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Abstract：
OBJECTIVE: NPRL3-related epilepsy (NRE) is an emerging condition set within the wide GATOR-1 spectrum with a particularly heterogeneous and elusive phenotypic expression. Here, we delineated the genotype-phenotype spectrum of NRE, reporting an illustrative familial case and reviewing pertinent literature.
METHODS: Through exome sequencing (ES), we investigated a 12-year-old girl with recurrent focal motor seizures during sleep, suggestive of sleep-related hypermotor epilepsy (SHE), and a family history of epilepsy in siblings. Variant segregation analysis was performed by Sanger sequencing. All previously published NRE patients were thoroughly reviewed and their electroclinical features were analyzed and compared with the reported subjects.
RESULTS: In the proband, ES detected the novel NPRL3 frameshift variant (NM_001077350.3): c.151_152del (p.Thr51Glyfs*5). This variant is predicted to cause a loss of function and segregated in one affected brother. The review of 76 patients from 18 publications revealed the predominance of focal-onset seizures (67/74-90%), with mainly frontal and frontotemporal (32/67-47.7%), unspecified (19/67-28%), or temporal (9/67-13%) onset. Epileptic syndromes included familial focal epilepsy with variable foci (FFEVF) (29/74-39%) and SHE (11/74-14.9%). Fifteen patients out of 60 (25%) underwent epilepsy surgery, 11 of whom achieved complete seizure remission (11/15-73%). Focal cortical dysplasia (FCD) type 2A was the most frequent histopathological finding.
CONCLUSIONS: We reported an illustrative NPRL3-related epilepsy (NRE) family with incomplete penetrance. This condition consists of a heterogeneous spectrum of clinical and neuroradiological features. Focal-onset motor seizures are predominant, and almost half of the cases fulfill the criteria for SHE or FFEVF. MRI-negative cases are prevalent, but the association with malformations of cortical developments (MCDs) is significant, especially FCD type 2a. The beneficial impact of epilepsy surgery in patients with MCD-related epilepsy further supports the inclusion of brain MRI in the workup of NRE patients.
METHODS: Through exome sequencing (ES), we investigated a 12-year-old girl with recurrent focal motor seizures during sleep, suggestive of sleep-related hypermotor epilepsy (SHE), and a family history of epilepsy in siblings. Variant segregation analysis was performed by Sanger sequencing. All previously published NRE patients were thoroughly reviewed and their electroclinical features were analyzed and compared with the reported subjects.
RESULTS: In the proband, ES detected the novel NPRL3 frameshift variant (NM_001077350.3): c.151_152del (p.Thr51Glyfs*5). This variant is predicted to cause a loss of function and segregated in one affected brother. The review of 76 patients from 18 publications revealed the predominance of focal-onset seizures (67/74-90%), with mainly frontal and frontotemporal (32/67-47.7%), unspecified (19/67-28%), or temporal (9/67-13%) onset. Epileptic syndromes included familial focal epilepsy with variable foci (FFEVF) (29/74-39%) and SHE (11/74-14.9%). Fifteen patients out of 60 (25%) underwent epilepsy surgery, 11 of whom achieved complete seizure remission (11/15-73%). Focal cortical dysplasia (FCD) type 2A was the most frequent histopathological finding.
CONCLUSIONS: We reported an illustrative NPRL3-related epilepsy (NRE) family with incomplete penetrance. This condition consists of a heterogeneous spectrum of clinical and neuroradiological features. Focal-onset motor seizures are predominant, and almost half of the cases fulfill the criteria for SHE or FFEVF. MRI-negative cases are prevalent, but the association with malformations of cortical developments (MCDs) is significant, especially FCD type 2a. The beneficial impact of epilepsy surgery in patients with MCD-related epilepsy further supports the inclusion of brain MRI in the workup of NRE patients.
摘要：
目的：NPRL3相关癫痫（NRE）是GATOR-1广谱范围内的一种新兴疾病，具有特别异质性和难以捉摸的表型表达。这里,我们描绘了NRE的基因型-表型谱，报告一个说明性的家庭病例并回顾相关文献。
方法：通过外显子组测序（ES），我们调查了一名12岁女性在睡眠期间复发性局灶性运动性癫痫发作，提示睡眠相关的运动过度癫痫（SHE），兄弟姐妹有癫痫家族史。通过Sanger测序进行变体分离分析。对所有先前发表的NRE患者进行了全面审查，并分析了他们的电临床特征并与报告的受试者进行了比较。
结果：在先证中，ES检测到新的NPRL3移码变体（NM_001077350.3）：c.151_152del（p。Thr51Glyfs*5）。预计该变体会导致功能丧失，并在一个受影响的兄弟中隔离。对来自18篇出版物的76例患者的回顾显示，局灶性发作性癫痫发作占主导地位（67/74-90％），以额叶和额颞叶为主(32/67-47.7%)，未指定（19/67-28%），或时间（9/67-13％）发作。癫痫综合征包括具有可变病灶的家族性局灶性癫痫（FFEVF）（29/74-39％）和SHE（11/74-14.9％）。60名患者中有15名（25％）接受了癫痫手术，其中11人癫痫发作完全缓解(11/15-73%)。2A型局灶性皮质发育不良（FCD）是最常见的组织病理学发现。
结论：我们报道了一个具有不完全外显率的说明性NRE家族。这种情况包括临床和神经放射学特征的异质性。局灶性发作性运动性癫痫是主要的，几乎一半的病例符合SHE或FFEVF的标准。MRI阴性病例很普遍，但与MCD的关联很重要，尤其是2a型FCD。癫痫手术对MCD相关癫痫患者的有益影响进一步支持在NRE患者的检查中纳入脑MRI。
方法：通过外显子组测序（ES），我们调查了一名12岁女性在睡眠期间复发性局灶性运动性癫痫发作，提示睡眠相关的运动过度癫痫（SHE），兄弟姐妹有癫痫家族史。通过Sanger测序进行变体分离分析。对所有先前发表的NRE患者进行了全面审查，并分析了他们的电临床特征并与报告的受试者进行了比较。
结果：在先证中，ES检测到新的NPRL3移码变体（NM_001077350.3）：c.151_152del（p。Thr51Glyfs*5）。预计该变体会导致功能丧失，并在一个受影响的兄弟中隔离。对来自18篇出版物的76例患者的回顾显示，局灶性发作性癫痫发作占主导地位（67/74-90％），以额叶和额颞叶为主(32/67-47.7%)，未指定（19/67-28%），或时间（9/67-13％）发作。癫痫综合征包括具有可变病灶的家族性局灶性癫痫（FFEVF）（29/74-39％）和SHE（11/74-14.9％）。60名患者中有15名（25％）接受了癫痫手术，其中11人癫痫发作完全缓解(11/15-73%)。2A型局灶性皮质发育不良（FCD）是最常见的组织病理学发现。
结论：我们报道了一个具有不完全外显率的说明性NRE家族。这种情况包括临床和神经放射学特征的异质性。局灶性发作性运动性癫痫是主要的，几乎一半的病例符合SHE或FFEVF的标准。MRI阴性病例很普遍，但与MCD的关联很重要，尤其是2a型FCD。癫痫手术对MCD相关癫痫患者的有益影响进一步支持在NRE患者的检查中纳入脑MRI。
