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Purpose: Cone-rod dystrophies (CORD) are inherited retinal dystrophies characterized by primary cone degeneration with secondary rod involvement. We report two patients from the same family with a dominant variant in the guanylate cyclase 2D (GUCY2D) gene with different phenotypes in the electroretinogram (ERG). Observations: A 21-year-old lady (Patient 1) was referred due to experiencing blurry vision and color vision impairment. Visual field testing revealed a central scotoma. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) documented macula dysfunction. Reduced amplitude was observed in the photopic responses of ERG. Her 54-year-old father (Patient 2) had similar issues with blurry vision. A dilated fundus examination displayed bilateral macular atrophy. Loss of the ellipsoid zone line and collapse of the outer nuclear segment were noted on the SD-OCT. Photopic ERG responses were extinguished, and an electronegative ERG was observed in the dark-adapted 3.0 ERG. The gene report revealed a c.2512C > T (p.Arg838Cys) variant in GUCY2D for both patients. They were respectively diagnosed as cone dystrophy (COD) and cone-rod dystrophy (CORD). Conclusions: We report two different clinical phenotypes in GUCY2D-associated COD despite sharing the same variant. A dysfunction in the synaptic junction between the photoreceptor and the secondary neuron was proposed to explain the electronegative ERG. This explanation might extend to other gene-related cases of CORD with electronegative ERG.
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PURPOSE: Determine whether intravitreal injection of bevacizumab (IVB) exerts long-term effects on neurodevelopmental outcomes in children with retinopathy of prematurity (ROP) when reaching the age of 8 years. METHODS: We enrolled 277 children. Patients were stratified into the groups full-term, preterm without ROP, ROP without treatment, or ROP with treatment, based on gestational age (GA) and ROP status. Children under GA of 37 weeks were considered premature. Patients' cognitive outcomes were evaluated using Full-Scale Intelligence Quotient (FIQ) (full score and percentile) generated by the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) every 1 to 2 years. RESULTS: At the mean age of 7.8 years, ROP without and with treatment groups demonstrated lower FIQ scores and percentiles, compared with full-term and premature groups (both p<0.05). FIQ scores and percentiles didn't significantly differ between patients who received different treatments for ROP (full score p=0.19; percentile p=0.37). After adjusting for GA, LogMAR best corrected visual acuity (BCVA) was negatively associated with FIQ scores (p=0.0008) and percentiles (p=0.0002). CONCLUSIONS: At the mean age of 8 years, patients with ROP undergoing IVB didn't exhibit worse cognitive outcomes than those who underwent laser photocoagulation or both treatments. GA and BCVA correlated with cognitive development in children.
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Cardiac signaling pathways functionally important in the heart's response to exercise often protect the heart against pathological stress, potentially providing novel therapeutic targets. However, it is important to determine which of these pathways can be feasibly targeted in vivo. Transgenic overexpression of exercise-induced CITED4 has been shown to protect against adverse remodeling after ischemia/reperfusion injury (IRI). Here we investigated whether somatic gene transfer of CITED4 in a clinically relevant time frame could promote recovery after IRI. Cardiac CITED4 gene delivery via intravenous AAV9 injections in wild type mice led to an approximately 3-fold increase in cardiac CITED4 expression. After 4 weeks, CITED4-treated animals developed physiological cardiac hypertrophy without adverse remodeling. In IRI, delivery of AAV9-CITED4 after reperfusion resulted in a 6-fold increase in CITED4 expression 1 week after surgery, as well as decreased apoptosis, fibrosis, and inflammatory markers, culminating in a smaller scar and improved cardiac function 8 weeks after IRI, compared with control mice receiving AAV9-GFP. Somatic gene transfer of CITED4 induced a phenotype suggestive of physiological cardiac growth and mitigated adverse remodeling after ischemic injury. These studies support the feasibility of CITED4 gene therapy delivered in a clinically relevant time frame to mitigate adverse ventricular remodeling after ischemic injury.
