Muscle—eye—brain disease: A neuropathological study

Abstract

A combination of congenital central nervous, ocular and muscular abnormalities is characteristic of muscle-eye-brain disease (MEB), of Fukuyama congenital muscular dystrophy (FCMD), and of Walker-Warburg syndrome (WWS). The nosological relationship of these inherited malformative disorders is still unestablished, although the genetic locus for FCMD has been excluded in MEB. We present the first postmortem neuropathological study of MEB based on 2 male patients. Apart from sharply limited occipital agyric areas, their brains showed coarse gyri with an abnormally nodular surface ("cobblestone cortex"). Both the cerebral and cerebellar cortices showed a total disorganization without horizontal lamination. The haphazardly oriented cortical neurons formed irregular clusters or islands, separated by gliovascular strands extending from the pia. The ocular abnormalities included a pronounced glial preretinal membrane. Although MEB shares the cobblestone cortex-type malformation with FCMD and WWS, the cerebral and ocular manifestations are less severe than in WWS. Furthermore, a consistently weak staining for laminin alpha2 chain (merosin) was found in muscle biopsy specimens from 4 MEB patients, while normal immunoreactivity was observed for the laminin beta2 chain, reported to be severely deficient in WWS. These findings support nosological independence of MEB.

Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré type

“…In these syndromes, the gyral pattern varies from smooth to irregular, and on autopsy the cortex is very disorganized with neurons and glia mixed with fibroblasts and blood vessels in superficial regions. [18][19][20] The malformation results from defects in the basal lamina (pial limiting membrane) that allow inappropriate migration of neurons and glia into the subarachnoid space to form extensive marginal glio-neuronal heterotopia. 21,22 These syndromes are associated with mutations in six genes that encode known or putative O-linked glycosyltransferases: FCMD, FKRP, LARGE, POMGnT1, POMT1, and POMT2.…”

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

“…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).…”

Developmental Expression of the Neuron-specific N-Acetylglucosaminyltransferase Vb (GnT-Vb/IX) and Identification of Its in Vivo Glycan Products in Comparison with Those of Its Paralog, GnT-V

“…Genetic disorders that affect O-mannosyl glycosylation lead to forms of congenital muscular dystrophies that are characterized by muscular dystrophy, type II lissencephaly, and eye abnormalities (1)(2)(3)(4)(5)(6)(7)(8). Studies have demonstrated that disruption of the activity of several key enzymes in the O-mannosyl glycosylation pathway likely mediates their pathological effects through altered glycosylation of ␣-dystroglycan (9 -11).…”

“…Converging evidence has demonstrated the severe phenotypic effects of altered glycosylation in congenital muscular dystrophies (CMD). 3 Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, and congenital muscular dystrophy 1D (MDC1D) are caused by mutations in genes that encode known or putative glycosyltransferases or glycan-modifying enzymes (16 -26). The disrupted genes underlying these diseases appear to encode proteins that contribute to the O-mannosyl glycosylation pathway.…”