Conference

Lissencephaly type II is a group of complex brain malformations that anatomically consists of “cobblestone” cortex, abnormal white matter, enlarged ventricles, small brainstem, hypoplastic vermis, and cerebellar polymicrogyria. The spectrum varies from a mild disorganization of the brain layers to severely dysplastic brains. All these conditions are usually associated with eye malformations and congenital muscular dystrophy (MDC). This chapter reviews the syndromes that are associated with muscle pathology and focuses on the association between the genes or proteins and the brain in lissencephaly type II. Defects in glycosylation have been linked to all these conditions and the common mechanism is the defective post-translational processing of α-dystroglycan, a heavily glycosylated peripheral membrane component of the dystrophin-associated glycoprotein complex. Mutations in the enzymes involved in the synthesis of O-linked glycans on α-dystroglycan indicate that these diseases are all congenital disorders of glycosylation in the form of O-mannosylation defects. The chapter also reviews some related disorders in the chronological order of biochemistry, cellular aspects, and molecular pathology.

The congenital muscular dystrophies (CMD) are clinically and genetically heterogeneous. The merosin (laminin α2 chain) deficient form (MDC1A), is characterized clinically by neonatal hypotonia, delayed motor milestones and associated contractures. It is caused by deficiency in the basal lamina of muscle fibers of the α2 chain of laminins 2 and 4 (LAMA2 gene at 6q22–23). Laminin α2 chain is also expressed in fetal trophoblast, which provides a suitable tissue for prenatal diagnosis in families where the index case has total deficiency of the protein. This article reports the collective experience of five centers over the past 10 years in 114 prenatal diagnostic studies using either protein analysis of the chorionic villus (CV) of the trophoblast plus DNA molecular studies with markers flanking the 6q22–23 region and intragenic polymorphisms (n=58), or using only DNA (n=44) or only protein (n=12) approaches. Of the 102 fetuses studied by molecular genetics, 27 (26%) were predicted to be affected while 75 (74%) were considered as unaffected, with 52 (51%) being heterozygous, thus conforming closely to an autosomal recessive inheritance. In 18 of the 27 affected fetuses, the trophoblast was studied by immunocytochemistry and there was a total or only traces deficiency of the protein in CV basement membrane in all. In 10 cases material from the presumably affected fetus was available for analysis after termination of the pregnancy and immunohistochemical study confirmed the diagnosis in all of them. Prenatal studies of ‘at risk’ pregnancies in the five centers produced neither false negative (merosin-deficiency in CVs in a normal fetus), nor false positive (normal merosin expression in CVs and affected child), indicating the reliability of the technique, when all the necessary controls are done. Our experience suggests that protein and DNA analysis can be used either independently or combined, according to the facilities of each center, to provide accurate prenatal diagnosis of the MDC1A, and have an essential role in genetic counseling.

The congenital muscular dystrophies are a heterogeneous group of inherited disorders. The clinical features range from severe and often early fatal disorders to relatively mild conditions compatible with survival into adult life. The recent advances in the genetic basis of congenital muscular dystrophies have allowed to significantly improve our understanding of their pathogenesis and clinical diversity. These advances have also allowed to classify these forms according to a combination of clinical features and primary biochemical defects. In this review we present how the congenital muscular dystrophies field has evolved over the last decade from a clinical and genetic point of view.

Mutations disrupting the interaction of extra-cellular ligands and α-dystroglycan are responsible for an etiologically heterogeneous group of autosomal recessive congenital muscular dystrophies (CMD) that can have associated brain and eye abnormalities. The objective is to develop a diagnostic test for one of these CMDs, Muscle-Eye-Brain disease (MEB), due to mutations in the gene encoding Protein O-Mannosyl β-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1).

POMGnT1 enzyme activity was determined in extracts of muscle biopsies from four MEB patients and various controls using commercially available reagents.

All four MEB muscle samples showed a highly significant decrease in POMGnT1 activity relative to controls.

The assay of POMGnT1 activity in MEB muscle provides a rapid and relatively simple diagnostic test for this disease. CMDs associated with brain malformations such as MEB, WWS and FCMD are heterogenous in clinical presentation and on radiologic examination, suggesting that POMGnT1 assays of muscle biopsies should be used as a screening procedure for MEB in all CMD patients associated with brain malformations.

A Turkish patient with cobblestone lissencephaly and eye involvement without characteristic muscular changes for congenital muscular dystrophy died at the age of 3 months presented with neonatal apneic periods and generalized seizures. Serum creatine kinase level, electromyography, chromosome analysis and blood biochemistry were normal. Unilateral microphthalmia, retinal dysplasia and internal strabismus were the ocular findings. Magnetic resonance imaging clearly demonstrated the thickened, irregular, nearly agyric cobblestone cerebral cortex with underlying unmyelinated white matter, hydrocephalus, hypoplastic corpus callosum, brain stem and cerebellum with retrocerebellar cyst and posterior cephalocele.