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A posteriorly dislocated lens is often managed with a fragmatome through a pars plana approach because it is difficult to manage anteriorly. The lens often sinks to the surface of the retina or floats around in the vitreous cavity during pars plana lensectomy. Mechanical trauma can occur while removing the dislocated lens fragments. However, sometimes the lens can be confined to the anterior vitreous cavity even though the zonules are completely disrupted. It would be ideal if there was a simple way to stabilize and support the lens so that the lens could remain in the posterior chamber while phacoemulsification is performed through a corneal incision as usual. We describe a technique using a trocar blade to stabilize the lens while performing phacoemulsification through a corneal incision. We found it to be a useful and safe instrument to support the subluxated lens during phacoemulsification.
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BACKGROUND: Copy number variations (CNVs) have emerged as significant contributors to the elusive genetic causality of inherited eye diseases. In this study, we describe a case with optic atrophy and a brain aneurysm, in which a de novo CNV 3q29 deletion was identified. CASE PRESENTATION: A 40-year-old female patient was referred to our department after undergoing aneurysm transcatheter arterial embolization for a brain aneurysm. She had no history of systemic diseases, except for unsatisfactory best-corrected visual acuity (BCVA) since elementary school. Electrophysiological tests confirmed the findings in retinal images, indicating optic nerve atrophy. Chromosomal microarray analysis revealed a de novo deletion spanning 960 kb on chromosome 3q29, encompassing OPA1 and six neighboring genes. Unlike previously reported deletions in this region associated with optic atrophy, neuropsychiatric disorders, and obesity, this patient displayed a unique combination of optic atrophy and a brain aneurysm. However, there is no causal relationship between the brain aneurysm and the CNV. CONCLUSION: In conclusion, the optic atrophy is conclusively attributed to the OPA1 deletion, and the aneurysm could be a coincidental association. The report emphasizes the likelihood of underestimating OPA1 deletions due to sequencing technology limitations. Recognizing these constraints, healthcare professionals must acknowledge these limitations and consistently search for OPA1 variants/deletions in Autosomal Dominant Optic Atrophy (ADOA) patients with negative sequencing results. This strategic approach ensures a more comprehensive exploration of copy-number variations, ultimately enhancing diagnostic precision in the field of genetic disorders.
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Aneurisma Intracraneal , Atrofia Óptica , Femenino , Humanos , Adulto , Mutación , Variaciones en el Número de Copia de ADN , Aneurisma Intracraneal/genética , Atrofia Óptica/genética , Fenotipo , Cromosomas , Linaje , GTP Fosfohidrolasas/genéticaRESUMEN
PURPOSE: To evaluate stereopsis in term-born, preterm, and preterm children with and without retinopathy of prematurity (ROP) and its treatment. METHODS: The cross-sectional study included 322 children between 3 and 11 years of age born term or preterm, with or without ROP, and with or without treatment for ROP. The ROP treatments were laser therapy, intravitreal injection (IVI) of anti-vascular endothelial growth factor, or their combination. Stereoacuity was measured using the Titmus Stereo Test, and the results among various age groups were analyzed. RESULTS: Stereopsis was found to improve with increasing age at testing (P < 0.001) across the entire study population. The term group exhibited significantly better stereoacuity than the preterm group (P < 0.001). At 3-5 years and 6-8 years, the preterm children without ROP exhibited significantly better stereoacuity than did those with ROP (P < 0.001 and P = 0.02, respectively); however, at 9-11 years, both groups exhibited similar stereoacuity (P = 0.34). The stereoacuity in the children with untreated ROP was similar to that of the children with treated ROP in all age groups (P > 0.05). No significant differences in stereopsis were identified between children with ROP treated with laser versus with IVI (P > 0.05). From multivariate analysis, younger age at testing (P = 0.001) and younger gestational age (P < 0.001) were associated with poorer stereopsis. CONCLUSIONS: Stereopsis development gradually improved with age in all groups. The children born preterm exhibited poorer stereoacuity than those born term. Children with ROP treated with laser photocoagulation versus IVI may exhibit similar levels of stereoacuity. Younger age at testing and gestational age were independent risk factors for poorer stereoacuity.
