Novel BEST1 mutations and clinical characteristics of autosomal recessive bestrophinopathy in a Spanish patient

2021 ◽  
pp. 112067212110106
Author(s):  
Marina Soto-Sierra ◽  
María José Morillo-Sánchez ◽  
Marta Martín-Sánchez ◽  
Manuel Ramos-Jiménez ◽  
Mireia López-Domínguez ◽  
...  
Keyword(s):  
Fluorescein Angiography ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Fundus Autofluorescence ◽  
Index Patient ◽  
Ophthalmological Examination ◽  
Genetic Characteristics ◽  
Spanish Patient ◽  
Autosomal Recessive Bestrophinopathy ◽  
The Right

Purpose: To describe the clinical and genetic characteristics (novel mutation in BEST1 gene) of a Spanish patient with autosomal recessive bestrophinopathy (ARB). Methods: The detailed ophthalmological examination included best corrected visual acuity (BCVA), color and autofluorescence photography, fluorescein angiography, optical coherence tomography, and electrophysiology tests. A next-generation sequencing (NGS) strategy was applied to the index patient, and then sequenced in an Illumina NextSeq500 system. Results: A 55-year-old male presented with a BCVA of 20/25 in the right eye and 20/20 in the left eye. Fundoscopy revealed perifoveal yellow flecked-like lesions. Fluorescein angiography and fundus autofluorescence results were consistent with pattern dystrophy. A homozygous frameshift mutation in BEST1 (c.341_342del; p.(Leu114Glnfs*57)) was identified as the cause of the disease. Conclusion: ARB is a genetic disease that leads to irreversible visual loss. In this report we found a novel mutation responsible for this disease.

scholarly journals Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene

2020 ◽  
Vol 21 (24) ◽  
pp. 9353
Author(s):  
Karsten Hufendiek ◽  
Katerina Hufendiek ◽  
Herbert Jägle ◽  
Heidi Stöhr ◽  
Marius Book ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Age Of Onset ◽  
Fundus Autofluorescence ◽  
Serous Retinal Detachment ◽  
Fundus Photography ◽  
Macular Dystrophy ◽  
Ophthalmological Examination ◽  
Hyperreflective Foci ◽  
Autosomal Recessive Bestrophinopathy ◽  
Biallelic Mutations

Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02–1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.

scholarly journals Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB)

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 953 ◽  
Author(s):  
Imen Habibi ◽  
Yosra Falfoul ◽  
Margarita G. Todorova ◽  
Stefan Wyrsch ◽  
Veronika Vaclavik ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Macular Dystrophy ◽  
Phenotype Correlation ◽  
Corrected Visual Acuity ◽  
Light Rise ◽  
Autosomal Recessive Bestrophinopathy ◽  
Biallelic Mutations

Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 individuals. Here we report 6 families and searched for a genotype-phenotype correlation. All patients were referred due to reduced best-corrected visual acuity (BCVA), ranging from 0.1/10 to 3/10. They all showed vitelliform lesions located at the macula, sometimes extending into the midperiphery, along the vessels and the optic disc. Onset of the disease varied from the age of 3 to 25 years. Electrooculogram (EOG) revealed reduction in the EOG light rise in all patients. Molecular analysis revealed previously reported mutations p.(E35K);(E35K), p.(L31M);(L31M), p.(R141H);(A195V), p.(R202W);(R202W), and p.(Q220*);(Q220*) in five families. One family showed a novel mutation: p.(E167G);(E167G). All mutations were heterozygous in the parents. In one family, heterozygous children showed various reductions in the EOG light rise and autofluorescent deposits. Autosomal recessive Bestrophinopathy (ARB), although rare, can be recognized by its phenotype and should be validated by molecular analysis. Genotype-phenotype correlations are difficult to establish and will require the analysis of additional cases.

scholarly journals Autosomal Recessive Bestrophinopathy: Clinical and Genetic Characteristics of Twenty-Four Cases

