Department of Pediatrics, Peking University First Hospital, No. 1 Xi'an Men Street, West District, Beijing, 100034, China.
Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Peking University First Hospital, Beijing, 100034, China.
World J Pediatr. 2019 Oct;15(5):454-464. doi: 10.1007/s12519-019-00284-w. Epub 2019 Aug 1.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis, characterized by macrocephaly, delayed motor and cognitive development, and bilateral abnormal signals in cerebral white matter (WM) with or without cysts on magnetic resonance imaging (MRI). This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance.
Clinical information and peripheral venous blood were collected from six families. Genetic analysis was performed by Sanger sequencing of GLIALCAM. Glialcam and Glialcam mouse models were generated based on mutations from patients (c.274C>T(p.Arg92Trp) (c.203A>T(p.Lys68Met), and c.395C>A (p.Thr132Asn))). Brain pathologies of the mouse models at different time points were analyzed.
Six patients were clinically diagnosed with MLC. Of the six patients, five (Pt1-Pt5) presented with a heterozygous mutation in GLIALCAM (c.274C>T(p.Arg92Trp) or c.275G>C(p.Arg92Pro)) and were diagnosed with MLC2B; the remaining patient (Pt6) with two compound heterozygous mutations in GLIALCAM (c.203A>T (p.Lys68Met) and c.395C>A (p.Thr132Asn)) was diagnosed with MLC2A. The mutation c.275C>G (p.Arg92Pro) has not been reported before. Clinical manifestations of the patient with MLC2A (Pt6) progressed with regression, whereas the course of the five MLC2B patients remained stable or improved. The Glialcam and Glialcam mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months, respectively. At 9 months, the vacuolization of the Glialcam mouse model was heavier than that of the Glialcam mouse model. Decreased expression of Glialcam in Glialcam and Glialcam mice may contribute to the vacuolization.
Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation, expanding the spectrum of GLIALCAM mutations. The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated. The two mouse models with different modes of inheritance showed different degrees of brain pathological features, which were consistent with the patients' phenotype and further confirmed the pathogenicity of the corresponding mutations.
巨脑性脑白质营养不良伴皮质下囊肿（MLC）是一种罕见的神经退行性疾病，由 MLC1 或 GLIALCAM 的突变引起，呈常染色体隐性或显性遗传，具有不同的预后，其特征为大头畸形、运动和认知发育迟缓，以及大脑白质（WM）双侧异常信号，伴或不伴囊肿磁共振成像（MRI）。本研究旨在揭示具有 GLIALCAM 突变的 MLC 患者的临床和遗传特征，并探讨不同遗传方式的小鼠模型的脑病理学特征和预后。
收集六个家庭的临床信息和外周静脉血。通过 Sanger 测序对 GLIALCAM 进行遗传分析。根据患者的突变（c.274C>T(p.Arg92Trp)（c.203A>T(p.Lys68Met）和 c.395C>A(p.Thr132Asn))，生成 Glialcam 和 Glialcam 小鼠模型。分析不同时间点小鼠模型的脑病理学特征。
六个患者被临床诊断为 MLC。其中五名患者（Pt1-Pt5）存在 GLIALCAM 杂合突变（c.274C>T(p.Arg92Trp)或 c.275G>C(p.Arg92Pro)），被诊断为 MLC2B；另一名患者（Pt6）存在 GLIALCAM 两种复合杂合突变（c.203A>T(p.Lys68Met)和 c.395C>A(p.Thr132Asn)），被诊断为 MLC2A。突变 c.275C>G(p.Arg92Pro)以前未被报道过。MLC2A 患者（Pt6）的临床表现进行性恶化，而 5 名 MLC2B 患者的病程保持稳定或改善。Glialcam 和 Glialcam 小鼠模型在 1 月龄时在前连合 WM 出现空泡化，在 3 和 6 月龄时在小脑 WM 出现空泡化，在 9 月龄时，Glialcam 小鼠模型的空泡化比 Glialcam 小鼠模型更严重。Glialcam 和 Glialcam 小鼠中 Glialcam 表达减少可能导致空泡化。
对 MLC 和 GLIALCAM 突变患者的临床和遗传特征进行分析，揭示了一种新的突变，扩大了 GLIALCAM 突变谱。首次建立了常染色体隐性遗传的 Glialcam 小鼠模型和新的常染色体显性遗传的 Glialcam 小鼠模型。两种具有不同遗传方式的小鼠模型表现出不同程度的脑病理学特征，与患者的表型一致，进一步证实了相应突变的致病性。