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Percepción de Profundidad , Edad Gestacional , Recien Nacido Prematuro , Retinopatía de la Prematuridad , Agudeza Visual , Humanos , Retinopatía de la Prematuridad/fisiopatología , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/cirugía , Percepción de Profundidad/fisiología , Masculino , Femenino , Estudios Transversales , Preescolar , Niño , Agudeza Visual/fisiología , Estudios de Seguimiento , Recién Nacido , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Visión Binocular/fisiología , Inyecciones Intravítreas , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Coagulación con Láser/métodosRESUMEN
PURPOSE: To evaluate choroidal changes over time in school-age children with a history of prematurity. METHODS: A study of 416 eyes of 208 eligible participants, including 88, 190, 36, 56, and 46 eyes in the full-term control, preterm, spontaneously regressed retinopathy of prematurity, intravitreal bevacizumab (injection of bevacizumab)-treated retinopathy of prematurity, and laser-treated retinopathy of prematurity groups, respectively, were enrolled in this study. The choroidal thickness was measured 4 times at 6-month intervals using optical coherence tomography. RESULTS: Of all the groups, the laser-treated children had the thinnest choroid compared with full-term children (-52.3 µ m, P = 0.04). Preterm children exhibited greater attenuation in choroidal thickness over time than did full-term children (-6.3 ± 26.9 and -1.1 ± 12.8 µ m/year, P = 0.03), whereas no difference was observed between injection of bevacizumab and laser treatments (-4.6 ± 18.9 and -2.0 ± 15.7 µ m/year, P = 0.46). In all groups, the changes in axial length were negatively associated with the changes in choroidal thickness (all P < 0.05). CONCLUSION: A greater attenuation in choroid thickness over time was observed in preterm children than in full-term children, but this attenuation did not differ between injection of bevacizumab and laser treatments. Axial elongation was associated with choroidal thinning in school-age children.
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Inhibidores de la Angiogénesis , Bevacizumab , Coroides , Edad Gestacional , Inyecciones Intravítreas , Retinopatía de la Prematuridad , Tomografía de Coherencia Óptica , Humanos , Coroides/patología , Coroides/diagnóstico por imagen , Estudios Prospectivos , Masculino , Tomografía de Coherencia Óptica/métodos , Femenino , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Niño , Bevacizumab/administración & dosificación , Estudios de Seguimiento , Recién Nacido , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Recien Nacido Prematuro , Coagulación con Láser/métodos , Agudeza VisualRESUMEN
Rhegmatogenous retinal detachment (RRD) is a significant cause of vision loss and requires appropriate surgical intervention. There are several approaches available, including observation, laser demarcation, pneumatic retinopexy, scleral buckling, and pars plana vitrectomy, which are chosen based on patient condition, surgeon experience, and national health insurance policies. Despite the various options, there is still no consensus on the optimal intervention. To address this, the Taiwan Retina Society assembled an expert committee with 11 experienced retina specialists to review the current evidence and develop a guideline with seven recommendations for managing RRD patients. Additionally, a survey was conducted with six questions to assess treatment patterns in Taiwan, which included input from the expert committee and an open poll at the 2023 Congress of the Taiwan Retina Society. This report provides a comprehensive summary of the current knowledge and expert consensus on the treatment of RRD, discussing the characteristics of current approaches and providing an overview of current treatment patterns in Taiwan. These findings aim to provide ophthalmologists with the best possible treatment for RRD.
