Variable expressivity of BEST1-associated autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a three-generation pedigree

ObjectiveAutosomal dominant vitreoretinochoroidopathy (ADVIRC) is associated with pathogenic variants in BEST1, which typically causes visual impairment in the late stage of disease. We present a pedigree with variable expressivity and the youngest case in the literature with visual impairment in early childhood.Methods and analysisThis is a retrospective, observational, case series describing multigenerational members of one family affected with ADVIRC. Patients underwent examination, ultra-widefield fundus photography and angiography, optical coherence tomography, full-field electroretinography (ffERG) and full-field perimetry.ResultsThree affected members of the pedigree, one from each successive generation, were found to harbour a mutation, c.715G>A:p.Val239Met, in BEST1. The proband characterised in this report is, to our knowledge, the youngest documented case of ADVIRC in early childhood. Yet, this patient has the most severe retinal dysfunction compared with the father and paternal grandmother, whom exhibit classic characteristics of ADVIRC. Longitudinal data from the paternal grandmother showed that there was a rapid decline in ffERG responses (photopic decline worse than scotopic) from the fourth to fifth decade of life, which correlated with severe concentric constriction of visual fields.ConclusionThis multigenerational case series provides new insights into the ADVIRC disease spectrum and rate of progression. While ADVIRC typically causes a slowly progressive disease, we show that variable phenotypic expressivity is possible among affected members of the same family with the same mutation in BEST1. Thus, ADVIRC must also be considered in the differential diagnosis of paediatric patients with severe retinal dystrophy in early childhood.

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Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1275-2 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 2

Author(s):

Jin Kyun Oh ◽

Jose Ronaldo Lima de Carvalho ◽

Young Joo Sun ◽

Sara Ragi ◽

Jing Yang ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Dominant ◽

Fundus Autofluorescence ◽

Retinal Dystrophy ◽

Protein Modeling ◽

Fundus Photography ◽

Imaging Biomarkers ◽

Loss Of Function ◽

Gene Panel Testing ◽

Sd Oct

Abstract Background Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Results Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. Conclusions We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

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The role of an ophthalmologist in the Alström syndrome diagnosis

Vojnosanitetski pregled ◽

10.2298/vsp170314160k ◽

2019 ◽

Vol 76 (8) ◽

pp. 843-846

Author(s):

Jelena Karadzic ◽

Jelica Pantelic ◽

Igor Kovacevic ◽

Marija Trenkic-Bozinovic

Keyword(s):

Early Childhood ◽

Visual Impairment ◽

Genetic Disorder ◽

Single Gene ◽

Retinal Dystrophy ◽

Clinical Manifestations ◽

Molecular Genetic Analysis ◽

Chromosome 2 ◽

Gamma Glutamyl Transpeptidase ◽

Genetic Syndrome

Introduction. The Alstr?m syndrome (AS) is an extremely rare autosomal recessive genetic disorder, affecting fewer than 1: 1,000,000 people globally. It is a single gene disorder due to the mutation of ALMS1 on chromosome 2 (2p13). The AS affects multiple organs and systems. Approximately 800 affected individuals have been identified worldwide so far. Some cases of the AS may go unrecognized for years as many of the clinical features develop over a longer period of time. As the nystagmus and retinitis pigmentosa are the most consistent findings, usually the first visible sign and present at the early infant period, the main aim of this article is to emphasize the importance of the ophthalmologist in establishing an adequate diagnosis of this rare syndrome. Case report. This article describes a Serbian patient with the Alstr?m syndrome, whose diagnosis was genetically confirmed using the whole exome sequencing. Our patient was a 7-year-old obese male with symptoms of progressive visual impairment, photophobia and nystagmus diagnosed in early childhood. On admission, the bilateral visual acuity was poor, RE 0.06, LE 0.01, the intraocular pressure within range. The funduscopy showed central retinal pigmentation, thus suggesting cone-rod retinal dystrophy with ?bull?s eye maculopathy?. The initial laboratory work at the time of the consultation revealed the elevated triglycerides levels and hyperinsulinemia, increased transaminases and gamma-glutamyl transpeptidase serum activity, whereas the glucose and glycated hemoglobin (HbA1C) levels were normal. The bilirubin test results were normal. Overall, the clinical manifestations were absent. The patient?s cardiac function was normal and the echocardiography did not indicate any abnormalities at the time. His sensorineural hearing was normal as well. A molecular genetic analysis was performed. Two composite heterozygous mutations were discovered within the ALMS1 gene sequence. In addition to the clinical presentation, the mutation detection confirmed the initial diagnosis of the AS. Conclusion. The Alstr?m syndrome should be kept in mind in case of an obese child with photophobia, nystagmus and visual impairment present from early childhood. Fundus examination by an ophthalmologist may significantly help to establish the diagnosis of this rare genetic syndrome.

