Late onset Lafora disease and novel EPM2A mutations: Breaking paradigms
Late onset Lafora disease and novel EPM2A mutations: Breaking paradigms
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DOI：
10.1016/j.eplepsyres.2014.08.017
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发表时间：
2014-11-01
影响因子：
2.2
通讯作者：
Martinez-Juarez, Iris E.
中科院分区：
文献类型：
--
作者：
Jara-Prado, Aurelio;Ochoa, Adriana;Martinez-Juarez, Iris E.
拉福拉病(LD)是一种常染色体隐性遗传性进行性肌阵挛癫痫，具有典型的青春期刺激敏感型癫痫发作。患者通常在25岁之前迅速恶化，出现痴呆症、共济失调、植物衰竭和死亡。LD是由EPM2A或EPM2B基因纯合突变引起的。我们发现了EPM2A的四个新突变--三个位于外显子4(Q247X，H265R G279C)和一个位于外显子1(Y86D)-以及一个先前描述的外显子4(R241X)突变。这5个EPM2A突变是在4个首发病例和受影响亲属中发现的。例1为外显子4的H265R和R241X双重杂合子，例2为外显子4的Q247X纯合子。例3为外显子1的Y86D纯合子，但其患病兄弟的相同突变表现为不典型的早幼年发病。我们首次描述了患者4和她的三个姐妹的EPM2A缺乏性LD发病较晚且进展缓慢，她们在外显子4上存在R241X和G279C双重杂合子。在这些姐妹中，癫痫发作开始较晚，年龄在21-28岁之间，患者年龄超过30岁时进展缓慢。我们的观察表明，EPM2A缺陷型LD的表型变化，如较早的儿童或青少年或较晚的成人起病，病程较快或较慢，取决于与EPM2A突变的致病性或外显子位置分开的第二个修饰因素。患者的遗传背景或环境因素中的修饰基因可能影响患者的发病年龄和LD的快速或缓慢进展。(C)2014爱思唯尔B.V.保留所有权利。
Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy with classic adolescent onset of stimuli sensitive seizures. Patients typically deteriorate rapidly with dementia, ataxia, vegetative failure and death by 25 years of age. LD is caused by homozygous mutations in EPM2A or EPM2B genes. We found four novel mutations in EPM2A - three in exon 4 (Q247X, H265R G279C) and one in exon 1 (Y86D) - and a previously described mutation in exon 4 (R241X). These five EPM2A mutations were found in four index cases and affected relatives. Patient 1 with classic LD was doubly heterozygous for H265R and R241X in exon 4; while Patient 2, who also had classic LD, was homozygous for Q247X in exon 4. Patient 3 with classic LD was homozygous for Y86D in exon 1, but the same mutation in his affected brother manifested an atypical earlier childhood onset. For the first time, we describe a later onset and slower progression of EPM2A-deficient LD seen in Patient 4 and her three sisters who were doubly heterozygous for R241X and G279C in exon 4. In these sisters, seizures started later at 21 to 28 years of age and progressed slowly with patients living beyond 30 years of age. Our observations suggest that variations in phenotypes of EPM2A-deficient LD, like an earlier childhood or adolescent or later adult onset with a rapid or slower course, depend on a second modifying factor separate from pathogenicity or exon location of EPM2A mutations. A modifying gene amongst the patient's genetic background or environmental factors may condition age of onset and rapid or slow progression of LD. (C) 2014 Elsevier B.V. All rights reserved.