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Desprendimiento de Retina , Humanos , Consenso , Retina , Desprendimiento de Retina/cirugía , Desprendimiento de Retina/etiología , Taiwán , Resultado del Tratamiento , VitrectomíaRESUMEN
OBJECTIVES: To investigate the changes in the temporal vascular angles after epiretinal membrane (ERM) surgery and utilize the angles to predict visual outcomes. METHODS: A total of 168 eyes from 84 patients with unilateral ERM who underwent vitrectomy were enrolled from a single institution. The angles of temporal venous (anglevein) and arterial arcades (angleartery) were measured on fundus photographs. The relationships between the angles and the best-corrected visual acuity (BCVA) were explored and multivariable logistic models and receiver operating characteristic (ROC) curves were analyzed to identify the factors that predicted visual outcomes. RESULTS: At baseline, both angleartery and anglevein were narrower in the eyes with ERM than the fellow eyes (p < 0.001 and 0.007) but had no correlation with the baseline BCVA (p = 0.754 and 0.804). Postoperatively, the angleartery and anglevein significantly widened (both p < 0.001) and a greater BCVA improvement was associated with a greater widening of the angleartery (p = 0.029) and anglevein (p = 0.050). Multivariable logistic analyses found a narrower baseline angleartery compared to the fellow eye had a higher chance for BCVA improvement ⧠2 lines (Odds ratio = 0.97; 95% CI, 0.94-0.99; p = 0.016). ROC curve showed the baseline difference in the angleartery between bilateral eyes predicted BCVA improvement ⧠2 lines (area under the curve = 0.74; p = 0.035), and a 0.73 sensitivity and 0.80 specificity with a cut-off value of -27.19 degrees. CONCLUSIONS: The retinal vascular angles widened after ERM surgery and the fundus photograph-derived angles may serve as a highly-accessible biomarker to predict postoperative visual outcomes.
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Membrana Epirretinal , Mácula Lútea , Humanos , Membrana Epirretinal/cirugía , Tomografía de Coherencia Óptica , Agudeza Visual , Vitrectomía , Biomarcadores , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVES: A significant portion of medical education takes place in primary care settings with family medicine clinician teachers that have variable backgrounds in teaching. Ernest Boyer's concept of education scholarship calls on faculty to systematically study and innovate their teaching practices. This meta-ethnographic review synthesizes the literature on primary care clinician teachers' perspectives and experiences of integrating education scholarship in practice. METHODS: We conducted an electronic database search in PubMed/Medline, Scopus, ERIC, and Web of Science for primary research articles published between January 2000 and August 2021. In the included articles, researchers studied primary care physicians' and/or residents' perspectives of clinical teaching and reported qualitative results (eg, interviews, focus groups). Of the 1,454 articles found in the search, we included 33 in the final synthesis. We used line-by-line descriptive coding of the qualitative data to develop analytical themes. RESULTS: Four main themes emerged from our synthesis: (1) perceptions of clinical teaching (lack of confidence, presumed teaching competency, lack of formal recognition); (2) clinical teaching strategies (learner-centered teaching, ad hoc teaching, role modeling, mentorship); (3) benefits of clinical teaching (shared learning experience, networking, personal interest, career satisfaction); and (4) challenges of clinical teaching (inadequate time, compensation, conflicting responsibilities). CONCLUSIONS: Clinician teachers identified several common factors regarding their scholarly roles but had difficulty describing them in relation to education scholarship. Institutional support, resources, and awareness are needed to assist family medicine clinician teachers to further implement Boyer's concept of education scholarship in practice-specifically, to study, evaluate, and innovate current clinical teaching strategies.