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Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-318034 ◽

2021 ◽

pp. bjophthalmol-2020-318034

Author(s):

Manickam Nick Muthiah ◽

Angelos Kalitzeos ◽

Kate Oprych ◽

Navjit Singh ◽

Michaelis Georgiou ◽

...

Keyword(s):

Adaptive Optics ◽

Autosomal Dominant ◽

Visual Fields ◽

Fundus Photography ◽

Large Field ◽

Field Pattern ◽

Cone Dystrophy ◽

Incomplete Penetrance ◽

Variable Expression ◽

Molecular Features

AimTo describe the clinical and molecular features of a novel, autosomal dominant RDH12-retinopathy.MethodsRetrospective cross-sectional study. Twelve individuals from a four-generation British pedigree underwent ophthalmic examination, genotyping using next generation sequencing, including whole genome sequencing and multimodal retinal imaging including fundus photography, optical coherence tomography (OCT), autofluorescence imaging and adaptive optics (AO) scanning light ophthalmoscopy were performed. Visual electrophysiology was performed in a subset.ResultsEight family members were confirmed as affected by genotyping heterozygous for RDH12 c.763delG. Visual acuity ranged from −0.1 to 0.2 logMAR. Affected individuals had constricted visual fields. A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area. Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied. One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging. Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction.ConclusionsThis novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression. Determination of the degree of penetrance may depend on the modality employed to phenotypically characterise an individual. This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants.

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Visual outcomes endorse surgery of patients with spheno-orbital meningioma with minimal visual impairment or hyperostosis

Acta Neurochirurgica ◽

10.1007/s00701-020-04554-9 ◽

2020 ◽

Vol 163 (1) ◽

pp. 73-82

Author(s):

Amir H. Zamanipoor Najafabadi ◽

Stijn W. Genders ◽

Wouter R. van Furth

Keyword(s):

Visual Acuity ◽

Visual Impairment ◽

Linear Regression Analysis ◽

Visual Fields ◽

Case Series ◽

Who Grade ◽

Visual Outcomes ◽

Simpson Grade ◽

Orbital Meningioma

Abtract Background Most spheno-orbital meningioma series span multiple decades, and predictors of visual outcomes have not yet been systemically assessed. We describe visual outcomes in a recent cohort and assess predictors of postoperative visual outcomes. Methods Consecutive case series operated by a team of a neurosurgeon and orbital surgeon between May 2015 and January 2019. Best corrected visual acuity (BCVA), visual fields (static perimetry), and relative proptosis were measured preoperatively and postoperatively at 3/6/12 months after which it was assessed yearly. Predictors were assessed with linear regression analysis. Results Nineteen patients (all WHO grade I) were operated by the pterional approach (median follow-up 2.4 years). Preoperative visual acuity deficits (n = 10) normalized in 70% and improved in 10% (median preoperative: 0.8, postoperative: 1.2, p = 0.021). Preoperative visual field deficits (n = 8) normalized in all patients (preoperative: − 6.5 dB, postoperative: − 1.5 dB, p = 0.008). Preoperative proptosis (n = 16) normalized in 44% and improved in 56% (preoperative: 5 mm, postoperative: 2 mm, p < 0.001). BCVA and visual fields remained stable at longer follow-up in 95% of patients, while 21% showed progression of proptosis. Predictors for worse longer-term (> 12 months) BCVA were worse preoperative BCVA (p = 0.002) and diagnosis of multiple meningioma (p = 0.021). Predictors for worse longer-term visual fields were higher diameter of hyperostosis (p = 0.009) and higher Simpson grade (p = 0.032). Predictor for short-term (3 months) proptosis was preoperative proptosis (p = 0.006). Conclusion We recommend surgery, even of patients with minimal visual impairment or hyperostosis, as patients who present with deteriorated visual function or extensive hyperostosis are less likely to have postoperative visual outcomes restored to normal.

