Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset motor neuron disease characterized by the loss of the upper and lower motor neurons. Our understanding of the molecular basis of ALS pathology remains elusive, complicating the development of efficient treatment. Gene-set analyses of genome-wide data have offered insight into the biological processes and pathways of complex diseases and can suggest new hypotheses regarding causal mechanisms. Our aim in this study was to identify and explore biological pathways and other gene sets having genomic association to ALS. Two cohorts of genomic data from the dbGaP repository were combined: (a) the largest available ALS individual-level genotype dataset (N = 12,319), and (b) a similarly sized control cohort (N = 13,210). Following comprehensive quality control pipelines, imputation and meta-analysis, we assembled a large European descent ALS-control cohort of 9244 ALS cases and 12,795 healthy controls represented by genetic variants of 19,242 genes. Multi-marker analysis of genomic annotation (MAGMA) gene-set analysis was applied to an extensive collection of 31,454 gene sets from the molecular signatures database (MSigDB). Statistically significant associations were observed for gene sets related to immune response, apoptosis, lipid metabolism, neuron differentiation, muscle cell function, synaptic plasticity and development. We also report novel interactions between gene sets, suggestive of mechanistic overlaps. A manual meta-categorization and enrichment mapping approach is used to explore the overlap of gene membership between significant gene sets, revealing a number of shared mechanisms.

Variable phenotypic presentations of renal involvement in Fabry disease: a case series.

Fabry disease is an X-linked genetic deficiency in the alpha-galactosidase enzyme resulting in intracellular accumulation of glycosphingolipids and multisystem organ dysfunction. Typically 50% of males and 20% of affected females have renal involvement, ranging from proteinuria or reduced renal function, renal parapelvic cysts and progressive renal disease ultimately requiring transplantation or dialysis. The phenotypic presentation of Fabry disease is incredibly varied and will even vary between family members with the same confirmed genetic mutation. In a cohort of patients affected by Fabry disease in the North East of England we examine the different phenotypic presentations of eight index cases (6 male, 2 female) with predominantly renal disease and the renal manifestations within their family members. The mean age of presentation was 40 years of age (range 23-59 years). Various multisystem manifestations were observed including cardiac, neurological, cerebrovascular and skin involvement. Two of the male index patients reached end stage renal disease (ESRD) requiring renal replacement therapy. Two female index patients had phenotypes limited to hypertension and proteinuria at presentation and the remaining patients had either stable or progressive chronic kidney disease at the time of diagnosis. We demonstrate the need for a high index of suspicion in order to consider Fabry disease as a diagnosis and the importance of cascade genetic screening to identify affected family members so that treatment can be initiated in a timely fashion.

International migration patterns of Red-throated Loons (Gavia stellata) from four breeding populations in Alaska.

Identifying post-breeding migration and wintering distributions of migratory birds is important for understanding factors that may drive population dynamics. Red-throated Loons (Gavia stellata) are widely distributed across Alaska and currently have varying population trends, including some populations with recent periods of decline. To investigate population differentiation and the location of migration pathways and wintering areas, which may inform population trend patterns, we used satellite transmitters (n = 32) to describe migration patterns of four geographically separate breeding populations of Red-throated Loons in Alaska. On average (± SD) Red-throated Loons underwent long (6,288 ± 1,825 km) fall and spring migrations predominantly along coastlines. The most northern population (Arctic Coastal Plain) migrated westward to East Asia and traveled approximately 2,000 km farther to wintering sites than the three more southerly populations (Seward Peninsula, Yukon-Kuskokwim Delta, and Copper River Delta) which migrated south along the Pacific coast of North America. These migration paths are consistent with the hypothesis that Red-throated Loons from the Arctic Coastal Plain are exposed to contaminants in East Asia. The three more southerly breeding populations demonstrated a chain migration pattern in which the more northerly breeding populations generally wintered in more northerly latitudes. Collectively, the migration paths observed in this study demonstrate that some geographically distinct breeding populations overlap in wintering distribution while others use highly different wintering areas. Red-throated Loon population trends in Alaska may therefore be driven by a wide range of effects throughout the annual cycle.

Yersinia pseudotuberculosis aortitis in a patient with diverticulosis and polycystic kidney disease.

An 81-year-old gentleman with chronic kidney disease presented with pyrexia and a new systolic cardiac murmur. Investigations revealed infective aortitis of a pre-existing aortic aneurysm graft repair. Peripheral blood cultures were positive for Yersinia pseudotuberculosis and the patient was successfully treated with an extended course of antibiotics. Abdominal imaging also revealed progressive bilateral polycystic kidney disease with associated diverticular disease, which was postulated as the source of the Y. pseudotuberculosis. An autosomal dominant polycystic kidney disease may present late in life and extra-renal manifestations of this disease are an important cause of morbidity.

From a fish tank injury to hospital haemodialysis: the serious consequences of drug interactions.

We present the case of a 68-year-old man admitted to hospital with severe acute kidney injury secondary to statin-induced rhabdomyolysis. Five weeks previously, the patient started a course of clarithromycin for infection of a finger wound with Mycobacterium marinum. His current medications included simvastatin, which he continued along with clarithromycin. The severity of the acute kidney injury necessitated initial continuous venovenous haemofiltration followed by 12 haemodialysis sessions before a spontaneous improvement in renal function occurred. Statins are widely prescribed and we report this case to encourage increased vigilance in avoiding drug interactions known to increase the risk of statin-induced myopathy, including macrolide antibiotics, calcium channel antagonists and amiodarone. The authors would also like to highlight recent guidance on atorvastatin as the statin of choice in patients with chronic kidney disease, and of the need for dose adjustment in those with an estimated glomerular filtration rate less than 30 mLs/min/1.73 m².