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Educación Médica , Becas , Humanos , Aprendizaje , Docentes , Atención Primaria de Salud , Enseñanza , Investigación CualitativaRESUMEN
Purpose: This study investigated the clinical characteristics of patients with PROM1-related inherited retinal diseases (IRDs). Methods: Patients diagnosed with IRDs who had mutations in PROM1 were identified at Linkou Chang Gung Memorial Hospital and Kaohsiung Medical University Hospital in Taiwan. Information on clinical characteristics and best-corrected visual acuity was recorded. Color fundus (CF) images, fundus autofluorescence photography (FAF), spectral-domain optical coherence tomography (SD-OCT), and electroretinograms (ERGs) were analyzed to examine patient phenotypes. PROM1 variants were detected using whole exome sequencing and verified by Sanger sequencing. Results: Fourteen patients from nine families with PROM1-related IRDs were analyzed. Most patients exhibited chorioretinal atrophy in the macular area, with or without extramacular involvement on CF. Similarly, hypo-autofluorescence confined to the macular area, with or without extramacular involvement, was present for most patients on FAF. Furthermore, SD-OCT revealed outer retinal tubulations and focal or diffuse retinal thinning. ERGs showed variable findings, including maculopathy with normal ERG, subnormal cone response, and extinguished rod and cone responses. We detected five variants of the PROM1 gene, including c.139del, c.794del, c.1238T>A, c.2110C>T, and c.1117C>T. Conclusions: In this study, we evaluated 14 Taiwanese patients with five PROM1 variants. Additionally, incomplete penetrance of heterozygous PROM1 variants was observed. Furthermore, patients with autosomal dominant PROM1 variants had lesions in the macular area and the peripheral region of the retina. SD-OCT serves as a useful tool for early detection of PROM1-related IRDs, as it captures certain signs of such diseases.
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Degeneración Macular , Degeneración Retiniana , Humanos , Retina/patología , Degeneración Retiniana/genética , Degeneración Macular/diagnóstico , Células Fotorreceptoras Retinianas Conos , Mutación , Electrorretinografía , Tomografía de Coherencia Óptica/métodos , Antígeno AC133/genéticaRESUMEN
Proteinuria is common in heart failure with preserved ejection fraction (HFpEF), but its biologic correlates are poorly understood. We assessed the relation between 49 plasma proteins and the urinary protein/creatinine ratio (UPCR) in 365 participants in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. Linear regression and network analysis were used to represent relations between protein biomarkers and UPCR. Higher UPCR was associated with older age, a greater proportion of female gender, smaller prevalence of previous myocardial infarction, and greater prevalence of diabetes, insulin use, smoking, and statin use, in addition to a lower estimated glomerular filtration rate, hematocrit, and diastolic blood pressure. Growth differentiation factor 15 (GDF-15; ß = 0.15, p <0.0001), followed by N-terminal proatrial natriuretic peptide (NT-proANP; ß = 0.774, p <0.0001), adiponectin (ß = 0.0005, p <0.0001), fibroblast growth factor 23 (FGF-23, ß = 0.177; p <0.0001), and soluble tumor necrosis factor receptors I (ß = 0.002, p <0.0001) and II (ß = 0.093, p <0.0001) revealed the strongest associations with UPCR. Network analysis showed that UPCR is linked to various proteins primarily through FGF-23, which, along with GDF-15, indicated node characteristics with strong connectivity, whereas UPCR did not. In a model that included FGF-23 and UPCR, the former was predictive of the risk of death or heart-failure hospital admission (standardized hazard ratio 1.83, 95% confidence interval 1.49 to 2.26, p <0.0001) and/or all-cause death (standardized hazard ratio 1.59, 95% confidence interval 1.22 to 2.07, p = 0.0005), whereas UPCR was not prognostic. Proteinuria in HFpEF exhibits distinct proteomic correlates, primarily through its association with FGF-23, a well-known prognostic marker in HFpEF. However, in contrast to FGF-23, UPCR does not hold independent prognostic value.