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Hassan Khojasteh ◽  
Mohsen Azarmina ◽  
Nazanin Ebrahimiadib ◽  
Narsis Daftarian ◽  
Hamid Riazi-Esfahani ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Autosomal Recessive ◽  
Angle Closure Glaucoma ◽  
Enhanced Depth Imaging ◽  
Angle Closure ◽  
Optical Coherence ◽  
Genetic Characteristics ◽  
Female Ratio ◽  
Genetic Test Results ◽  
Autosomal Recessive Bestrophinopathy

Background. To describe ocular manifestations, imaging characteristics, and genetic test results of autosomal recessive bestrophinopathy (ARB). The study design is an observational case series. Methods. Forty-eight eyes of 24 patients diagnosed with ARB underwent complete ophthalmic examinations including refraction, anterior and posterior segment examination, enhanced depth imaging optical coherence tomography (EDI-OCT), fluorescein angiography (FA), electroretinography (ERG), and electrooculography (EOG). Optical coherence tomography angiography (OCTA) and BEST1 gene sequencing were performed in selected patients. Results. The age at onset was 4–35 years (mean: 18.6 years). The male-to-female ratio was 0.45. All patients were hyperopic, except one with less than one diopter myopia. EOG was abnormal in 18 cases with near-normal ERGs. Six patients did not undergo EOG due to their young age. Eighteen patients (75%) had a thick choroid on EDI-OCT, of which three had advanced angle-closure glaucoma, 15 patients were hyperopic, and eight of them had more than four diopters hyperopia in both eyes. Macular retinoschisis was observed in 46 eyes of 23 patients (95%) with cysts mostly located in the inner nuclear layer (INL) to the outer nuclear layer (ONL). Of the 18 patients who underwent FA, mild peripheral leakage was seen in eight eyes of four patients (22%). Subfoveal choroidal neovascularization (CNV) was seen in three eyes of two patients (6%) that responded well to intravitreal bevacizumab (IVB). Seven mutations of the bestrophin-1 (BEST1) gene were found in this study; however, only two of them (p.Gly34 = and p.Leu319Pro) had been previously reported as the cause of ARB based on ClinVar and other literature studies. Conclusions. ARB can be presented with a wide spectrum of ocular abnormalities that may not be easily diagnosed. Pachychoroid can occur alongside retinal schisis and may be the underlying cause of angle-closure glaucoma in ARB. Our study also expands the pathogenic mutation spectrum of the BEST1 gene associated with ARB.

scholarly journals X-linked Retinoschisis Associated with Retinitis Punctata Albescens Caused by a Mutation in the RS1 Gene: A Family Study

2021 ◽  
Vol 15 (1) ◽  
pp. 201-205
Author(s):  
Francisco de Borja Domínguez-Serrano ◽  
Marina Soto-Sierra ◽  
María González-del Pozo ◽  
María José Morillo-Sánchez ◽  
Manuel Ramos-Jiménez ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Index Patient ◽  
Ophthalmological Examination ◽  
Genetic Characteristics ◽  
Corrected Visual Acuity ◽  
Retinitis Punctata Albescens ◽  
The Family ◽  
Next Generation Sequencing Ngs ◽  
Unusual Phenotype ◽  
Generation Sequencing

Purpose: To describe the clinical and genetic characteristics (mutation in RS1 gene) of a Spanish family with X-linked retinoschisis (XLRS) associated with retinitis punctata albescens (RPA). Methods: The detailed ophthalmological examination included best corrected visual acuity (BCVA), colour and autofluorescence photography, fluorescein angiography, optical coherence tomography and electrophysiology tests. A next-generation sequencing (NGS) strategy was applied to the index patient, and then sequenced in an Illumina NextSeq500 system. Candidate variants considered to be disease-causing in the patient were confirmed and segregated in the family by Sanger sequencing. Results: We have studied three siblings of 54, 59 and 50 years old. Two of them presented with macular foveoschisis and a whitish mottling of the pigment epithelium in the peripheral and equatorial retina, while the other had macular atrophy. Electroretinography revealed a reduced b-wave, while a-wave remained unchanged. Mutation in RS1 (c.98G>A; p.Trp33*) was identified as the cause of the disease. Conclusion: XLRS is a genetic disease that leads to irreversible visual loss. We describe an unusual phenotype manifestation of a known mutation.

