Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date >2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated.
The aim of this review article is to describe the specific features of Stargardt disease and ABCA4 retinopathies (ABCA4R) using multimodal imaging and functional testing and to highlight their relevance to potential therapeutic interventions. Standardised measures of tissue loss, tissue function and rate of change over time using formal structured deep phenotyping in Stargardt disease and ABCA4R are key in diagnosis, and prognosis as well as when selecting cohorts for therapeutic intervention. In addition, a meticulous documentation of natural history will be invaluable in the future to compare treated with untreated retinas. Despite the familiarity with the term Stargardt disease, this eponymous classification alone is unhelpful when evaluating ABCA4R, as the ABCA4 gene is associated with a number of phenotypes, and a range of severity. Multimodal imaging, psychophysical and electrophysiologic measurements are necessary in diagnosing and characterising these differing retinopathies. A wide range of retinal dystrophy phenotypes are seen in association with ABCA4 mutations. In this article, these will be referred to as ABCA4R. These different phenotypes and the existence of phenocopies present a significant challenge to the clinician. Careful phenotypic characterisation coupled with the genotype enables the clinician to provide an accurate diagnosis, associated inheritance pattern and information regarding prognosis and management. This is particularly relevant now for recruiting to therapeutic trials, and in the future when therapies become available. The importance of accurate genotype-phenotype correlation studies cannot be overemphasised. This approach together with segregation studies can be vital in the identification of causal mutations when variants in more than one gene are being considered as possible. In this article, we give an overview of the current imaging, psychophysical and electrophysiological investigations, as well as current therapeutic research trials for retinopathies associated with the ABCA4 gene.
Coeliac disease is a chronic autoimmune enteropathy causing small intestinal inflammation, triggered by gluten ingestion. Strict lifelong adherence to a gluten-free diet (GFD) is the only available management strategy, however adherence varies among patients with coeliac disease. Studies have investigated the association between GFD adherence and knowledge, attitudes, experiences, symptoms or quality of life (QoL). These factors are often investigated in isolation, and yet may well themselves be related, however there is limited research on the associations among these variables and with their association with adherence to a GFD. The aim of this study was to identify the relationship between adherence to a GFD and demographic characteristics, knowledge, attitudes and beliefs regarding a GFD, experiences of following a GFD, symptoms and QoL. Patients with coeliac disease were recruited from specialist coeliac disease clinics in secondary care and completed a series of validated questionnaires. Adherence to GFD was assessed using the 'Coeliac Dietary Adherence Test' (CDAT) and 'GFD-Score' (GFD-S). Knowledge was measured using a 7-question knowledge questionnaire on gluten-containing foods and benefits of gluten exclusion. Attitudes were measured using the 'Beliefs about Medicines Questionnaire' (beliefs about the necessity of a GFD) and the 'Revised Illness Perception Questionnaire' (beliefs about coeliac disease). QoL was measured using the 'Coeliac Disease Questionnaire'. Symptoms were measured using the Coeliac Symptom Index questionnaire. Multivariate logistic regression was performed to identify associations between adherence to a GFD and demographic characteristics, beliefs, symptoms, QoL, knowledge. Overall, 116 patients with coeliac disease were included (47 ± 16 years, 70% female, 8.8 ± 10.1 years since diagnosis). Based upon the CDAT questionnaire, 58 (50%) adhered to a GFD, whereas based upon GFD-S 86 (74%) adhered to a GFD. Using CDAT adherence as an outcome, logistic regression revealed that being male was associated with being non-adherent to a GFD (OR = 0.36, p = 0.028). Having higher scores of emotional QoL was associated with being adherent to a GFD (OR = 1.19, p < 0.001). Using GFD-S adherence as an outcome, being a member of a patient support group (OR = 3.8, p = 0.012), having strong beliefs about coeliac disease and the necessity of a GFD (OR = 1.03, p = 0.030), and reporting that coeliac disease is a chronic condition (OR = 1.2, p = 0.008) were associated with being adherent to a GFD. Experiencing difficulties when eating with family/friends was associated with nonadherence (OR = 0.98, p = 0.007). Knowledge of the GFD was not a predictor of being adherent in the multivariate regression analysis. The significant association between sex, attending support groups, QoL, beliefs of coeliac disease and the GFD, and experiences with adherence to a GFD needs to be considered by dietitians and gastroenterologists managing patients with coeliac disease. Recent introduction of methods to quantify gluten ...
Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disease of unknown etiology. Typically presenting with cervical adenopathy and constitutional symptoms, RDD involves bone in less than 10% of cases—and rarely presents as a primary intraosseous lesion. In this report, we describe the presentation of primary, bilateral intraosseous RDD, the first known case in the literature. Asymmetrically involving the lateral femoral condyles of a 59-year-old male, the lesion was discovered incidentally during evaluation and workup for giant cell tumor of bone involving the left tibia. Confirmation of the diagnosis required multiple biopsies and extensive evaluation—reflecting the diagnostic challenge associated with this case. We discuss the clinical, radiological, and pathological findings that allowed us to establish the diagnosis—as well as key differential diagnostic considerations and clinical outcome to date.
BRAF mutations play an important role in the classification and prognostication of low-grade gliomas and may offer a therapeutic target. We report a case of a V600E mutant low-grade glioma with morphological features of a ganglioglioma diagnosed in a 22-year-old female. Sections demonstrated a lowgrade lesion with atypical astrocytic glial and neuronal elements, the latter stained positive for chromogranin A and BRAF V600E immunohistochemical stains; IDH-1 immunohistochemistry was negative. A provisional diagnosis of ganglioglioma (WHO grade I) was made with a differential diagnosis of pilocytic astrocytoma with gangliocytic differentiation. Subsequent molecular analysis confirmed the tumour to be IDH wild-type and contain a BRAF V600E point mutation, with absence of KIAA1549-BRAF fusion, supporting the initial diagnosis of a ganglioglioma. BRAF V600E point mutations are well recognised as a major genetic alteration in low grade paediatric glial tumours and confer prognostic information. Additionally, there is emerging evidence that BRAF and MEK inhibitors may have a therapeutic role in BRAF mutant gliomas.
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