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Insuficiencia Cardíaca , Humanos , Femenino , Factor 15 de Diferenciación de Crecimiento , Creatinina , Volumen Sistólico/fisiología , Proteómica , Biomarcadores , Pronóstico , ProteinuriaRESUMEN
OBJECTIVE: To characterise cardiac remodelling, exercise capacity and fibroinflammatory biomarkers in patients with aortic stenosis (AS) with and without diabetes, and assess the impact of diabetes on outcomes. METHODS: Patients with moderate or severe AS with and without diabetes underwent echocardiography, stress cardiovascular magnetic resonance (CMR), cardiopulmonary exercise testing and plasma biomarker analysis. Primary endpoint for survival analysis was a composite of cardiovascular mortality, myocardial infarction, hospitalisation with heart failure, syncope or arrhythmia. Secondary endpoint was all-cause death. RESULTS: Diabetes (n=56) and non-diabetes groups (n=198) were well matched for age, sex, ethnicity, blood pressure and severity of AS. The diabetes group had higher body mass index, lower estimated glomerular filtration rate and higher rates of hypertension, hyperlipidaemia and symptoms of AS. Biventricular volumes and systolic function were similar, but the diabetes group had higher extracellular volume fraction (25.9%±3.1% vs 24.8%±2.4%, p=0.020), lower myocardial perfusion reserve (2.02±0.75 vs 2.34±0.68, p=0.046) and lower percentage predicted peak oxygen consumption (68%±21% vs 77%±17%, p=0.002) compared with the non-diabetes group. Higher levels of renin (log10renin: 3.27±0.59 vs 2.82±0.69 pg/mL, p<0.001) were found in diabetes. Multivariable Cox regression analysis showed diabetes was not associated with cardiovascular outcomes, but was independently associated with all-cause mortality (HR 2.04, 95% CI 1.05 to 4.00; p=0.037). CONCLUSIONS: In patients with moderate-to-severe AS, diabetes is associated with reduced exercise capacity, increased diffuse myocardial fibrosis and microvascular dysfunction, but not cardiovascular events despite a small increase in mortality.
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Estenosis de la Válvula Aórtica , Diabetes Mellitus , Humanos , Tolerancia al Ejercicio , Renina , Estenosis de la Válvula Aórtica/diagnóstico por imagen , CorazónRESUMEN
Age-related macular degeneration (AMD) may be associated with ABCA4 variants and is characterized by the accumulation of visual cycle-byproduct lipofuscin. Reducing retinol-binding protein 4 (RBP4), a retinol transporter protein, may reduce lipofuscin production. This study aims to assess the associations between plasma RBP4, the ABCA4 variation, and AMD severity. Sixty-seven participants were grouped into healthy/mild AMD (n = 32) and severe AMD (n = 35) groups. The latter group was older than the former group and had higher levels of RBP4 (36.8 ± 8.3 vs. 30.4 ± 7.0 µg/mL, p = 0.0012). The ten participants with six ABCA4 linked-variants had higher RBP4 than those without (37.8 ± 7.7 vs. 32.4 ± 7.9 µg/mL; p = 0.026), and eight of them had severe AMD. Univariate analyses showed that severe AMD was related to older age (OR, 1.26; 95% CI, 1.13-1.40; p < 0.0001) and to higher RBP4 levels (OR, 1.12; 95% CI, 1.04-1.20; p = 0.003), whereas the linked ABCA4 variants had no associations. After adjustment, however, only age remained significantly associated with severe AMD. This pilot study shows a trend of higher plasma RBP4 levels in severe AMD or the ABCA4-linked variants, and further age-matched studies are warranted.
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Highlights from the Science family of journals.
