Is juvenile myoclonic epilepsy an autosomal recessive disease?
Is juvenile myoclonic epilepsy an autosomal recessive disease?
复制标题
青少年肌阵挛性癫痫是常染色体隐性遗传病吗？
作者：
D. Greenberg;M. Durner;A. Delgado;D. Janz
Panayiotopoulos和Obeid [l]收集了一组罕见的青少年肌阵挛性癫痫家族（UME）。该数据集有可能在阐明JME的遗传学方面非常有用。然而，他们的分析声称建立常染色体隐性遗传的JME包含了一些方法上的问题，其中一些讨论如下。首先，使用简单分离分析进行分析。作者没有给出分离分析的细节，但“简单分离分析”通常意味着核心家庭，没有近亲繁殖和哈迪-温伯格平衡。这些条件显然没有得到满足。其次，没有迹象表明如何确定谱系或如何进行确定偏倚校正。未能纠正确定偏倚或采用不严格的方案确定可能导致完全虚假的结果12，31。第三，在试图校正发病年龄时，所有小于14岁的患病兄弟姐妹都从分析中排除，但只有大约一半的患病兄弟姐妹被排除。因此，这一年龄组的隔离比率为1.0-只包括受影响的人，使结果偏高。适当的发病年龄校正应包括受影响的年龄相关概率。第四，隔离比据说在0.12和0.18之间，后一个数字包含了"发病校正年龄”。作者指出，这“不是特别接近0.25的理想比率。. .”检验最高值0.18是否与0.25有显著差异是适当的。缺乏兄弟姐妹或社会因素的临床信息解释这种差异的建议不能用来证明隔离比“真的”是0.25。家族“看起来”常染色体隐性遗传并不构成支持性证据。最后，提交人说，“有165个兄弟姐妹。. .在17个家族的20个兄弟姐妹中”这意味着几个“兄弟姐妹”是被视为独立的较大谱系的一部分。如果这样做了，那么被认为是独立的家庭将相互关联。在先前报道的家族研究中，我们可以拒绝JME的完全外显隐性遗传模式，即使临床上正常的家庭成员与异常脑电图（EEG）被认为是“受影响”[4}。我们不能拒绝两个基因位点相互作用产生异常脑电图和/或癫痫的模型。此外，已报道的JME与6号染色体的连锁
Panayiotopoulos and Obeid [l] have collected a rare set of families with juvenile myoclonic epilepsy UME). This data set has the potential to be very useful in elucidating the genetics of JME. However, their analysis claiming to establish autosomal recessive inheritance for JME contains a number of methodological problems, some of which are discussed below. First, simple segregation analysis was used for the analysis. The authors do not give details of the segregation analysis, but “simple segregation analysis” usually implies nuclear families, no inbreeding, and Hardy-Weinberg equilibrium. These conditions are apparently not met. Second, there is no indication how the pedigrees were ascertained or how ascertainment bias correction was carried out. Failure to correct the ascertainment bias or ascertaining with a nonrigorous protocol can lead to totally spurious results 12, 31. Third, in attempting to correct for age of onset, all ma$ jicted siblings younger than 14 years were eliminated from the analysis, but only about one-half of aflected siblings were eliminated. As a result, the segregation ratio for this age group was 1.0-only affected people were included, biasing the results upward. A proper age-of-onset correction would include the age-dependent probability of being affected. Fourth, the segregation ratio is said to be between 0.12 and 0.18, the latter figure incorporating the <‘age of onset correction.” The authors state that this is “not particularly close to the ideal ratio of 0.25 . . .” It would be proper to test whether the highest figure of 0.18 is signlficantly different from 0.25. Suggestions that a lack of clinical information on siblings or social factors account for this difference cannot be used to argue that the segregation ratio “really” is 0.25. Families “looking” autosomal recessive do not constitute supporting evidence. Finally, the authors state that “there were 165 siblings . . . in the 20 sibships of the 17 families.” This implies that several of the “sibships” were parts of larger pedigrees that were treated as independent. If this was done, then families assumed to be independent would be related to each other. In a previously reported family study, we could reject a fully penetrant recessive mode of inheritance for JME, even when clinically normal family members with abnormal electroencephalograms (EEGs) were considered “affected” [4}. We could not reject a model in which two genetic loci interact to produce abnormal EEGs andor epilepsy. Furthermore, the reported linkage of JME with the chromosome 6