Lissencephaly With Brainstem and Cerebellar Hypoplasia and Congenital Cataracts

I read with great interest the article by Abumansour et al ¹ published online 26 April 2013 in this journal. The authors described a neonate with a severe neurologic phenotype associated with hypotonia, oropharyngeal incoordination, intractable epilepsy, and congenital cataracts. Brain magnetic resonance imaging (MRI) showed classical lissencephaly, ventriculomegaly, absent corpus callosum, globular and ventricular hippocampi, and cerebellar and brainstem hypoplasia. Routine hematologic and biochemical investigations including creatinine kinase were normal. Toxoplasmosis, rubella, cytomegalovirus, and herpes simplex (TORCH) screen was negative. Array comparative genome hybridization was normal. There were no mutations in the TUBA1A gene. Gene sequencing of RELN revealed 2 heterozygous sequence variants of unknown significance. The authors concluded that the case represented a previously undescribed genetic lissencephaly syndrome. I want to draw attention to a point that could help in the diagnosis of the patient.

Dystroglycan is a component of the dystrophin-glycoprotein complex present at the sarcolemma of skeletal muscle, although it has a much wider tissue distribution. Dystroglycan is encoded by the DAG1 gene, which encodes a precursor protein that is posttranslationally cleaved into α and β subunits. Dystroglycan plays an important role in the organization of actin cytoskeleton and laminins during development of basement membranes in muscle and nonmuscle tissues.^2,3 The presence of functional laminin-α₂ is necessary to organize dystroglycan. Laminin-α₂ binding to α-dystroglycan is mediated by the C-terminal globular LG domains (LG4-5) domains in the laminin molecule and the O-linked carbohydrate moieties in the mucin-like domain of α-dystroglycan. ⁴ Disruption of the laminin-α₂-α-dystroglycan axis has severe consequences for muscle and brain function and structure. The defects in α-dystroglycan glycosylation cause perturbation of the basement membrane and this is believed to play a central role in muscle and central nervous system pathologies.^5,6 FKRP, Fukutin,POMT1,POMT2,POMTGnT1,LARGE,ISPD, and B3GALT2 genes affect O-mannosylation.^7,–9 DPM2 and DPM3 genes are responsible for N-glycosylation of α-dystroglycan and mutations in these genes result in a pattern of congenital disorders of glycosylation type I.^10,11 Recently, recessive DAG1 mutations were reported in a patient with a mild form of limb girdle muscular dystrophy with severe mental retardation and normal brain imaging. ¹² Normal basement membrane formation is essential for neuronal migration. During central nervous system development, cells proliferate in the periventricular zone of the neuroepithelium and migrate via radial glia to the cortical plate. Radial glia cells have an end feet attached to the pial basement membrane. α-Dystroglycan is highly expressed in pial membranes and its abnormal glycosylation results in reduced integrity and central nervous system developmental malformations. ¹³ The reported brain malformations resulting from defects of α-dystroglycan glycosylation include ventricular dilation, white matter changes, cerebellar cysts, hypoplastic-dysplastic vermis, cerebellar hypoplasia, brainstem hypoplasia, polymicrogyria, pachygyria, and lissencephaly. ¹⁴ Ocular findings are also common in defects of α-dystroglycan glycosylation and include myopia, cataracts, retinal detachment, microphthalmia, buphthalmus, persistent hyperplastic primary vitreous, Peters anomaly, and congenital glaucoma. ¹⁵ The patient of Abumansour et al ¹ had cataracts, lissencephaly, and cerebellar and brainstem hypoplasia as major malformations. Another common feature in defects of α-dystroglycan glycosylation is predominant involvement of proximal muscles in the upper and lower limbs and elevated serum creatine kinase. Clinical severity of muscle disease varies among different types of α-dystroglycanopathies. ¹⁵ In the report of Clement et al, ¹⁴ the authors discussed a patient withPOMTGnT1 mutations in whom serum creatine kinase concentrations were normal, but α-dystroglycan expression was reduced in muscle biopsy (F. Muntoni, P. Guicheney, and T. Voit, presented at the 158th ENMC Workshop on Congenital Muscular Dystrophy). The authors concluded that there are no systematic studies where the analysis of glycosyltransferases mutated in dystroglycanopathies had been performed in patients without muscle phenotype. ¹⁴

In conclusion, I suggest that although serum creatine kinase level of the case is in normal values, the patient should be searched for α-dystroglycanopathies.