 11778G>A or m. 14484T>C. Results In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m. 3460G>A and m. 14484T>C mutations compared with the m. 11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) >= 0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA Conclusions Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor.Peer reviewe

Clinical utility gene card for : inherited optic neuropathies including next-generation sequencing-based approaches

Non peer reviewe

WFS1-Associated Optic Neuropathy : Genotype-Phenotype Correlations and Disease Progression

center dot OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON).center dot DESIGN: Multicenter cohort study. center dot METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. Main Outcome Measures: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile.center dot RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. center dot CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON. (Am J Ophthalmol 2022;241: 927. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ))Peer reviewe

Ancient Fennoscandian genomes reveal origin and spread of Siberian ancestry in Europe

European population history has been shaped by migrations of people, and their subsequent admixture. Recently, ancient DNA has brought new insights into European migration events linked to the advent of agriculture, and possibly to the spread of Indo-European languages. However, little is known about the ancient population history of north-eastern Europe, in particular about populations speaking Uralic languages, such as Finns and Saami. Here we analyse ancient genomic data from 11 individuals from Finland and north-western Russia. We show that the genetic makeup of northern Europe was shaped by migrations from Siberia that began at least 3500 years ago. This Siberian ancestry was subsequently admixed into many modern populations in the region, particularly into populations speaking Uralic languages today. Additionally, we show that ancestors of modern Saami inhabited a larger territory during the Iron Age, which adds to the historical and linguistic information about the population history of Finland