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Purpose: To assess changes in surgical decisions and outcomes of rhegmatogenous retinal detachment (RRD) during the COVID-19 pandemic at a tertiary center in Taiwan. Methods: Patients undergoing pars plana vitrectomy (PPV) or scleral buckling (SB) for primary RRD during Taiwan's first wave of domestic COVID-19 cases surge between May and July 2021 (COVID cohort, n = 100) were compared to controls in the closest pre-COVID year, 2019 (pre-COVID cohort, n = 121). Results: The COVID cohort had significantly worse RRD presentation, received more PPV (alone or combined with SB (PPV + SB)) and less SB alone, and had comparable single-surgery anatomic success (SSAS) rates. In patients who underwent PPV, more underwent PPV + SB instead of PPV alone. The decision to combine SB in PPV surgery was significantly affected by the COVID pandemic (odds ratio [OR], 3.1860 [95% confidence interval (CI), 1.1487-8.8361]). However, a shorter duration of symptoms before the first presentation (0.9857 [95% CI, 0.9720-0.9997]) was the only factor related to SSAS, whereas the surgical method had no association. The SSAS rate remained close to or over 90% in patients with a duration of symptoms before surgery ≤4 weeks but dropped to 83.3% in patients with duration >4 weeks. Conclusion: During the COVID-19 pandemic, worse RRD presentations led to a shift in preference for PPV over SB alone as the primary surgery. The pandemic affected surgeons' decision to combine SB during PPV. Nevertheless, SSAS was only associated with the duration of symptoms but not with surgical methods.
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COVID-19 , Desprendimiento de Retina , Humanos , Desprendimiento de Retina/epidemiología , Desprendimiento de Retina/cirugía , Desprendimiento de Retina/diagnóstico , Pandemias , Taiwán/epidemiología , Centros de Atención Terciaria , Resultado del Tratamiento , Agudeza Visual , Estudios Retrospectivos , COVID-19/epidemiología , Curvatura de la Esclerótica/métodos , Vitrectomía/métodosRESUMEN
5-methylcytosine (5mC) is the most important DNA modification in mammalian genomes. The ideal method for 5mC localization would be both nondestructive of DNA and direct, without requiring inference based on detection of unmodified cytosines. Here we present direct methylation sequencing (DM-Seq), a bisulfite-free method for profiling 5mC at single-base resolution using nanogram quantities of DNA. DM-Seq employs two key DNA-modifying enzymes: a neomorphic DNA methyltransferase and a DNA deaminase capable of precise discrimination between cytosine modification states. Coupling these activities with deaminase-resistant adapters enables accurate detection of only 5mC via a C-to-T transition in sequencing. By comparison, we uncover a PCR-related underdetection bias with the hybrid enzymatic-chemical TET-assisted pyridine borane sequencing approach. Importantly, we show that DM-Seq, unlike bisulfite sequencing, unmasks prognostically important CpGs in a clinical tumor sample by not confounding 5mC with 5-hydroxymethylcytosine. DM-Seq thus offers an all-enzymatic, nondestructive, faithful and direct method for the reading of 5mC alone.
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5-Metilcitosina , Metilación de ADN , Animales , Citosina , ADN/genética , Análisis de Secuencia de ADN/métodos , Mamíferos/genéticaRESUMEN
Purpose: This study investigated the associations between vascular endothelial growth factor (VEGF) polymorphisms and retinopathy of prematurity (ROP) risk. Methods: Infants born prematurely at any time from 2009 to 2018 were included. Five single-nucleotide polymorphisms (SNPs) of VEGF were analyzed using real-time PCR in all infants. Multivariate logistic regression was applied to model the associations between VEGF polymorphisms and ROP susceptibility, severity, and premature clinicopathologic characteristics. Results: A total of 334 patients were included and categorized into three groups: those without ROP, those with mild ROP (i.e., ROP not requiring treatment), and those with severe ROP (i.e., ROP for whom treatment was indicated). Among the female patients with ROP, those with VEGF rs3025035 CT (3.231-fold; 95% confidence interval [CI], 1.238-8.431) and a combination of CT and TT genotypes (2.643-fold; 95% CI, 1.056-6.619) exhibited significantly higher risks of severe ROP compared with those with wild-type genotypes. Female ROP infants with VEGF rs3025010 C (TC + CC) alleles had a lower risk of ROP stage ≥3 (odds ratio [OR] = 0.406; 95% CI, 0.165-0.999) than those with TT homozygotes. ROP patients with the VEGF rs10434 A allele (GA + AA) exhibited higher risks of necrotizing enterocolitis (OR = 2.750; 95% CI, 1.119-6.759) and lower risk of bronchopulmonary dysplasia (OR = 0.390; 95% CI, 0.173-0.877) than those with GG homozygotes did. Conclusions: VEGF polymorphisms affect ROP risks differently in male and female infants. In female infants, VEGF rs3025035 with T alleles may predict ROP severity, and VEGF rs3025010 with C alleles may protect against severe ROP.
