An unusually mild presentation of megalencephalic leukoencephalopathy with subcortical cysts

Kocaman, Gulsen; Eryigit, Gozde; Abbink, Truus E.M.; Kılıçarslan, Rukiye; Asıl, Talip; Alkan, Alpay; Knaap, Marjo S. van der; Koçer, Abdülkadir

doi:10.1016/j.clineuro.2013.01.024

Cited by 10 publications

(13 citation statements)

References 6 publications

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“…Diffusion‐weighted imaging indicates highly increased size of white matter water spaces 3. After several years, patients with MLC develop slowly progressive cerebellar ataxia and spasticity 1, 4. Slow and mild cognitive decline ensues over the years.…”

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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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: 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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“…1, 3,4 Magnetic resonance imaging (MRI) shows diffuse signal abnormality and swelling of the cerebral white matter, which are most severe in the first few years and then slowly decrease. 1, 3,4 Magnetic resonance imaging (MRI) shows diffuse signal abnormality and swelling of the cerebral white matter, which are most severe in the first few years and then slowly decrease.…”

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confidence: 99%

Mice with megalencephalic leukoencephalopathy with cysts: A developmental angle

Dubey

Bugiani

Ridder

et al. 2014

Annals of Neurology

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Mlc1-null mice replicate early stages of the human disease with early onset intramyelinic edema. The cellular functional defects, described for human MLC, were confirmed. The earliest change was astrocytic swelling, substantiating that in MLC the primary defect is in volume regulation by astrocytes. MLC1 expression affects expression of GlialCAM and ClC-2. Abnormal interplay between these proteins is part of the pathomechanisms of MLC.

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“…There are many differences in the clinical features and evolution between patients of the same family and others with the same mutation. Other clinical findings, including ataxia, spasticity, extrapyramidal signs, and mental retardation are inconsistent across cases, and when they exist, the time of onset is variable (Table 1) (6,8,(18)(19)(20)(21)(22)(23). Recently, Masuda and Ueda reported a patient without the classical features of MLC on MRI.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, our patient exhibited significant deterioration over one year. Her communication and social skills were significantly affected such that she never developed language, and her attitude was that of a child with mental retardation and hyperkinesias (8)(9)(10)(11). In general, the literature defines MLC by normal to mildly decreased cognitive capacity initially, with increases in deterioration over several years.…”

Section: Discussionmentioning

confidence: 99%