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Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.
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Fenotipo , Animales , Femenino , Humanos , Masculino , Ratones , Aciltransferasas , Hidrolasas de Éster Carboxílico/genética , Mutación Missense , Fosfolipasas/genética , Enfermedades de la Retina/genéticaRESUMEN
PURPOSE: To report the cumulative incidence of complications and to describe refractive error and visual acuity (VA) outcomes in children undergoing secondary intraocular lens (IOL) implantation after previous surgery for nontraumatic cataract. DESIGN: Pediatric cataract registry. PARTICIPANTS: Eighty children (108 eyes: 60 bilateral, 48 unilateral) undergoing lensectomy at younger than 13 years of age. METHODS: Annual data collection from medical record review through 5 years after lensectomy. MAIN OUTCOME MEASURES: Cumulative incidence of newly emergent complications after secondary IOL implantation; refractive error and VA by 5 years after lensectomy. RESULTS: Median follow-up after secondary IOL implantation was 2.7 years (interquartile range [IQR], 0.8-3.3 years; range, 0.6-5.0 years) for bilateral and 2.1 years (range, 0.5-6.4 years) for unilateral cases. A common complication after secondary IOL implantation was a glaucoma-related adverse event (GRAE; glaucoma or glaucoma suspect); the cumulative incidence was 17% (95% confidence interval [CI], 3%-29%) in bilateral cases and 12% (95% CI, 0%-23%) in unilateral cases. The cumulative incidence of surgery for visual axis opacification was 2% (95% CI, 0%-7%) for bilateral cases and 4% (95% CI, 0%-10%) for unilateral cases. The median prediction error within 90 days of implantation was 0.88 diopter (D; IQR, -0.50 to +3.00 D) less hyperopic than intended among 21 eyes for bilateral cases and 1.50 D (IQR, -0.25 to +2.38 D) less among 19 unilateral cases. The median spherical equivalent refractive error at 5 years (at a median of 5.1 years of age) in eyes receiving a secondary IOL was +0.50 D (IQR, -2.38 to +2.94 D) for 48 bilateral cases and +0.06 D (IQR, -2.25 to +0.75 D) for 22 unilateral cases. Median monocular VA at 5 years was 20/63 (IQR, 20/50-20/100) for bilateral cases (n = 42) and 20/400 (IQR, 20/160-20/800) for unilateral cases (n = 33). CONCLUSIONS: Eyes with secondary IOL implantation have a risk of developing new GRAEs. Five years after lensectomy (approximately 2.5 years after secondary IOL implantation), the average refractive error was less hyperopic than desired given the anticipated further myopic shift before refraction stabilizes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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INTRODUCTION: The aim of this study was to evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed ABCA4-associated Stargardt disease type 1 (STGD1) over a 24-month period in a multicenter prospective cohort study. METHODS: SD-OCT images from 428 eyes of 236 patients were analyzed. Change of mean thickness (MT) and intact area were estimated after semiautomated segmentation for the following individual layers in the central subfield (CS), inner ring (IR), and outer ring (OR) of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OSs), inner segments (IS), outer nuclear layer (ONL) inner retina (IR), and total retina. RESULTS: Statistically significant decreases of all outer retinal layers (RPE, OS, IS, and ONL) could be observed over a 24-month period both in decline of mean retinal thickness and intact area (p < 0.0001, respectively), whereas the IR showed an increase of retinal thickness in the CS and IR and remained unchanged in the OR. CONCLUSIONS: Significant loss could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with STGD1. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of STGD1.
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Progresión de la Enfermedad , Degeneración Macular , Epitelio Pigmentado de la Retina , Enfermedad de Stargardt , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Tomografía de Coherencia Óptica/métodos , Enfermedad de Stargardt/diagnóstico , Masculino , Estudios Prospectivos , Femenino , Adulto , Adulto Joven , Persona de Mediana Edad , Degeneración Macular/diagnóstico , Degeneración Macular/congénito , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/diagnóstico por imagen , Adolescente , Estudios de Seguimiento , Retina/diagnóstico por imagen , Retina/patología , NiñoRESUMEN
BACKGROUND: The intraoperative relaxed muscle positioning (IRMP) technique for strabismus surgery in thyroid eye disease (TED) involves recessing muscles' insertions to positions where they rest without tension. We evaluate the long-term outcomes of patients who underwent surgery using this technique. METHODS: The medical records of patients with TED and diplopia who underwent strabismus surgery with IRMP between 1999 and 2021 were reviewed retrospectively. Excellent outcomes were defined as no diplopia in primary and reading gazes without the use of prisms; good outcomes, as residual deviation of <10Δ with diplopia in primary and reading gazes. Good or excellent outcomes were considered successes. Poor outcomes were defined as residual deviation >10Δ with diplopia in primary and reading gazes or the inability of patients to tolerate prismatic correction. RESULTS: A total of 129 patients were followed for an average of 4.24 ± 5.13 years (longest follow-up 20 years): 96 (73.6%) underwent a single surgery, and 33 (26.4%) underwent additional interventions. Seven of these had been planned as staged procedures, and all were successful. Five patients experienced disease reactivation and underwent additional surgery, with successful outcomes in 4 (80%). Of the remaining 21 patients, 6 underwent a third procedure, and a single patient underwent a fourth. Overall, 93.6% of patients had a successful outcome: 77.5% excellent and 16.3% good. CONCLUSIONS: In our study cohort, the IRMP approach resulted in durable relief from large-angle strabismus and diplopia in a large majority of patients.