Clinical and Genetic Heterogeneity in Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC)

Blattner, Regine; Moers, A von; Leegwater, P.A.J.; Hanefeld, F; Knaap, Marjo S. van der; Köhler, Wolfgang

doi:10.1055/s-2003-42210

Cited by 45 publications

(6 citation statements)

References 15 publications

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“…This was the third time worldwide to report MLC patients with mutations in GlialCAM [ 8 – 9 ], and also the first time to identify mutations in GlialCAM in Chinese. Clinical severity varies among Pt24 and Pt25 siblings, Pt17’s families which were often seen in patients with the same mutation or even siblings [ 27 – 28 ], but similar features were detected in Pt9 and Pt10, Pt27 and Pt28 in this research.…”

Section: Discussionsupporting

confidence: 68%

“…Neither macrocephaly nor development delay were shown at his maternal grandfather’s young age by his families’ medical histories recalling. Different degrees of severity revealed in Pt17’s family might be a result of heterogeneity of MLC or unreliable memories of Pt17’s mother and grandfather [ 27 – 28 ]. 2 mutations (p.T132N, p.K68M) of GlialCAM occurred in the Ig-domain V-set where recessive mutations were identified previously in Pt19[ 8 ], changing the chemical properties of residues from hydroxyl (T) to amidic(N) for mutation p.T132N and from basic(K) to sulfureted(M) for the mutation p.K68M, which might alter the secondary structure and function of the protein, considered to be pathological.…”

Section: Discussionmentioning

confidence: 99%

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Ten Novel Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts and a Long-Term Follow-Up Research

et al. 2016

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ObjectiveMegalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rare neurological deterioration disease. We aimed to clarify clinical and genetic features of Chinese MLC patients.MethodsClinical information and peripheral venous blood of 20 patients and their families were collected, Sanger-sequencing and Multiple Ligation-dependent Probe Amplification were performed to make genetic analysis. Splicing-site mutation was confirmed with RT-PCR. UPD was detected by haplotype analysis. Follow-up study was performed through telephone for 27 patients.ResultsOut of 20 patients, macrocephaly, classic MRI features, motor development delay and cognitive impairment were detected in 20(100%), 20(100%), 17(85%) and 4(20%) patients, respectively. 20(100%) were clinically diagnosed with MLC. 19(95%) were genetically diagnosed with 10 novel mutations in MLC1, MLC1 and GlialCAM mutations were identified in 15 and 4 patients, respectively. Deletion mutation from exon4 to exon9 and a homozygous point mutation due to maternal UPD of chromosome22 in MLC1 were found firstly. c.598-2A>C in MLC1 leads to the skip of exon8. c.772-1G>C in MLC1 accounting for 15.5%(9/58) alleles in Chinese patients might be a founder or a hot-spot mutation. Out of 27 patients in the follow-up study, head circumference was ranged from 56cm to 61cm in patients older than 5yeas old, with a median of 57cm. Motor development delay and cognitive impairment were detected in 22(81.5%) and 5(18.5%) patients, respectively. Motor and cognitive deterioration was found in 5 (18.5%) and 2 patients (7.4%), respectively. Improvements and MRI recovery were first found in Chinese patients. Rate of seizures (45.5%), transient motor retrogress (45.5%) and unconsciousness (13.6%) after head trauma was much higher than that after fever (18.2%, 9.1%, 0%, respectively).SignificanceIt’s a clinical and genetic analysis and a follow-up study for largest sample of Chinese MLC patients, identifying 10 novel mutations, expanding mutation spectrums and discovering clinical features of Chinese MLC patients.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Ten Novel Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts and a Long-Term Follow-Up Research

et al. 2016

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“…Vanishing white matter disease is caused by mutations in the eukaryotic initiation translation factor 2B (eIF2B), and is characterized by dysmorphic astrocytes with abnormal intermediate filament architecture (Bugiani et al, 2011). A phenotypically similar but genotypically distinct disorder, megalencephalic leukoencephalopathy with subcortical cysts, is caused by mutations in MLC1 , which codes for a protein that is almost exclusively present in astrocytic vascular endfeet (Blattner et al, 2003). Both of these diseases are similar to Alexander disease in that they are characterized by childhood abnormalities of white matter.…”

Section: Disease Mechanismsmentioning

confidence: 99%

Alexander Disease

Messing¹,

Brenner²,

Feany³

et al. 2012

J. Neurosci.

210

212

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“…Mutations in the MLC1 gene are found in approximately 80% of the MLC patients (Ilja Boor et al, 2006; Leegwater et al, 2001; Leegwater et al, 2002; Montagna et al, 2006); there is evidence that other unknown genes are also involved (Blattner et al, 2003; Patrono et al, 2003). MLC1 (the protein product of MLC1 ) is an oligomeric membrane protein with some degree of homology to ion channels (Leegwater et al, 2001; Teijido et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of MLC1 in primary astrocytes causes cell vacuolation: A MLC disease cell model

Duarri

Heredia

Capdevila-Nortes

et al. 2011

Neurobiology of Disease

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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy, in the majority of cases caused by mutations in the MLC1 gene. MRI from MLC patients shows diffuse cerebral white matter signal abnormality and swelling, with evidence of increased water content. Histopathology in a MLC patient shows vacuolation of myelin, which causes the cerebral white matter swelling. MLC1 protein is expressed in astrocytic processes that are part of blood- and cerebrospinal fluid-brain barriers. We aimed to create an astrocyte cell model of MLC disease. The characterization of rat astrocyte cultures revealed MLC1 localization in cell-cell contacts, which contain other proteins described typically in tight and adherent junctions. MLC1 localization in these contacts was demonstrated to depend on the actin cytoskeleton; it was not altered when disrupting the microtubule or the GFAP networks. In human tissues, MLC1 and the protein Zonula Occludens 1 (ZO-1), which is linked to the actin cytoskeleton, co-localized by EM immunostaining and were specifically co-immunoprecipitated. To create an MLC cell model, knockdown of MLC1 in primary astrocytes was performed. Reduction of MLC1 expression resulted in the appearance of intracellular vacuoles. This vacuolation was reversed by the co-expression of human MLC1. Reexamination of a human brain biopsy from an MLC patient revealed that vacuoles were also consistently present in astrocytic processes. Thus, vacuolation of astrocytes is also a hallmark of MLC disease.

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Clinical and Genetic Heterogeneity in Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC)

Abstract: The genetic findings in our patients suggest at least a second gene locus for MLC.

Cited by 45 publications

References 15 publications

Ten Novel Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts and a Long-Term Follow-Up Research

Ten Novel Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts and a Long-Term Follow-Up Research

Alexander Disease

Knockdown of MLC1 in primary astrocytes causes cell vacuolation: A MLC disease cell model

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