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Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL

Genes ◽

10.3390/genes11121497 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1497

Author(s):

Susan M. Downes ◽

Tham Nguyen ◽

Vicky Tai ◽

Suzanne Broadgate ◽

Mital Shah ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Fundus Autofluorescence ◽

Age At Onset ◽

Visual Fields ◽

Case Series ◽

Clinical Findings ◽

Fundus Photography ◽

Presenting Symptoms ◽

Ceramide Kinase ◽

Pathogenic Variants

Autosomal recessive retinitis pigmentosa is caused by mutations in over 40 genes, one of which is the ceramide kinase-like gene (CERKL). We present a case series of six patients from six unrelated families diagnosed with inherited retinal dystrophies (IRD) and with two variants in CERKL recruited from a multi-ethnic British population. A retrospective review of clinical data in these patients was performed and included colour fundus photography, fundus autofluorescence (AF) imaging, spectral domain–optical coherence tomography (SD–OCT), visual fields and electroretinogram (ERG) assessment where available. Three female and three male patients were included. Age at onset ranged from 7 years old to 45 years, with three presenting in their 20s and two presenting in their 40s. All but one had central visual loss as one of their main presenting symptoms. Four patients had features of retinitis pigmentosa with significant variation in severity and extent of disease, and two patients had no pigment deposition with only macular involvement clinically. Seven variants in CERKL were identified, of which three are novel. The inherited retinopathies associated with the CERKL gene vary in age at presentation and in degree of severity, but generally are characterised by a central visual impairment early on.

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Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series

Neurogenetics ◽

10.1007/s10048-021-00634-9 ◽

2021 ◽

Author(s):

Luca Magistrelli ◽

Roberta Croce ◽

Fabiola De Marchi ◽

Chiara Basagni ◽

Miryam Carecchio ◽

...

Keyword(s):

Autosomal Dominant ◽

Case Series ◽

Dominant Trait ◽

Autosomal Dominant Trait ◽

Phenotypic Spectrum ◽

Primary Familial Brain Calcification ◽

Psychiatric Disturbances ◽

Brain Calcification ◽

Uncertain Significance ◽

Six Genes

AbstractPrimary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.

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A Three-Generation Family with Idiopathic Facial Palsy Suggesting an Autosomal Dominant Inheritance with High Penetrance

Case Reports in Otolaryngology ◽

10.1155/2015/683938 ◽

2015 ◽

Vol 2015 ◽

pp. 1-3

Author(s):

Christian Grønhøj Larsen ◽

Mette Gyldenløve ◽

Aia Elise Jønch ◽

Birgitte Charabi ◽

Zeynep Tümer

Keyword(s):

Facial Palsy ◽

Autosomal Dominant ◽

Case Series ◽

Neurologic Disorder ◽

Complete Penetrance ◽

Generation Family ◽

Number Variation ◽

Microarray Studies ◽

Idiopathic Facial Palsy ◽

Chromosome Microarray

Idiopathic facial palsy (IFP), also known as Bell’s palsy, is a common neurologic disorder, but recurrent and familial forms are rare. This case series presents a three-generation family with idiopathic facial palsy. The mode of inheritance of IFP has previously been suggested as autosomal dominant with low or variable penetrance, but the present family indicates an autosomal dominant trait with high or complete penetrance. Chromosome microarray studies did not reveal a pathogenic copy number variation, which could enable identification of a candidate gene.

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Beyond Sector Retinitis Pigmentosa: Expanding the Phenotype and Natural History of the Rhodopsin Gene Codon 106 Mutation (Gly-to-Arg) in Autosomal Dominant Retinitis Pigmentosa

Genes ◽

10.3390/genes12121853 ◽

2021 ◽

Vol 12 (12) ◽

pp. 1853

Author(s):

Brian G. Ballios ◽

Emily M. Place ◽

Luis Martinez-Velazquez ◽

Eric A. Pierce ◽

Jason I. Comander ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Dominant ◽

Peripheral Vision ◽

Visual Fields ◽

Macular Disease ◽

History Of ◽

Intrafamilial Variability ◽

Long Term Prognosis

Sector and pericentral are two rare, regional forms of retinitis pigmentosa (RP). While usually defined as stable or only very slowly progressing, the available literature to support this claim is limited. Additionally, few studies have analyzed the spectrum of disease within a particular genotype. We identified all cases (9 patients) with an autosomal dominant Rhodopsin variant previously associated with sector RP (RHO c.316G > A, p.Gly106Arg) at our institution. Clinical histories were reviewed, and testing included visual fields, multimodal imaging, and electroretinography. Patients demonstrated a broad phenotypic spectrum that spanned regional phenotypes from sector-like to pericentral RP, as well as generalized disease. We also present evidence of significant intrafamilial variability in regional phenotypes. Finally, we present the longest-reported follow-up for a patient with RHO-associated sector-like RP, showing progression from sectoral to pericentral disease over three decades. In the absence of comorbid macular disease, the long-term prognosis for central visual acuity is good. However, we found that significant progression of RHO p.Gly106Arg disease can occur over protracted periods, with impact on peripheral vision. Longitudinal widefield imaging and periodic ERG reassessment are likely to aid in monitoring disease progression.

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