Adelaide Medical School, the University of Adelaide, Adelaide, SA, Australia.
Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia.
Adv Exp Med Biol. 2020;1298:177-187. doi: 10.1007/5584_2020_574.
Protocadherin-19 (PCDH19) pathogenic variants cause an infantile onset epilepsy syndrome called Girls Clustering Epilepsy due to the vast majority of affected individuals being female. This syndromic name was developed to foster early recognition and diagnosis in infancy. It has, however, sparked debate, as, there are rare males with postzygotic somatic, and therefore, mosaic, PCDH19 pathogenic variants with similar clinical features to females. Conversely, "transmitting" males with germline inherited PCDH19 variants are considered asymptomatic. To date, there has been no standardized neuropsychiatric assessment of males with PCDH19 pathogenic variants. Here, we studied 15 males with PCDH19 pathogenic variants (nine mosaic and six transmitting) aged 2 to 70 years. Our families completed a survey including standardized clinical assessments: Social Responsiveness Scale, Strengths and Difficulties Questionnaire, Behavior Rating Inventory of Executive Function, and Dimensional Obsessive-Compulsive Scale. We identified neuropsychiatric abnormalities in two males with germline PCDH19 possibly pathogenic variants. One had a prior history of a severe encephalopathic illness, which may have been unrelated. We also describe a non-penetrant somatic mosaic male with mosaicism confirmed in blood, but not identified in skin fibroblasts. Our data suggest that transmitting hemizygous males are generally unaffected, in contrast to males with postzygotic somatic mosaic variants who show a similar neuropsychiatric profile to females who are naturally mosaic, due to X-chromosome inactivation. The penetrance of PCDH19 pathogenic variants has been estimated to be 80%. Like females, not all mosaic males are affected. From our small sample, we estimate that males with mosaic PCHD19 pathogenic variants have a penetrance of 85%. With these insights into the male phenotypic spectrum of PCDH19 epilepsy, we propose the new term Clustering Epilepsy (CE). Both affected females and males typically present with infantile onset of clusters of seizures.
原钙黏蛋白 19 （PCDH19）致病性变异导致一种婴儿期发病的癫痫综合征，称为“女孩聚类性癫痫”，因为绝大多数受影响的个体为女性。这个综合征的命名是为了促进婴儿期的早期识别和诊断。然而，这一命名引发了争议，因为极少数男性存在合子后体体细胞、因此是嵌合体 PCDH19 致病性变异，具有与女性相似的临床特征。相反，具有种系遗传 PCDH19 变异的“传递”男性被认为是无症状的。迄今为止，还没有针对 PCDH19 致病性变异男性进行标准化的神经精神评估。在这里，我们研究了 15 名携带 PCDH19 致病性变异（9 名嵌合体和 6 名传递）的男性，年龄在 2 至 70 岁之间。我们的家庭完成了一项包括标准化临床评估的调查：社会反应量表、优势与困难问卷、执行功能行为评定量表和多维强迫症量表。我们在两名具有种系 PCDH19 可能致病性变异的男性中发现了神经精神异常。一名男性有严重脑病的既往病史，可能与变异无关。我们还描述了一名非表现性体嵌合男性，其嵌合体在血液中得到证实，但在皮肤成纤维细胞中未发现。我们的数据表明，传递性半合子男性通常不受影响，与具有合子后体细胞嵌合体变异的男性形成对比，后者由于 X 染色体失活，具有与自然嵌合体女性相似的神经精神特征。PCDH19 致病性变异的外显率估计为 80%。与女性一样，并非所有嵌合体男性都受到影响。根据我们的小样本，我们估计 PCHD19 致病性变异嵌合体男性的外显率为 85%。通过对男性 PCHD19 癫痫表型谱的这些了解，我们提出了新的术语聚类性癫痫（CE）。受影响的女性和男性通常表现为婴儿期发作性癫痫发作群。