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Retinopatía de la Prematuridad , Factor A de Crecimiento Endotelial Vascular , Humanos , Recién Nacido , Nacimiento Prematuro , Factor A de Crecimiento Endotelial Vascular/genética , Retinopatía de la Prematuridad/genéticaRESUMEN
BACKGROUND: Optic atrophy-13 with retinal and foveal abnormalities (OPA13) (MIM #165510) is a mitochondrial disease in which apparent bilateral optic atrophy is present and sometimes followed by retinal pigmentary changes or photoreceptors degeneration. OPA13 is caused by heterozygous mutation in the SSBP1 gene, associated with variable mitochondrial dysfunctions. RESULTS: We have previously reported a 16-year-old Taiwanese male diagnosed with OPA13 and SSBP1 variant c.320G>A (p.Arg107Gln) was identified by whole exon sequence (WES). This variant was assumed to be de novo since his parents were clinically unaffected. However, WES and Sanger sequencing further revealed the proband's unaffected mother carrying the same SSBP1 variant with a 13% variant allele frequency (VAF) in her peripheral blood. That finding strongly indicates the maternal gonosomal mosaicism contributing to OPA13, which has not been reported before. CONCLUSIONS: In summary, we described the first case of OPA13 caused by maternal gonosomal mosaicism in SSBP1. Parental mosaicism could be a serious issue in OPA13 diagnosis, and appropriate genetic counseling should be considered.
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Atrofia Óptica , Degeneración Retiniana , Humanos , Femenino , Masculino , Adolescente , Mosaicismo , Degeneración Retiniana/genética , Asesoramiento Genético , Mutación/genética , Proteínas de Unión al ADN , Proteínas MitocondrialesRESUMEN
Purpose: To investigate vascular abnormalities, including persistent avascular retina (PAR), in a large cohort of patients with regressed or treated retinopathy of prematurity (ROP) through long-term follow-up until school age. Design: Retrospective large cohort study. Participants: We included pediatric patients (< 18 years old) with a history of nontreated or treated ROP (treated with either photocoagulation or intravitreal injection [IVI]) and regularly followed up until 2020. Methods: Upon enrollment, we categorized patients into 4 groups: prematurity, regressed ROP, and IVI and laser treatment ROP groups. All patients had undergone visual acuity examinations, OCT, and ultrawide-field fluorescein angiography. Main Outcome Measures: Percentage of eyes with PAR (greater than or equal to the area of 2 disc diameters from the ora serrata to vascular termini) and with vascular abnormalities in the peripheral and posterior retina. Results: In total, we included 187 eyes of 95 patients. The prevalence of PAR was 0%, 33.33%, and 31.65% in eyes in the prematurity, regressed ROP, and IVI treatment groups, respectively (P < 0.0001). There was no significant difference in the percentage of PAR eyes when comparing regressed ROP group (33.33%) with the IVI treatment group (31.65%). At least 1 type of vascular abnormality was noted until school age in all (100%) treated ROP eyes. Although multivariate analysis found a significant association between IVI treatment and PAR (odds ratio: 10.28, 95% confidence interval: 3.29-32.14) until the school age of 6 to 8 years old, there were no stage 3 eyes in the spontaneously regressed group, suggesting that stage 3 ROP in the IVI group could also drive the association. Conclusions: Approximately one-third of ROP eyes with spontaneous regression or IVI treatment still exhibit PAR when the child reaches school age. Several distinct vascular anomalies at the vascular-avascular juncture and within the vascularized retina can persist in these children. The clinical significance of these anomalies and the decision whether to treat them warrant further investigation to optimize their outcomes. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.