The D409H variant in GBA1: Challenges in predicting the Gaucher phenotype in the newborn screening era

Gaucher disease (GD) is an autosomal recessive disorder resulting from glucocerebrosidase deficiency due to pathologic variants in GBA1. While clinically heterogeneous, GD encompasses three types, non-neuronopathic (GD1), acute neuronopathic (GD2), and chronic neuronopathic (GD3). Newborn screening (NBS), which has made remarkable inroads in detecting certain diseases before detrimental health consequences and fatality ensues, is now being piloted for GD in several states and countries. Early on, clinical features of GD2 can overlap with GD3; hence, predicting outcome is challenging. As NBS for GD becomes more available, the increased detection of GD in neonates is inevitable. As a result, health care providers and families will be faced with uncertainty with respect to clinical management. Since more severe GBA1 variants are generally associated with neuronopathic GD, there has been an increased dependence on genotypic information. We present an infant detected by NBS with genotype D409H(p.Asp448His)/RecNciI (p.Leu483Pro; p.Ala495Pro;p.Val499=). To assist in genetic counseling, we performed a retrospective review of other patients in our cohort carrying D409H and reviewed the literature. The study illustrates the challenges faced in counseling for infants with neuronopathic GD, even with known GBA1 variants, and the tough management decisions that can ensue from detection in newborns.     

Serologic and molecular characterization of the T15 idiotype--I. Topologic mapping of idiotopes on TEPC15

The present study was designed to determine the minimum number of idiotopic determinants (Id) comprising the T15 idiotype and to construct a topological map of Id on the TEPC15 immunoglobulin molecule. Seven monoclonal anti-Id antibodies were used to map determinants by solid phase competition radioimmunoassay. The binding of some anti-Id to T15 was inhibited by phosphorylcholine-protein conjugates, while other anti-Id were not, suggesting that these anti-Id bind to different portions of T15 relative to the paratope. In addition, Id were mapped relative to one another in reciprocal competition assays between the anti-Id for binding to T15 coated plates. The topologic relationships between six Id were discerned by this method. A seventh binding site was identical or so close that it could not be discriminated. These studies suggest that the T15 idiotype is composed of at least six discrete overlapping Id whose locations range from the antigen binding region to the CH1 domain on TEPC15.     

Renal and endocrine responses to a renin inhibitor, enalkiren, in normal humans

Interpretation of renin-angiotensin blockade with angiotensin converting enzyme inhibitors is potentially confounded by their multiple effects. We used a selective renin inhibitor (enalkiren, A-64662) to explore the renal and endocrine effects of angiotensin II in healthy men. Each received 90-minute enalkiren infusions at 2-day intervals, on a low (10 mmol, 16 subjects) and high (200 mmol, 12 subjects) salt diet. Plasma renin activity, immunoreactive plasma angiotensin II and aldosterone concentrations, inulin, and p-aminohippurate clearance were measured by standard methods. Plasma renin activity fell at 0.1 micrograms/kg, but the threshold for biologic effect was 256 micrograms/kg, where plasma immunoreactive angiotensin II and aldosterone concentration fell, and renal plasma flow rose (p less than 0.01). The maximal renal vascular response (+152 +/- 23 ml/min/1.73 m2) occurred at 512 micrograms/kg (p less than 0.01). Diastolic and mean blood pressure fell modestly but significantly (p less than 0.05). Responses were limited on a high salt diet. We confirm that conventional plasma renin activity measurement is misleading in humans receiving a renin inhibitor. The renal vascular response to renin inhibition in this study appeared to substantially exceed reported responses to angiotensin converting enzyme inhibition, perhaps reflecting a crucial and relatively inaccessible intrarenal locus.     

From the Cover: Climate mediates hypoxic stress on fish diversity and nursery function at the land–sea interface

Coastal ecosystems provide numerous important ecological services, including maintenance of biodiversity and nursery grounds for many fish species of ecological and economic importance. However, human population growth has led to increased pollution, ocean warming, hypoxia, and habitat alteration that threaten ecosystem services. In this study, we used long-term datasets of fish abundance, water quality, and climatic factors to assess the threat of hypoxia and the regulating effects of climate on fish diversity and nursery conditions in Elkhorn Slough, a highly eutrophic estuary in central California (United States), which also serves as a biodiversity hot spot and critical nursery grounds for offshore fisheries in a broader region. We found that hypoxic conditions had strong negative effects on extent of suitable fish habitat, fish species richness, and abundance of the two most common flatfish species, English sole (Parophrys vetulus) and speckled sanddab (Citharichthys stigmaeus). The estuary serves as an important nursery ground for English sole, making this species vulnerable to anthropogenic threats. We determined that estuarine hypoxia was associated with significant declines in English sole nursery habitat, with cascading effects on recruitment to the offshore adult population and fishery, indicating that human land use activities can indirectly affect offshore fisheries. Estuarine hypoxic conditions varied spatially and temporally and were alleviated by strengthening of El Niño conditions through indirect pathways, a consistent result in most estuaries across the northeast Pacific. These results demonstrate that changes to coastal land use and climate can fundamentally alter the diversity and functioning of coastal nurseries and their adjacent ocean ecosystems.Over a third of Earth’s human population is concentrated along coastal margins (1), and much of the planet is dependent on the many functions and services provided by coastal ecosystems. Coastal ecosystems face multiple threats that include habitat loss and modification through urban development, intensification of agriculture and subsequent eutrophication, climate change, and overfishing, all of which decrease ecosystem functioning and diminish the ecological and economic value of continental shelves around the world (2–6). The effect of multiple stressors, such as climate change and hypoxia, over spatial and temporal scales relevant to the diversity and function of coastal systems is poorly understood. Furthermore, there are very few predictions on how climate change will interact with other anthropogenic threats to influence ecosystem functioning and services.Certain critical functions and services of coastal ecosystems, such as estuaries, are potentially affected by anthropogenic threats. These services include supporting biodiversity (7) and the provision of nursery habitat for species, where estuaries can contribute disproportionately to offshore fisheries productivity (8, 9). The nursery function, in particular, could be affected by a suite of anthropogenic stressors, manifesting in declines to offshore fisheries production. Along the California Current, factors potentially influencing the coastal nursery function include climatic effects, such as El Niño and upwelling (10–12), as well as anthropogenic factors operating on multiple scales, such as ocean warming on ocean basin scales (12–14), or anthropogenic nutrient loading on local to regional scales. The latter can drive the depletion of oxygen from the water column, hypoxia, with negative consequences to aquatic life (2, 14–17).Using a highly altered, albeit regionally important estuarine ecosystem, we examined how anthropogenically induced hypoxia influences vital ecosystem services, such as the maintenance of biodiversity and nursery function, and investigated whether climate indirectly drives these ecosystem services through the modulation of hypoxia. By determining the climatic drivers of hypoxia and its association with fish diversity and nursery function, we are able to show the linkages between human stressors, climate, and ecosystem services.