Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.
Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/−). Survival analysis of 84 mice showed that in gba+/−//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.
Background and study aims Gastric outlet obstruction (GOO) is common in the late stage of many malignant tumors of the digestive system. Endoscopic ultrasound (EUS)-guided gastroenterostomy (EUS-GE) is commonly used for palliative treatment of malignant GOO. The objective of this study was to investigate the safety, efficacy, and prognosis of EUS-GE in treatment of malignant GOO in Chinese patients.
Patients and methods This was a retrospective, single-center study with 36 consecutive patients with malignant GOO who were treated with EUS-GE. The main outcome measures were technical success rate, clinical success rate, incidence of adverse events (AEs), and median survival time.
Results A total of 36 patients with malignant GOO underwent double-balloon-assisted EUS-GE between March 2017 and June 2019 in our hospital. GOO occurred mainly in elderly men (mean age 69.0 years, M:F 0.89). The most common etiology of GOO was pancreatic cancer (41.7 %). The most common obstruction site was the second part of the duodenum (63.9 %). The technical success rate was 100 % (36/36). The clinical success rate was 94.4 % (34/36). Median time for the total procedure was 52 minutes (range 34 – 156 min). Median time for determination of puncture site was 20 minutes (range 15 – 28 min). Median time between puncture and successful delivery of the stent was 38 minutes (range 19 – 128 min). The GOOSS score was 0.2 before EUS-GE. The GOO Scoring System (GOOSS) score was 2.2 at 15 days after the EUS-GE (P = 0.001). The GOOSS score was still higher than 2 during a median follow-up period of 89 days. AEs were observed in nine patients (25.0 %) and 13 total AEs occurred. One patient died as a result of delayed stent migration and bleeding. Mean length of hospital stay was 5.8 ± 4.7 days. The median survival period was 103 days. The rate of GOO recurrence was 2.7 % (1/36).
Conclusion EUS-GE was associated with increased safety and efficacy for treatment of malignant GOO in Chinese Mainland.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.