Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

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A Developmental and Genetic Classification for Malformations of Cortical Development: Update 2012.

https://cyberleninka.org/article/n/1515084.pdf

Diagnostic approach to the congenital muscular dystrophies

Dystroglycan, which serves as a major extracellular matrix receptor in muscle and the central nervous system, requires extensive O-glycosylation to function. We identified a dystroglycan missense mutation (Thr192→Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment. A mouse model harboring this mutation recapitulates the immunohistochemical and neuromuscular abnormalities observed in the patient. In vitro and in vivo studies showed that the mutation impairs the receptor function of dystroglycan in skeletal muscle and brain by inhibiting the post-translational modification, mediated by the glycosyltransferase LARGE, of the phosphorylated O-mannosyl glycans on α-dystroglycan that is required for high-affinity binding to laminin.

/pdf/a-dystroglycan-mutation-associated-with-limb-girdle-muscular-4h5ric06dp.pdf

A dystroglycan mutation associated with limb-girdle muscular dystrophy.

Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant α-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated α-dystroglycan. These results implicate ISPD in α-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.

/pdf/mutations-in-ispd-cause-walker-warburg-syndrome-and-145s7zxxhx.pdf

Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan.

Malformations of cortical development (MCDs) are macroscopic or microscopic abnormalities of the cerebral cortex that arise as a consequence of an interruption to the normal steps of formation of the cortical plate The human cortex develops its basic structure during the first two trimesters of pregnancy as a series of overlapping steps, beginning with proliferation and differentiation of neurons, which then migrate before finally organizing themselves in the developing cortex Abnormalities at any of these stages, be they environmental or genetic in origin, may cause disruption of neuronal circuitry and predispose to a variety of clinical consequences, the most common of which is epileptic seizures, A large number of MCDs have now been described, each with characteristic pathological, clinical, and imaging features The causes of many of these MCDs have been determined through the study of affected individuals, with many MCDs now established as being secondary to mutations in cortical development genes This review will highlight the best-known of the human cortical malformations associated with epilepsy The pathological, clinical, imaging, and etioiogic features of each MCD will be summarized, with representative magnetic resonance imaging (MRI) images shown for each MCD, The malformations tuberous sclerosis, focal cortical dysplasia, hemimegalencephaiy, classical iissencephaly, subcortical band heterotopia, periventricular nodular heterotopia, polymicrogyria, and schizencephaly will be presented

/pdf/malformations-of-cortical-development-and-epilepsy-4umwxio737.pdf

Malformations of cortical development and epilepsy.

Intragenic homozygous deletions in the Large gene are associated with a severe neuromuscular phenotype in the myodystrophy (myd) mouse These mutations result in a virtual lack of glycosylation of alpha-dystroglycan Compound heterozygous LARGE mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual alpha-dystroglycan glycosylation in patient cells We hypothesized that more severe LARGE mutations are associated with a more severe CMD phenotype in humans Here we report a 63-kb intragenic LARGE deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the alpha-dystroglycan protein

/pdf/intragenic-deletion-in-the-large-gene-causes-walker-warburg-48c77hu3cn.pdf

Mohamed M. Shaheed

Papers

Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome.