Romasko Edward J, DeChene Elizabeth T, Balciuniene Jorune, Akgumus Gozde T, Helbig Ingo, Tarpinian Jennifer M, Keena Beth A, Vogiatzi Maria G, Zackai Elaine H, Izumi Kosuke, Massey Shavonne L, Tayoun Ahmad N Abou
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
Epilepsy Res. 2018 Sep;145:89-92. doi: 10.1016/j.eplepsyres.2018.06.008. Epub 2018 Jun 18.
Heterozygous de novo or inherited pathogenic variants in the PCDH19 gene cause a spectrum of neurodevelopmental features including developmental delay and seizures. PCDH19 epilepsy was previously known as "epilepsy and mental retardation limited to females", since the condition almost exclusively affects females. It is hypothesized that the co-existence of two populations of neurons, some with and some without PCDH19 protein expression, results in pathologically abnormal interactions between these neurons, a mechanism also referred to as cellular interference. Consequently, PCDH19-related epilepsies are inherited in an atypical X-linked pattern, such that hemizygous, non-mosaic, 46,XY males are typically unaffected, while individuals with a disease-causing PCDH19 variant, mainly heterozygous females and mosaic males, are affected. As a corollary to this hypothesis, an individual with Klinefelter syndrome (KS) (47,XXY) who has a heterozygous disease-causing PCDH19 variant should develop PCDH19-related epilepsy. Here, we report such evidence: - a male child with KS and PCDH19-related epilepsy - supporting the PCDH19 cellular interference disease hypothesis.
PCDH19基因的杂合性新生或遗传性致病变异会导致一系列神经发育特征，包括发育迟缓与癫痫发作。PCDH19癫痫以前被称为“仅限于女性的癫痫和智力障碍”，因为这种病症几乎只影响女性。据推测，两类神经元的共存，即一些表达PCDH19蛋白而另一些不表达的神经元，会导致这些神经元之间出现病理上的异常相互作用，这一机制也被称为细胞干扰。因此，PCDH19相关癫痫以非典型的X连锁模式遗传，即半合子、非嵌合的46,XY男性通常不受影响，而携带致病PCDH19变异的个体，主要是杂合子女性和嵌合男性，则会受到影响。作为这一假设的必然结果，患有克兰费尔特综合征（KS）（47,XXY）且携带杂合致病PCDH19变异的个体应该会患上PCDH19相关癫痫。在此，我们报告这样一个证据：一名患有KS且患有PCDH19相关癫痫的男童，这支持了PCDH19细胞干扰疾病假说。
