90%到95% 肌萎缩性侧索硬化症 病例是“零星的”, meaning these patients had no clear family history of the condition, and therefore no indication that they were at risk. A new study by investigators at University of Utah Health shows that approximately one-fifth of these cases do have signs of a genetic predisposition toward the disease: they carry detrimental mutations associated with the familial form of 肌萎缩性侧索硬化症.
最近发表于 神经学, the findings highlight a new appreciation for the role of genetics in 肌萎缩性侧索硬化症, which could help scientists better understand the causes of disease and bring forth new approaches for caring for this subset of patients.
"Our results highlight that genetic factors play a significant role in the disease, which is important in an era of genetic-focused treatments," 萨默·吉布森，m.s.D., an 肌萎缩性侧索硬化症 specialist at the Clinical Neurosciences Center 在大发娱乐.
Gibson was co-first author on the study together with M.D./Ph.D. 学生乔纳森·唐尼. Lynn Jorde博士.D., chair of human genetics, and 斯蒂芬·普斯特，硕士.D., Dr. 地中海., chair of neurology 在大发娱乐, are co-senior authors.
肌萎缩性侧索硬化症, also called Lou Gehrig's disease, causes nerve cells in the brain and spinal cord to degenerate. 病人 gradually lose the ability to speak, 吞下, 和呼吸, typically living for three to five years following symptom onset.
Previous studies had hinted that genetic factors contributed to anywhere from 11 to 27 percent of sporadic 肌萎缩性侧索硬化症 cases. Those estimates were based on the discovery of rare genetic anomalies in some of these patients. But these studies did not investigate whether the DNA changes impacted the function of the genes, information that is necessary for knowing whether the variations are likely responsible for the disease.
Gibson and colleagues addressed the question by analyzing the genomes of 87 patients with sporadic 肌萎缩性侧索硬化症. 特别是, they carefully examined 33 genes linked to the disease, looking for variations in DNA sequence that are rarely found in the general population. Advanced software tools predicted whether the changes would break the gene, for example by disrupting the enzymatic function of the protein made by the gene.
Among this 肌萎缩性侧索硬化症 patient population, a relatively high proportion, 17 percent (15 individuals) had rare, deleterious genetic defects in genes linked to the disease. By comparison, just 4 percent of healthy controls (13 of 324) carried mutations in this category. The results support the idea that these genetic factors increase the risk for developing 肌萎缩性侧索硬化症, even among patients with the sporadic form of the disease.
"Among patients with no clear family history of 肌萎缩性侧索硬化症, we are finding the same genes are affected as those who do have familial 肌萎缩性侧索硬化症,约德说。. "These results blur the line between the two categories of disease."
Of the 19 rare and deleterious mutations found in the sporadic 肌萎缩性侧索硬化症 population, five had never before been described. Experimental work will need to be done to verify the damaging effects of these mutations.
The fact that healthy patients also carry some of these mutations may demonstrate that although the genetic changes likely increase the risk for developing 肌萎缩性侧索硬化症, they do not guarantee that the disease will arise. Although Gibson points out that it is possible that some of these healthy patients could still develop 肌萎缩性侧索硬化症 later in life.
"This study contributes to our increasing knowledge that DNA variants in some genes may not cause disease, but greatly increase the risk to develop the disease in concert with other genetic and environmental factors,普尔斯特解释道。.
"We have come a long way in our understanding of 肌萎缩性侧索硬化症 but we still have a lot to learn. The causes for the vast majority of 肌萎缩性侧索硬化症 cases are still unknown," 道妮 adds.
The team is continuing to search for additional genes that increase susceptibility for 肌萎缩性侧索硬化症, and are investigating how environmental factors might contribute to the disease.
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"The evolving genetic risk for sporadic 肌萎缩性侧索硬化症发表在网上 神经学 2017年6月21日. 除了吉布森, 道妮, Jorde和Pulst, co-authors are Spyridoula Tsetsou, 朱莉Feusier, 卡拉菲格罗亚, and Mark Bronberg for University of Utah Health.
The research reported in this publication was supported in part by Target 肌萎缩性侧索硬化症 and by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1TR001067 and TL1TR001066. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.