Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterised by chronic white matter oedema. The disease has an infantile onset and leads to slow neurological deterioration in most cases, but, surprisingly, some patients recover. The first disease gene, MLC1, identified in 2001, is mutated in 75% of patients. At that time, nothing was known about MLC1 protein function and the pathophysiology of MLC. More recently, HEPACAM (also called GLIALCAM) has been identified as a second disease gene. GlialCAM serves as an escort for MLC1 and the chloride channel CLC2. The defect in MLC1 has been shown to hamper the cell volume regulation of astrocytes. One of the most important consequences involves the potassium siphoning process, which is essential in brain ion and water homoeostasis. An understanding of the mechanisms of white matter oedema in MLC is emerging. Further insight into the specific function of MLC1 is necessary to find treatment targets.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(12)70192-8.pdf

Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis

Mutations in the MLC1 gene are responsible for one form of the neurological disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC). The disease is a type of vacuolating myelinopathy. The biochemical properties and the function of the MLC1 protein are unknown. To characterize MLC1, we generated polyclonal antibodies. The MLC1 protein was detected in the brain, assembled into higher molecular complexes, as assessed by assembly-dependent trafficking assays. In situ hybridization and immunohistochemistry were used to determine MLC1 localization within the adult mouse brain. MLC1 was expressed in neurons, detected preferentially in particular axonal tracts. This expression pattern correlates with the major phenotype observed in the disease. In addition, it was expressed in some astrocytes, concentrating in Bergmann glia, the astrocyte end-feet membranes adjacent to blood vessels and in astrocyte-astrocyte membrane contact regions. Other neuronal barriers, such as the ependyma and the pia mater, were also positive for MLC1 expression. MLC1 was detected in vivo and in heterologous systems at the plasma membrane. MLC mutations impaired folding, and the defect was corrected in vitro by addition of curcumin, a Ca(2+)-ATPase inhibitor. In summary, this study provides an explanation as to why mutations in MLC1 provoke the disease and points to a possible therapy for some patients.

/pdf/localization-and-functional-analyses-of-the-mlc1-protein-4ikrxf1y1j.pdf

Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive cerebral white matter disorder in children. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC is caused by mutations in the gene MLC1, which encodes a novel protein, MLC1. Since the first report, 50 mutations in this gene have been found. Mutations occur throughout the entire coding region and include all different types: 11 splice-site mutations; one nonsense mutation; 24 missense mutations; and 14 deletions and insertions. Until now, six polymorphisms within the coding sequence of MLC1 had been reported. In about 20% of the patients with a typical clinical and MRI picture, no mutations in the MLC1 gene are found. Several of the families, in which no mutations are found, also do not show linkage with the MLC1 locus, which suggests a second gene involved in MLC. The absence of mutations may also be the consequence of performing standard mutation analysis that can miss heterozygous deletions, mutations in the promoter, 3' and 5' untranslated regions (UTRs), and intron mutations, which may influence the amino acid composition of the end product. In this work we describe 13 novel mutations, including those found with extended mutation analysis on MLC patients. This study shows that extended mutation analysis is a valuable tool to identify at least some of the missing mutations. Therefore, we suggest extended mutation analysis for the MLC1 gene, if no mutations are found during standard analysis.

Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disease characterized by early infantile macrocephaly and delayed motor and cognitive deterioration. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen cerebral white matter and subcortical cysts. On follow-up, atrophy ensues. Approximately 80% of MLC patients have mutations in MLC1. We report 16 MLC patients without MLC1 mutations. Eight retained the classical clinical and MRI phenotype. The other 8 showed major MRI improvement. They lacked motor decline. Five had normal intelligence; 3 displayed cognitive deficiency. In conclusion, 2 phenotypes can be distinguished among the non-MLC1 mutated MLC patients: a classical and a benign phenotype.

Megalencephalic Leukoencephalopathy with Cysts without MLC1 Defect Two Phenotypes

Objective Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. Methods A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. Results In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. Conclusion This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.

Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.

To the Editor:

In a recent article, Gorospe et al.1 describe the occurrence of a leukoencephalopathy, commonly called megalencephalic leukoencephalopathy with subcortical cysts (MLC), in an Asian-Indian group, the Agarwals. They describe the clinical and MRI findings in the patients and report on the founder mutation in the MLC1 gene, responsible for the disease in this community, which is an insertion of a cytosine-residue (C-residue) in a stretch of six C-residues in exon 2.

The authors refer to …

Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation

Objectives Listeria meningoencephalitis (LMM) is very rare in healthy children. We aimed to assess the clinical features, differential diagnosis, treatment options, and outcomes of LMM in immunocompetent children through a retrospective study. Methods The clinical symptoms, laboratory findings, imaging features, antibiotic use, and metagenomic next-generation sequencing (mNGS) results of the cerebrospinal fluid (CSF) were obtained from immunocompetent children who were diagnosed with LMM and admitted to the Xi'an Children's Hospital from May 2018 to July 2020. Results The data from 8 immunocompetent children were retrospectively analyzed in this study. The cohort included data from 5 males and 3 females who were aged from 1 year and 7 months to 16 years and 6 months. A total of 4 patients had chilled food before onset. The complications included hyponatremia (3/8), hydrocephalus (2/8), and hemophagocytic syndrome (1/8). In total, 8 patients were diagnosed with Listeria monocytogenes by positive CSF culture or mNGS results. The positive rate of CSF culture was 62.5% (5/8). A total of 5 patients conducted CSF mNGS, and the results of the mNGS were positive in 4 patients (80%, 4/5) and suspected in 1 patient. A total of 7 patients changed their therapeutic regimen to combined antibacterial therapies that included linezolid and meropenem (5/8), or ampicillin and meropenem (2/8). A total of 5 patients had favorable outcomes (Glasgow Outcome Scale, GOSE = 5) while two patients had unfavorable outcomes (GOSE = 1) and were complicated with hyponatremia and hydrocephalus. Conclusions Listeria meningoencephalitis (LMM) can occur in children with normal immune function and is commonly mistaken for other central nervous system infections. L. monocytogenes can be quickly and accurately detected by mNGS. Hyponatremia and hydrocephalus may indicate unfavorable outcomes.

A Retrospective Study of Rare Listeria Meningoencephalitis in Immunocompetent Children in China

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Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation

A Retrospective Study of Rare Listeria Meningoencephalitis in Immunocompetent Children in China