Background-Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease.

No abstract

No abstract

The ABCs of PXE Pseudoxanthoma elasticum (PXE) is a genetic disorder caused by mutations in ABCC6 that is characterized by calcium deposition outside of the skeletal system, specifically in the blood vessels, skin, and eyes. Using patient-derived fibroblasts and genetic knockout mouse models, Ziegler et al. demonstrate that ABCC6 mutant cells are osteogenic and that loss of ABCC6 reduces pyrophosphate, an inhibitor of calcification. In mice, ectopic calcification was seen only when ABCC6 was deleted jointly from the liver and from Wnt1+ cells, suggesting systemic and local contributions to the phenotype. Treating mice and cells with a tissue-nonspecific alkaline phosphatase (TNAP) inhibitor prevented pyrophosphate degradation and ectopic calcification progression. Biallelic mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), a disease characterized by calcification in the skin, eyes, and blood vessels. The function of ATP-binding cassette C6 (ABCC6) and the pathogenesis of PXE remain unclear. We used mouse models and patient fibroblasts to demonstrate genetic interaction and shared biochemical and cellular mechanisms underlying ectopic calcification in PXE and related disorders caused by defined perturbations in extracellular adenosine 5′-triphosphate catabolism. Under osteogenic culture conditions, ABCC6 mutant cells calcified, suggesting a provoked cell-autonomous defect. Using a conditional Abcc6 knockout mouse model, we excluded the prevailing pathogenic hypothesis that singularly invokes failure of hepatic secretion of an endocrine inhibitor of calcification. Instead, deficiency of Abcc6 in both local and distant cells was necessary to achieve the early onset and penetrant ectopic calcification observed upon constitutive gene targeting. ABCC6 mutant cells additionally had increased expression and activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme that degrades pyrophosphate, a major inhibitor of calcification. A selective and orally bioavailable TNAP inhibitor prevented calcification in ABCC6 mutant cells in vitro and attenuated both the development and progression of calcification in Abcc6−/− mice in vivo, without the deleterious effects on bone associated with other proposed treatment strategies.