Clinical and genetic distinction between Walker–Warburg syndrome and muscle–eye–brain disease

Cormand, Bru; Pihko, Helena; Bayés, Mònica; Valanne, Leena; Santavuori, Pirkko; Talim, Beril; Gershoni‐Baruch, Ruth; Ahmad, Arsalan; Bokhoven, Hans van; Brunner, Han G.; Voït, Thomas; Topaloǧlu, Haluk; Dobyns, William B.; Lehesjoki, Ana Elina

doi:10.1212/wnl.56.8.1059

Cited by 169 publications

(103 citation statements)

References 47 publications

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“…These conditions include Muscle-Eye-Brain disease, WalkerWarburg syndrome, and Fukuyama congenital muscular dystrophy (Fukuyama et al, 1981;Haltia et al, 1997;Kobayashi et al, 1998;Cormand et al, 2001). Affected patients present with a myriad of abnormalities, including cobblestone cortex, severe mental retardation, seizures, muscular dystrophy, and cerebellar and ocular abnormalities (Muntoni and Voit, 2004).…”

Section: Role Of Ilk In the Pathogenesis Of Congenital Muscular Dystrmentioning

confidence: 99%

Integrin-Linked Kinase Deletion from Mouse Cortex Results in Cortical Lamination Defects Resembling Cobblestone Lissencephaly

Niewmierzycka¹,

Mills²,

St‐Arnaud³

et al. 2005

J. Neurosci.

113

100

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Integrin-linked kinase (Ilk) is a scaffold and kinase that links integrin receptors to the actin cytoskeleton and to signaling pathways involved in cell adhesion, migration, and extracellular matrix deposition. Targeted deletion of Ilk from embryonic mouse dorsal forebrain neuroepithelium results in severe cortical lamination defects resembling cobblestone (type II) lissencephaly. Defects in adult mutants include neuronal invasion of the marginal zone, downward displacement of marginal zone components, fusion of the cerebral hemispheres, and scalloping of the dentate gyrus. These lesions are associated with abundant astrogliosis and widespread fragmentation of the basal lamina at the cortical surface. During cortical development, neuronal ectopias are associated with severe disorganization of radial glial processes and displacement of Cajal-Retzius cells. Lesions are not seen when Ilk is specifically deleted from embryonic neurons. Interestingly, targeted Ilk deletion has no effect on proliferation or survival of cortical cells or on phosphorylation of two Ilk substrates, Pkb/Akt and Gsk-3␤, suggesting that Ilk does not regulate cortical lamination via these enzymes. Instead, Ilk acts in vivo as a major intracellular mediator of integrin-dependent basal lamina formation. This study demonstrates a critical role for Ilk in cortical lamination and suggests that Ilk-associated pathways are involved in the pathogenesis of cobblestone lissencephalies.

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Section: Role Of Ilk In the Pathogenesis Of Congenital Muscular Dystrmentioning

confidence: 99%

Integrin-Linked Kinase Deletion from Mouse Cortex Results in Cortical Lamination Defects Resembling Cobblestone Lissencephaly

Niewmierzycka¹,

Mills²,

St‐Arnaud³

et al. 2005

J. Neurosci.

113

100

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“…The myopathy, which in the latter is pronounced, congenital and global, is understandably milder in our patient, who has limited myopathic signs in her leg muscle (as shown by the histopathology of her muscle biopsy), frank muscle weakness only in her face and possibly postural muscles, and a chronically elevated serum CK level. Of the brain malformations observed in MEB/WWS, our patient has subcortical white matter abnormalities and ventricular dilatation, 9,10 but not the more severe structural anomalies such as lissencephaly. She also has considerable learning difficulties, with significant speech delay compounded by oral-motor dyspraxia.…”

Section: Discussionmentioning

confidence: 65%

“…7 Although the milder disorders result in an apparently simple myopathy reminiscent of the DMD-BMD spectrum, 8 FCMD, MEB and WWS also have a variety of ocular and brain defects (including cobblestone lissencephaly, white matter abnormalities, learning difficulties, agenesis of the corpus callosum, myopia, cataracts and microphthalmia). 9,10 The relationship between degree of dystroglycan hypoglycosylation and phenotypic severity is significant but complex. 11 Dystroglycan is known to bind to a number of intracellular and extracellular partners.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities

et al. 2010

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Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin a2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a B2-Mb region of chromosome 3, which includes the dystroglycan gene (DAG1). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle-eye-brain disease and WarkerWarburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation observed in the Dag1 +/À mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations.

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“…WWS and MEB are clinically similar autosomal recessive disorders that are characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies, but WWS is a more severe syndrome than MEB. 48), 53) Patients with WWS are severely affected from birth (brain malformation is particularly common), and few live beyond infancy. In MEB, the cerebral and ocular anomalies are also severe, but some patients reach adulthood.…”

Section: )46)mentioning

confidence: 99%

“…In MEB, the cerebral and ocular anomalies are also severe, but some patients reach adulthood. 44), 53) The difference of severity between the two diseases may be explained as follows: If POMGnT1, which is responsible for the formation of the GlcNAcβ1-2Man linkage of O-mannosyl glycans, 30) is non-functional, only O-mannose residues may be present on α-dystroglycan in MEB. On the other hand, POMT1 mutations cause complete loss of O-mannosyl glycans in WWS.…”

Section: )46)mentioning

confidence: 99%

Human genetic deficits in glycan formation.

Endo

2004

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Glycans are associated with most proteins found in secretions and on the surface of mammalian cells. Glycans of secreted glycoproteins affect many protein properties such as solubility, stability, protease sensitivity, and polarity, while glycans on cell surface glycoproteins are involved in various cellular functions including cell-cell and cell-matrix interactions during embryogenesis, immune reactions, and tumor development. Recent advances in human genomic research together with newly developed and sensitive methods for the analysis of glycan structures have elucidated the etiology of a growing number of human genetic diseases with aberrant glycan formation. Among these diseases, defects of protein N-glycosylation and O-mannosylation are reviewed here. The former is relatively common and the latter is rather uncommon. Both types of defects lead to severe abnormalities, which indicate the importance of glycosylation. Sequencing of the human genome is essentially complete and now glycobiology becomes an important area of postgenomic research. Glycobiology is expected to produce remarkable advances in the understanding and treatment of certain genetic diseases.

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Clinical and genetic distinction between Walker–Warburg syndrome and muscle–eye–brain disease

Abstract: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

Cited by 169 publications

References 47 publications

Integrin-Linked Kinase Deletion from Mouse Cortex Results in Cortical Lamination Defects Resembling Cobblestone Lissencephaly

Integrin-Linked Kinase Deletion from Mouse Cortex Results in Cortical Lamination Defects Resembling Cobblestone Lissencephaly

Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities

Human genetic deficits in glycan formation.

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