Identification in Chinese patients with GLIALCAM mutations of megalencephalic leukoencephalopathy with subcortical cysts and brain pathological study on Glialcam knock-in mouse models

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Zhen Shi^1,2, Hui-Fang Yan^1,2, Bin-Bin Cao^1,3

¹Department of Pediatrics, Peking University First Hospital, No. 1 Xi'an Men Street, West District, Beijing, 100034, China.

World Journal of Pediatrics : WJP

|August 3, 2019

Abstract

Background:

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.

Methods:

Clinical information and peripheral venous blood were collected from six families. Genetic analysis was performed by Sanger sequencing of GLIALCAM. Glialcam^Arg92Trp/+ and Glialcam^{Lys68Met/Thr132Asn} 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.

Results:

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^Arg92Trp/+ and Glialcam^{Lys68Met/ Thr132Asn} 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^{Lys68Met/ Thr132Asn} mouse model was heavier than that of the Glialcam^Arg92Trp/+ mouse model. Decreased expression of Glialcam in Glialcam^Arg92Trp/+ and Glialcam^{Lys68Met/ Thr132Asn} mice may contribute to the vacuolization.

Conclusions:

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.

Insights

This study identifies a novel GLIALCAM mutation in Megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare neurological disorder. Mouse models with different inheritance patterns revealed distinct brain pathologies, correlating with patient phenotypes.

Area of Science:

Neurogenetics
Molecular Neurology
Rare Diseases

Background:

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological disorder.
MLC is caused by mutations in MLC1 or GLIALCAM genes, presenting with macrocephaly and developmental delays.
Genetic mutations lead to varied prognoses and distinct white matter abnormalities on MRI.

Purpose of the Study:

To characterize the clinical and genetic features of MLC patients with GLIALCAM mutations.
To investigate brain pathology and prognosis in mouse models of MLC with different inheritance modes.
To establish novel mouse models for studying GLIALCAM-related leukoencephalopathies.

Main Methods:

Collected clinical data and blood samples from six families with MLC.
Performed Sanger sequencing to identify GLIALCAM mutations.
Generated Glialcam mouse models (Arg92Trp/+ and Lys68Met/Thr132Asn) to mimic patient mutations.
Analyzed brain pathologies in mouse models at various time points.

Main Results:

Identified five patients with MLC2B (autosomal dominant) and one with MLC2A (autosomal recessive) due to GLIALCAM mutations.
Discovered a novel GLIALCAM mutation (c.275C>G (p.Arg92Pro)).
MLC2A patient showed disease regression; MLC2B patients remained stable or improved.
Mouse models exhibited progressive white matter vacuolization, with more severe pathology in the autosomal recessive model.
Decreased Glialcam expression correlated with observed vacuolization.

Conclusions:

A novel GLIALCAM mutation expands the known spectrum of mutations causing MLC.
Generated the first Glialcam mouse model for autosomal recessive inheritance and a new model for autosomal dominant inheritance.
Mouse models accurately reflect patient phenotypes, confirming the pathogenicity of GLIALCAM mutations and their varying inheritance patterns.

Read full analysis

Keywords:

GLIALCAM Knock-in mouse model Macrocephaly Megalencephalic leukoencephalopathy with subcortical cysts Vacuolization

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