Neurology and Neurometabolic Departments, Cairo University Children Hospital, Cairo, Egypt.
Stem Cell Research Laboratory, Centre for Advanced Sciences-National Research Centre, Cairo, Egypt.
Pediatr Neurol. 2014 Feb;50(2):140-8. doi: 10.1016/j.pediatrneurol.2013.10.008. Epub 2013 Oct 24.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and genetically heterogeneous cerebral white matter disease. Clinically, it is characterized by macrocephaly, developmental delay, and seizures. We explore the clinical spectrum, neuroimaging characteristics, and gene involvement in the first patients with megalencephalic leukoencephalopathy with subcortical cysts described from Egypt.
Six patients were enrolled from three unrelated families. Patient inclusion criteria were macrocephaly, developmental delay, normal urinary organic acids, and brain imaging of diffuse cerebral white matter involvement. Direct sequencing of the MLC1 gene in patients' families and GliaCAM in one questionable case was performed using BigDye Terminator cycle sequencing.
Clinical heterogeneity, both intra- and interfamilial, was clearly evident. Developmental delays ranged from globally severe or moderate to mild delay in achieving walking or speech. Head circumference above the ninety-seventh percentile was a constant feature. Neuroimaging featured variability in white matter involvement and subcortical cysts. However, findings of posterior fossa changes and brain stem atrophy were frequently (66.6%) identified in these Egyptian patients. Discrepancy between severe brain involvement and normal mental functions was evident, particularly in patients from the third family. MLC1 mutations were confirmed in all patients. Deletion/insertion mutation in exon 11 (c.908-918delinsGCA, p.Val303 Gly fsX96) was recurrent in two families, whereas a missense mutation in exon 10 (c.880 C > T, p.Pro294Ser) was identified in the third family.
This report extends our knowledge of the clinical and neuroimaging features of megalencephalic leukoencephalopathy with subcortical cysts. It confirms the apparent lack of selective disadvantage of MLC1 mutations on gamete conception and transmission as supported by the presence of multiple affected siblings in Egyptian families.
巨脑性脑白质营养不良伴皮质下囊肿（MLC）是一种罕见的、遗传异质性的脑白质疾病。临床上，其特征为大头畸形、发育迟缓及癫痫发作。我们对首次从埃及描述的患有巨脑性脑白质营养不良伴皮质下囊肿的患者的临床谱、神经影像学特征和基因进行了研究。
从三个不相关的家庭中纳入了 6 名患者。患者纳入标准为大头畸形、发育迟缓、尿液有机酸酸正常、大脑影像学显示弥漫性脑白质受累。对患者家系的 MLC1 基因和一个可疑病例的 GliaCAM 进行直接测序，采用 BigDye Terminator 循环测序。
明显存在家族内和家族间的临床异质性。发育迟缓范围从全面严重或中度到轻度，表现为行走或言语延迟。头围一直高于第 97 百分位。神经影像学表现为白质受累和皮质下囊肿的变化。然而，在这些埃及患者中，后颅窝改变和脑干萎缩的发现常常（66.6%）被识别。严重的脑受累和正常的精神功能之间的差异明显，特别是在第三个家系的患者中。所有患者均证实存在 MLC1 突变。在两个家系中，第 11 外显子的缺失/插入突变（c.908-918delinsGCA，p.Val303 GlyfsX96）是重复的，而第三个家系则发现了第 10 外显子的错义突变（c.880C>T，p.Pro294Ser）。
本报告扩展了我们对巨脑性脑白质营养不良伴皮质下囊肿的临床和神经影像学特征的认识。它证实了 MLC1 突变对配子发生和传递没有明显的选择劣势，这一点得到了埃及家系中多个受影响的兄弟姐妹的支持。
