Phenotyping of ABCA4 Retinopathy by Machine Learning Analysis of Full-Field Electroretinography

PURPOSE: Biallelic pathogenic variants in ABCA4 are the commonest cause of monogenic retinal disease. The full-field electroretinogram (ERG) quantifies severity of retinal dysfunction. We explored application of machine learning in ERG interpretation and in genotype–phenotype correlations. METHODS: International standard ERGs in 597 cases of ABCA4 retinopathy were classified into three functional phenotypes by human experts: macular dysfunction alone (group 1), or with additional generalized cone dysfunction (group 2), or both cone and rod dysfunction (group 3). Algorithms were developed for automatic selection and measurement of ERG components and for classification of ERG phenotype. Elastic-net regression was used to quantify severity of specific ABCA4 variants based on effect on retinal function. RESULTS: Of the cohort, 57.6%, 7.4%, and 35.0% fell into groups 1, 2, and 3 respectively. Compared with human experts, automated classification showed overall accuracy of 91.8% (SE, 0.169), and 96.7%, 39.3%, and 93.8% for groups 1, 2, and 3. When groups 2 and 3 were combined, the average holdout group accuracy was 93.6% (SE, 0.142). A regression model yielded phenotypic severity scores for the 47 commonest ABCA4 variants. CONCLUSIONS: This study quantifies prevalence of phenotypic groups based on retinal function in a uniquely large single-center cohort of patients with electrophysiologically characterized ABCA4 retinopathy and shows applicability of machine learning. Novel regression-based analyses of ABCA4 variant severity could identify individuals predisposed to severe disease. Translational Relevance: Machine learning can yield meaningful classifications of ERG data, and data-driven scoring of genetic variants can identify patients likely to benefit most from future therapies

Spectrum of genetic variants in the commonest genes causing inherited retinal disease in a large molecularly characterised UK cohort

PURPOSE: Inherited retinal disease (IRD) is a leading cause of blindness. Recent advances in gene-directed therapies highlight the importance of understanding the genetic basis of these disorders. This study details the molecular spectrum in a large UK IRD patient cohort. DESIGN: Retrospective study of electronic patient records. PARTICIPANTS: Patients with IRD who have attended the Genetics Service at Moorfields Eye Hospital between 2003 and July 2020, in whom a molecular diagnosis has been identified. METHODS: Genetic testing was undertaken via a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. Likely disease-causing variants were identified from entries within the genetics module of the hospital electronic patient record (OpenEyes Electronic Medical Record, UK). Analysis was restricted to only genes listed in the Genomics England PanelApp R32 Retinal disorders panel (Version 3.24), which includes 412 genes associated with IRD. Manual curation ensured consistent variant annotation and included only plausible disease-associated variants. MAIN OUTCOME MEASURES: Detailed analysis was performed for variants in the five most frequent genes (ABCA4, USH2A, RPGR, PRPH2, BEST1), as well as for the commonest variants encountered in the IRD study cohort. RESULTS: We identified 4415 individuals from 3953 families with molecularly diagnosed IRD (variants in 166 genes). 42.7% of families had variants in one of the five commonest IRD genes. Complex disease alleles contributed to disease in 16.9% of affected families with ABCA4-associated retinopathy. USH2A exon 13 variants were identified in 43% of affected individuals with USH2A-associated IRD. 71% of RPGR variants were clustered in the ORF15 region. PRPH2 and BEST1 variants were associated with a range of dominant and recessive IRD phenotypes. Of the 20 most prevalent variants identified, five were not in the commonest genes; these included founder variants in CNGB3, BBS1, TIMP3, EFEMP1 and RP1. CONCLUSIONS: We describe the commonest pathogenic IRD alleles in a large single-center multi-ethnic UK cohort, and the burden of disease, in terms of families affected, attributable to these variants. Our findings will inform IRD diagnoses in future patients and helps delineate the cohort of patients eligible for gene-directed therapies under development

De mythe van het maagdenvlies

The hymen can be ruptured during sexual intercourse, but also in many different, non-sexual ways. In cultures where female virginity is highly valued, premarital defloration is a source of shame for both the girl and her family. Thus, these young women, including brides whose virginity cannot be demonstrated at their wedding, run the risk of public humiliation, repudiation, violence, etc. Considering these sanctions, some girls feel forced to request a surgical repair of their hymen. Nevertheless, gynaecologists may refuse to comply with requests to undertake a hymen reconstruction. To justify this point of view, they esteem that this type of medical surgery is misleading and not medically indicated. Furthermore, a double moral standard is maintained: young women – but not men – are expected to remain virgins until their marriage. On the contrary, hymen (re)constructions are justifiable when considered as procedures improving the mental and social well-being, and consequently the overall health of the patient. Moreover, the decisions taken by competent women concerning their own body should be respected. Hymen (re)constructions are in many ways distinguishable from female genital mutilation (FGM)

Description of a patient cohort with Hereditary Sensory Neuropathy Type 1 without retinal disease Macular Telangiectasia type 2 – implications for retinal screening in HSN1

BACKGROUND AND AIMS: Pathogenic variants in the genes encoding serine palmitoyl transferase (SPTLC1 or SPTLC2) are the most common causes of the rare peripheral nerve disorder Hereditary Sensory Neuropathy Type 1 (HSN1). Macular telangiectasia type 2 (MacTel), a retinal disorder associated with disordered serine-glycine metabolism and has been described in some patients with HSN1. This study aims to further investigate this association in a cohort of people with HSN1. METHODS: Fourteen patients with a clinically and genetically confirmed diagnosis of HSN1 from the National Hospital for Neurology and Neurosurgery (NHNN, University College London Hospitals NHS Foundation Trust, London, United Kingdom) were recruited to the MacTel Registry, between July 2018 and April 2019. Two additional patients were identified from the dataset of the international clinical registry study (www.lmri.net). Ocular examination included fundus autofluorescence, blue light and infrared reflectance, macular pigment optical density mapping, and optical coherence tomography. RESULTS: Twelve patients had a pathogenic variant in the SPTLC1 gene, with p.Cys133Trp in eleven cases (92%) and p.Cys133Tyr in one case (8%). Four patients had a variant in the SPTLC2 gene. None of the patients showed clinical evidence of MacTel. INTERPRETATION: The link between HSN1 and MacTel seems more complex than can solely be explained by the genetic variants. An extension of the spectrum of SPTLC1/2-related disease with phenotypic pleiotropy is proposed. HSN1 patients should be screened for visual symptoms and referred for specialist retinal screening, but the association of the two diseases is likely to be variable and remains unexplained. This article is protected by copyright. All rights reserved

Anesthesia and analgesia in rabbits and rodents

Rabbits and rodents are popular pets and are often presented to veterinarians for evaluation and medical treatment. Anesthesia in exotic pets is required for many diagnostic and surgical procedures and is associated with a higher perioperative risk in rabbits and rodents when compared with dogs and cats. Inhalation anesthetic agents are commonly used as the sole source of anesthesia in small rodents, whereas injectable agents in combination with inhalation anesthesia are often used for rabbits and larger rodents. Analgesia is an important component of exotic pet medicine. Although it may be difficult to recognize signs of pain in companion exotic mammals, adequate pain management should always be provided. Opioid and nonsteroidal antiinflammatory drugs are the analgesic medications of choice, but others should be considered (e.g., local anesthetic agents). This article provides an update of the current literature regarding anesthesia and analgesia in rabbits and rodents