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Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia.
European Journal of Human Genetics ( IF 5.2 ) Pub Date : 2020-05-28 , DOI: 10.1038/s41431-020-0641-9
Diane Doummar 1, 2 , Christel Dentel 3 , Romane Lyautey 4 , Julia Metreau 5 , Boris Keren 6 , Nathalie Drouot 7, 8 , Ludivine Malherbe 4 , Viviane Bouilleret 9 , Jérémie Courraud 7, 8 , Maria Paola Valenti-Hirsch 10 , Lorella Minotti 11 , Blandine Dozieres-Puyravel 12 , Séverine Bär 4 , Julia Scholly 10 , Elise Schaefer 13, 14 , Caroline Nava 6 , Thomas Wirth 15 , Hala Nasser 16, 17 , Marie de Salins 1 , Anne de Saint Martin 18 , Marie Thérèse Abi Warde 18 , Philippe Kahane 11 , Edouard Hirsch 10 , Mathieu Anheim 7, 8, 19 , Sylvie Friant 4 , Jamel Chelly 7, 8, 20 , Cyril Mignot 6, 21, 22 , Gabrielle Rudolf 7, 8, 10, 15
Affiliation  

Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients’ movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.



中文翻译:

双等位基因PDE2A变体:综合征阵发性运动障碍的新病因。

在某些患者中,复杂的运动障碍的原因仍然难以捉摸。据报道一名纯合子错义变体导致PDE2A酶活性急剧下降,其中一名儿童发作性胆囊痉挛伴阵发性运动障碍,并伴有认知障碍和发作间期脑电图异常。在这里,我们报告了三例由三重全外显子组测序鉴定的双等位基因PDE2A变异的新病例。在对照和突变的原代成纤维细胞中对Mitotracker™Red染色后,分析了线粒体网络。回顾性分析了患者运动障碍的录像和表型的完善。我们确定了终止密码子变体c.1180C> T的纯合增益。p。(Gln394 *)在年轻成年人中的兄弟姐妹和复合杂合变异体中的PDE2A:错义c.446C> T;p。(Pro149Leu)和剪接位点变体c。1922 + 5G> A预测并显示产生缺少外显子22的框架外转录本。三名患者均患有认知障碍或发育迟缓。两名年龄最大的患者(分别为9岁和26岁)的表型的特征是儿童发作的难治性阵发性运动障碍,最初由于小儿脑电图异常而被误诊为癫痫。最年轻的患者在4个月大时表现出癫痫发作,在15个月时没有阵发性运动障碍。有趣的是,对PDE2A变体中具有双等位基因变体的成纤维细胞的分析揭示了线粒体网络形态变化。连同先前报道的病例,我们的三名患者证实了双等位基因 两名年龄最大的患者(分别为9岁和26岁)的表型的特征是儿童期难治性阵发性运动障碍,最初由于小儿脑电图异常而被误诊为癫痫病。最年轻的患者在4个月大时表现出癫痫发作,在15个月时没有阵发性运动障碍。有趣的是,对PDE2A变体中具有双等位基因变体的成纤维细胞的分析揭示了线粒体网络形态变化。连同先前报道的病例,我们的三名患者证实了双等位基因 两名年龄最大的患者(分别为9岁和26岁)的表型的特征是儿童期难治性阵发性运动障碍,最初由于小儿脑电图异常而被误诊为癫痫病。最年轻的患者在4个月大时表现出癫痫发作,在15个月时没有阵发性运动障碍。有趣的是,对PDE2A变体中具有双等位基因变体的成纤维细胞的分析揭示了线粒体网络形态变化。连同先前报道的病例,我们的三名患者证实了双等位基因 PDE2A变体中具有双等位基因变体的成纤维细胞的分析揭示了线粒体网络形态变化。连同先前报道的病例,我们的三名患者证实了双等位基因 PDE2A变体中具有双等位基因变体的成纤维细胞的分析揭示了线粒体网络形态变化。连同先前报道的病例,我们的三名患者证实了双等位基因PDE2A变异是导致儿童期难治性阵发性运动障碍并伴有认知障碍的原因,有时与舞蹈性肌张力障碍和发作间期基线脑电图异常或癫痫有关。

更新日期:2020-05-28
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