scholarly journals Genetic testing for non syndromic retinitis pigmentosa

2017 ◽  
Vol 1 (s1) ◽  
pp. 92-95
Author(s):  
Andi Abeshi ◽  
Alice Bruson ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Fabiana D’Esposito ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Fundus Autofluorescence ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Corrected Visual Acuity ◽  
Recessive Transmission ◽  
Autosomal Recessive Manner

Abstract We reviewed the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for non syndromic retinitis pigmentosa (NSRP). NSRP is determined by variations in the ABCA4, AGBL5, ARL2BP, ARL6, BBS2, BEST1, C2orf71, C8orf37, CA4, CDHR1, CERKL, CLRN1, CNGA1, CNGB1, CRB1, CRX, DHDDS, EYS, FAM161A, FSCN2, GUCA1B, HGSNAT, IDH3B, IFT140, IFT172, IMPDH1, IMPG2, KIZ, KLHL7, LRAT, MAK, MERTK, NEK2, NR2E3, NRL, OFD1, PDE6A, PDE6B, PDE6G, POMGNT1, PRCD, PROM1, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, RBP3, RDH12, RGR, RHO, RLBP1, ROM1, RP1, RP2, RP9, RPE65, RPGR, SAG, SEMA4A, SLC7A14, SNRNP200, SPATA7, TOPORS, TTC8, TULP1, USH2A, ZNF408 and ZNF513 genes. Its overall prevalence is 1 per 4000. It is mostly inherited in an autosomal recessive manner, fewer genes have autosomal dominant or X-linked recessive transmission. Clinical diagnosis is based on clinical findings, ophthalmological examination, best corrected visual acuity (BCVA), slit lamp biomicroscopy, fundus autofluorescence, electroretinography, color vision testing and optical coherence tomography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

scholarly journals Fanconi Bickel syndrome: clinical phenotypes and genetics in a cohort of Sudanese children

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Salwa A. Musa ◽  
Areej A. Ibrahim ◽  
Samar S. Hassan ◽  
Matthew B Johnson ◽  
Asmahan T. Basheer ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Novel Mutation ◽  
Wide Spectrum ◽  
Rare Condition ◽  
Neonatal Diabetes ◽  
Abdominal Ultrasound ◽  
Sub Saharan Africa ◽  
High Rate ◽  
Genetic Characteristics ◽  
Sub Saharan

Abstract Background Fanconi-Bickel syndrome (FBS) is a rare condition of carbohydrate metabolism, caused by a recessive defect in the facilitative glucose transporter GLUT2 encoded by the SLC2A2 gene and characterized by a wide spectrum of phenotypical features. There is a paucity of reported data on FBS from Sub-Saharan Africa. Here, we describe the clinical, biochemical and genetic characteristics of our patients with FBS from Sudan, a country with a high consanguinity rate. Patients & methods Eleven patients from ten unrelated Sudanese families were included. Clinical & biochemical data were documented and imaging studies done including bone survey and abdominal ultrasound. Liver biopsy was done to confirm the pathological diagnosis in 45% of cases and molecular genetics was performed through contribution with the Exeter genomics laboratory for ten patients. Results Reported consanguinity was 70% among our patients. Growth was significantly impaired at presentation with mean weights of (-5.3 ± 1.8) SD and heights (-5.4 ± 2.5) SD. Severe chest deformity was present in (27%) and all patients showed features of rickets at presentation. Three patients had neonatal diabetes requiring insulin therapy of which one has been reported before. Six families lost undiagnosed siblings with similar clinical presentations. We identified a total of four homozygous pathogenic SLC2A2 variants in our patients, one of whom had a novel mutation. Conclusions FBS is not uncommon in Sudan where there is a high rate of consanguinity. Many cases are likely missed because of variable presentation and lack of public and professionals’ awareness. This is the first series to describe this condition from Sub-Saharan Africa.

scholarly journals Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa

2021 ◽  
Vol 22 (5) ◽  
pp. 2374
Author(s):  
Laura Kuehlewein ◽  
Ditta Zobor ◽  
Katarina Stingl ◽  
Melanie Kempf ◽  
Fadi Nasser ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Genetic Testing ◽  
Retinitis Pigmentosa ◽  
Fundus Autofluorescence ◽  
Retinal Disease ◽  
New Drugs ◽  
Autofluorescence Imaging ◽  
Full Field ◽  
Tertiary Referral Center ◽  
The Right

