Megalencephalic leukoencephalopathy with cysts without <i>MLC1</i> defect

Knaap, Marjo S. van der; Lai, Vincent S.; Köhler, Wolfgang; Salih, Mustafa A.; Fonseca, M J; Benke, Tim A.; Wilson, Callum; Jayakar, Parul; Aine, Marjo-Riitta; Dom, L.; Lynch, Bryan; Kálmánchey, R.; Pietsch, P; Errami, Ab; Scheper, Gert C.

doi:10.1002/ana.21980

Cited by 60 publications

(46 citation statements)

References 12 publications

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“…Recessive mutations in MLC1 and GLIALCAM lead to loss of MLC1 function causing indistinguishable clinical phenotype and brain MRI abnormalities in patients 12, 14. In agreement with this, Glialcam ‐null and Mlc1 ‐null mice show largely overlapping neuropathology.…”

Section: Discussionsupporting

confidence: 57%

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Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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ObjectiveMegalencephalic leukoencephalopathy with cysts (MLC) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC1 function. Recessive mutations in either MLC1 or GLIALCAM cause the disease. MLC1 is involved in astrocytic volume regulation; GlialCAM ensures the correct membrane localization of MLC1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam‐null mice for further studies.MethodsWe investigated the consequences of loss of GlialCAM in Glialcam‐null mice and compared GlialCAM developmental expression in mice and men.Results Glialcam‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam‐null astrocytes showed abolished expression of MLC1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC1‐interacting proteins and the volume regulated anion channel LRRC8A was unchanged. In mice, GlialCAM expression increased until 3 weeks and then stabilized. In humans, GlialCAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years.Interpretation Glialcam‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC. GlialCAM expression affects expression of MLC1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.

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Section: Discussionsupporting

confidence: 57%

“…Recessive mutations in both genes cause loss of MLC1 function and an indistinguishable clinical phenotype 12, 14. Dominant, heterozygous GLIALCAM mutations initially lead to the same disease, but improvement occurs afterward and the white matter abnormalities largely disappear 12, 14…”

Section: Introductionmentioning

confidence: 99%

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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“…20,24,26,36 The importance of the volume regulation process in the brain is emphasised by the observation that it does not rely on just one protein or one pathway. Mutations in one protein only lead to partial and sometimes transient dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22] Mutations in MLC1 have been identifi ed in 75% of patients with this disorder. 23,24 No mutations in CLCN2 were reported in the patients without MLC1 mutations. 25 Recently, mutations in HEPACAM (also called GLIALCAM), which encodes the glial cell adhesion molecule (GlialCAM)-a putative auxiliary subunit of both ClC-2 and MLC1 26,27 -were identifi ed in patients without MLC1 mutations.…”

Section: Introductionmentioning

confidence: 99%

Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

Depienne¹,

Bugiani²,

Dupuits³

et al. 2013

The Lancet Neurology

153

204

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SummaryBackground Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confi rmed in human beings. We aimed to defi ne novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifi cally interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis.

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“…This result is similar with the reported incidence of approximately 80% of mutations in MLC1 found by van der Knaap. 7 Further studies in large cohorts are still needed to provide insight into the frequency of positive mutations.…”

Section: Clinical Features Of Chinese Mlc Patientsmentioning

confidence: 99%