The prevalence of anxiety and depression in people with age-related macular degeneration: a systematic review of observational study data

Background Comorbid mental health problems have been shown to have an adverse effect on the quality of life of people with common eye disorders. This study aims to assess whether symptoms of anxiety and/or depression are more prevalent in people with age-related macular degeneration (AMD) than in people without this condition. Methods A systematic search of electronic databases (Medline, CINAHL, EMBASE, PsycINFO) from inception to February 2012 was conducted to identify studies of AMD populations which measured symptoms of anxiety and/or depression. Reference checking of relevant articles was also performed. Data on the study setting, prevalence and how anxiety and depression were measured were extracted from the papers. Critical appraisal was performed using the Critical Appraisal Skills Programme (CASP) tools. Results A total of 16 papers were included in the review, from an original search result of 597. The prevalence estimates, taken from nine cross-sectional and cohort studies, ranged from 15.7%-44% for depressive symptoms and 9.6%-30.1% for anxiety symptoms in people with AMD. The seven case–control studies found that people with AMD were more likely to experience symptoms of depression compared with those without AMD, but not more likely to experience symptoms of anxiety. Conclusions Overall, the evidence suggests that symptoms of depression are more prevalent amongst AMD populations than anxiety symptoms. The heterogeneity of the studies included in this review means that it is difficult to draw strong conclusions as to the true estimates of depression and anxiety symptoms in AMD populations and prevented formal meta-analysis. Further research which specifies clinical anxiety and gives clear definitions as to the type of AMD being investigated is required

Disseminated aspergillosis with mediastinal invasion causing fatal stroke in an immunocompetent young man

Introduction: Aspergillus flavus is a common cause of aspergillosis. Case presentation: A previously fit and well, immunocompetent 27-year old male living in Australia developed disseminated Aspergillus flavus complex infection with mediastinal and cardiac invasion, superior vena cava obstruction and stroke, with fatal haemorrhagic transformation. Conclusion: Aspergillus Flavus is a rare but important cause of serious disease in the immunocompetent

Defective i⁶A37 Modification of Mitochondrial and Cytosolic tRNAs Results from Pathogenic Mutations in TRIT1 and Its Substrate tRNA

Identifying the genetic basis for mitochondrial diseases is technically challenging given the size of the mitochondrial proteome and the heterogeneity of disease presentations. Using next-generation exome sequencing, we identified in a patient with severe combined mitochondrial respiratory chain defects and corresponding perturbation in mitochondrial protein synthesis, a homozygous p.Arg323Gln mutation in TRIT1. This gene encodes human tRNA isopentenyltransferase, which is responsible for i⁶A37 modification of the anticodon loops of a small subset of cytosolic and mitochondrial tRNAs. Deficiency of i⁶A37 was previously shown in yeast to decrease translational efficiency and fidelity in a codon-specific manner. Modelling of the p.Arg323Gln mutation on the co-crystal structure of the homologous yeast isopentenyltransferase bound to a substrate tRNA, indicates that it is one of a series of adjacent basic side chains that interact with the tRNA backbone of the anticodon stem, somewhat removed from the catalytic center. We show that patient cells bearing the p.Arg323Gln TRIT1 mutation are severely deficient in i⁶A37 in both cytosolic and mitochondrial tRNAs. Complete complementation of the i⁶A37 deficiency of both cytosolic and mitochondrial tRNAs was achieved by transduction of patient fibroblasts with wild-type TRIT1. Moreover, we show that a previously-reported pathogenic m.7480A>G mt-tRNASer(UCN) mutation in the anticodon loop sequence A36A37A38 recognised by TRIT1 causes a loss of i⁶A37 modification. These data demonstrate that deficiencies of i⁶A37 tRNA modification should be considered a potential mechanism of human disease caused by both nuclear gene and mitochondrial DNA mutations while providing insight into the structure and function of TRIT1 in the modification of cytosolic and mitochondrial tRNAs

LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population

Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French-Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients’ fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post-transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French-Canadian population

A novel, pathogenic dinucleotide deletion in the mitochondrial MT-TY gene causing myasthenia-like features

Mitochondrial DNA (mtDNA)-related diseases often pose a diagnostic challenge and require rigorous clinical and laboratory investigation. Pathogenic variants in the mitochondrial tRNA gene MT-TY, which encodes the tRNATyr, are a rare cause of mitochondrial disease. Here we describe a novel m.5860delTA anticodon variant in the MT-TY gene in a patient who initially presented with features akin to a childhood onset myasthenic syndrome. Using histochemical, immunohistochemical and protein studies we demonstrate that this mutation leads to severe biochemical defects of mitochondrial translation, which is reflected in the early onset and progressive phenotype. This case highlights the clinical overlap between mtDNA-related diseases and other neuromuscular disorders, and demonstrates the potential pitfalls in analysis of next generation sequencing results, given whole exome sequencing of a blood DNA sample failed to make a genetics diagnosis. Muscle biopsy remains an important requirement in the diagnosis of mitochondrial disease and in establishing the pathogenicity of novel mtDNA variants.AL, RM and RWT are supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z); RM and RWT also receive support from the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Mitochondrial Disease Patient Cohort (UK) (G0800674), Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council L016354), UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, the Lily Foundation and the UK NHS Specialist Commissioners which funds the “Rare Mitochondrial Disorders of Adults and Children” Diagnostic Service in Newcastle upon Tyne (http://www.newcastle-mitochondria.com/). GM is supported by the Association of British Neurologists Clinical Research Training Fellowship. Biobanking and Biomedical Resources Research Infrastructure ‐ large prospective cohorts (BBMRI‐LPC) 2016 access call for Whole Exome Sequencing (FP7/2007‐2013), Grant Number: 313010. Data were analyzed using the RD‐Connect Genome‐Phenome Analysis platform developed under FP7/2007‐2013 funded project, Grant Number: 305444