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.

scholarly journals Levator palpabrae superioris myositis as an unusual cause of unilateral ptosis—case report

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Ahmed M. Abdrabou
Keyword(s):  
Previous History ◽  
Good Prognosis ◽  
Oculomotor Nerve Palsy ◽  
Ophthalmological Examination ◽  
Bilateral Ptosis ◽  
Mri Findings ◽  
Upper Eyelid ◽  
Unilateral Disease ◽  
The Right ◽  
Mri Study

Abstract Background Ptosis can be a manifestation of a more serious situation. Hence, the analysis of the complaint and the search for etiology are crucial in such cases. Ptosis has many causes; some of them lead to unilateral ptosis while others cause bilateral ptosis. For instance, myasthenia gravis is a cause of bilateral ptosis while oculomotor nerve palsy induces unilateral disease. Proper evaluation of the patient and identification of the cause are important to achieve accurate management and good prognosis. Case presentation A 47-year-old male patient attended the ER complaining of dropping the right eye lid of 2 days’ duration. There was no associated pain or diplopia. On examination, the extraocular muscles’ (EOM) motility was intact, normal pupil and corneal reflexes, and there was swelling of the upper eyelid. Ophthalmological examination revealed normal anterior and posterior chambers as well as the vitreous and retina. The patient had a previous history of traumatic intracranial hemorrhage that was resolved without surgical intervention. He also had diabetes mellitus and hypertension. The patient was transferred to the MRI unit to perform MRI study of the brain and orbit with MRA and IV contrast administration. MRI findings confirmed the diagnosis of LPS myositis, and the patient received medical treatment and improved. Conclusion Proper radiological diagnosis leads to accurate management and achieves rapid recovery and optimal patient care.

scholarly journals Genotypes Predispose Phenotypes—Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1421
Author(s):  
Yu-Chi Sung ◽  
Chang-Hao Yang ◽  
Chung-May Yang ◽  
Chao-Wen Lin ◽  
Ding-Siang Huang ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Retinal Degeneration ◽  
Medical Center ◽  
Fundus Autofluorescence ◽  
Genetic Diagnosis ◽  
Common Disease ◽  
Genetic Characteristics ◽  
Retinal Dystrophies ◽  
High Prevalence ◽  
Abca4 Gene

The ABCA4 gene is one of the most common disease-causing genes of inherited retinal degeneration. In this study, we report different phenotypes of ABCA4-associated retinal dystrophies in the Taiwanese population, its clinical progression, and its relationship with genetic characteristics. Thirty-seven subjects were recruited and all patients underwent serial ophthalmic examinations at a single medical center. Fundus autofluorescence (FAF) images were quantified for clinical evaluation, and panel-based next-generation sequencing testing was performed for genetic diagnosis. Visual preservation, disease progression, and genotype–phenotype correlation were analyzed. In this cohort, ABCA4-associated retinal degeneration presented as Stargardt disease 1 (STGD1, 62.16%), retinitis pigmentosa (32.43%), and cone-rod dystrophy (5.41%). STGD1 could be further divided into central and dispersed types. In each phenotype, the lesion areas quantified by FAF increased with age (p < 0.01) and correlated with poorer visual acuity. However, three patients had the foveal sparing phenotype and had relatively preserved visual acuity. Forty-two ABCA4 variants were identified as disease-causing, with c.1804C>T (p.Arg602Trp) the most frequent (37.84%). Patients with a combination of severe/null variants could have more extensive phenotypes, such as arRP and dispersed STGD1. This is the first cohort study of ABCA4-associated retinal degeneration in Taiwan with wide spectrums of both genotypic and phenotypic characteristics. An extremely high prevalence of c.1804C>T, which has not been reported in East Asia before, was noted. The extensiveness of retinal involvement might be regarded as a spectrum of ABCA4-associated retinal dystrophies. Different types of genetic variations could lead to distinctive phenotypes, according to the coding impact of variants.

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