Novel POMGnT1 mutations define broader phenotypic spectrum of muscle–eye–brain disease

Abstract

Muscle-eye-brain disease (MEB, OMIM 253280) is an autosomal recessive disorder characterized by a distinct triad of congenital muscular dystrophy, structural eye abnormalities, and cobblestone lissencephaly. Clinically, MEB patients present with early onset muscular hypotonia, severely compromised motor development, and mental retardation. Magnetic resonance imaging reveals a lissencephaly type II with hypoplasia of the brainstem and cerebellum. MEB is associated with mutations in the gene for protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1, OMIM 606822). In this paper, we report the clinical findings of nine MEB patients from eight families. Eight of the nine patients presented typical features of MEB. However, a broad phenotypic variability was observed, ranging from two patients with severe autistic features to another patient with an unusually mild phenotype, initially diagnosed as congenital muscular dystrophy. Furthermore, severe hydrocephalus was reported in two families during a previous pregnancy, emphasizing the phenotypic overlap with Walker-Warburg syndrome. In addition to three previously reported mutations, we identified six novel POMGnT1 mutations (one missense, five truncating) in the present patient cohort. Our data suggest mutational hotspots within the minimal catalytic domain at arginine residue 442 (exon 16) and in intron 17. It is interesting to note that all mutations analyzed so far result in a complete loss of enzyme activity. Therefore, we conclude that the type and position of the POMGnT1 mutations are not of predictive value for the clinical severity. This supports the notion that additional environmental and/or genetic factors may contribute to the observed broad spectrum of POMGnT1-associated phenotypes.

Genetic Assessment of Cortical Malformations

“…1e ) [ 46 ] . Therefore, the diagnosis of cobblestone lissencephaly is commonly supported by the presence of characteristic associated fi ndings on MR imaging including pre-and/or postnatal hydrocephalus or dilated ventricles, hypoplastic brain stem and cerebellum, multiple subcortical cerebellar cysts, as well as absent or hypoplastic corpus callosum [ 27 ] . Severe cases today are increasingly recognized during prenatal ultrasound, while the cortical malformation itself usually escapes prenatal sonographic detection [ 9 ] .…”

“…253800 613153, 613154) [ 18 ] , as well as the milder Fukuyama congenital muscular dystrophy described in the Japanese population (MIM 253800) [ 34 ] and the muscle-eye-brain disease, initially described in the Finnish population (MIM 253280) [ 61 ] , with reported patients in their second decade of life [ 27 ] , later shown to result from population-specifi c founder mutations within the Fukutin and POMGnT1 gene, respectively [ 15 , 37 ] . In addition, there is notable clinical overlap with the intermediate phenotypes of congenital muscular dystrophies within the group of dystroglycanopathies, which in cerebral MR imaging in almost 90 % also present with mild to moderate manifestations including cerebellar hypoplasia or cysts, enlarged ventricles or even characteristic cortical abnormalities suggestive of cobblestone lissencephaly [ 12 ] .…”

Angeborene Hirnfehlbildungen und geistige Behinderung

“…Häufig tritt die "Pflasterstein"-Lissenzephalie syndromal in Verbindung mit einer Muskeldystrophie und Augenfehlbildungen auf. Als klassische autosomal-rezessiv vererbte Syndrome wurden das Walker-Warburg-Syndrom (WWS), die Muscle-Eye-Brain-Erkrankung (MEB) [11] CMD kongenitale Muskeldystrophie ("congenital muscular dystrophy", CRB Zerebellum ("cerebellum"''), FCMD Fukuyama-kongenitale Muskeldystrophie, HPE Holoprosenzephalie, ILS isolierte Lissenzephalie, LGMD Gliedergürtelmuskeldystrophie ("limb girdle muscular dystrophy"), MEB Muscle-Eye-Brain-Erkrankung, MR mentale Retardierung, PVNH periventrikuläre noduläre Heterotopie, SBH subkortikale Bandheterotopie, WWS Walker-Warburg-Syndrom, XLAG X-chromosomale Lissenzephalie mit abnormen Genitalien…”

“…B. POMT1-Mutationen), welche sich dagegen z. B. für POMGnT1-Mutationen nicht finden[11].Die isolierten Polymikrogyrien wurden in der bisherigen Klassifizierung als postmigratorische Störungen in die Gruppe der kortikalen Organisationsstörungen eingeordnet. Allerdings ist die Abgrenzung gegenüber den Migrationsstörun-gen nicht sehr scharf, und es gibt sowohl bildgebend als auch pathophysiologisch Überschneidungen insbesondere mit den "Pflasterstein"-Lissenzephalien.Polymikrogyrien (PMG) kommen nicht selten auch kombiniert mit weiteren Hirnfehlbildungen wie periventrikuläre noduläre Heterotopie (PVNH), Kleinhirnhypoplasie, Balkendysgenesien und auch Mikrozephalien sowie bei verschiedenen Syndromen (z.…”

Two Cases of Walker-Warburg Syndrome Complicated by Hydrocephalus

“…Genetic examinations of newborns disclosed several independent mutations in a gene for the catalytic domain of the enzyme ‘protein O-mannose beta-1,2-N-acetylglucosaminyltransferase’ (POMGnT1, OMIM 606822) [4], which takes part in formation of cell-surface glycoproteins. Loss of function of O-mannosylation seems to compromise laminin binding, which plays a role in neuronal migration.…”