B3GALNT2-Related Dystroglycanopathy: Expansion of the Phenotype with Novel Mutation Associated with Muscle-Eye-Brain Disease, Walker–Warburg Syndrome, Epileptic Encephalopathy-West Syndrome, and Sensorineural Hearing Loss

Abstract

Mutations in B3GALNT2, encoding a glycosyltransferase enzyme involved in α-dystroglycan glycosylation, have been recently associated with dystroglycanopathy, a well-recognized subtype of congenital muscular dystrophy (CMD). Only a few cases have been reported with B3GALNT2-related dystroglycanopathy with variable severity ranging from mild CMD to severe muscle-eye-brain disease. Here, we describe a child with a novel homozygous nonsense mutation in B3GALNT2. The affected child has severe neurological disease since birth, including muscle disease manifested as hypotonia, muscle weakness, and wasting with elevated creatine kinase, eye disease including microphthalmia and blindness, brain disease with extensive brain malformations including massive hydrocephalus, diffuse cobblestone-lissencephaly, deformed craniocervical junction, and pontocerebellar hypoplasia. The clinical and radiologic findings are compatible with a diagnosis of severe muscle-eye-brain disease and more specifically Walker–Warburg syndrome. A more distinct aspect of the clinical phenotype in this child is the presence of refractory epilepsy in the form of epileptic spasms, epileptic encephalopathy, and West syndrome, as well as sensorineural hearing loss. These findings could expand the phenotype of B3GALNT2-related dystroglycanopathy. In this report, we also provide a detailed review of previously reported cases with B3GALNT2-related dystroglycanopathy and compare them to our reported child. In addition, we study the genotype–phenotype correlation in these cases.

Keywords

B3GALNT2 - dystroglycanopathy - West syndrome - brain malformations - hydrocephalus - congenital muscular dystrophy

• References

• 1 Bönnemann CG, Wang CH, Quijano-Roy S. , et al; Members of International Standard of Care Committee for Congenital Muscular Dystrophies. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord 2014; 24 (04) 289-311
• 2 Barkovich AJ. Neuroimaging manifestations and classification of congenital muscular dystrophies. AJNR Am J Neuroradiol 1998; 19 (08) 1389-1396
• 3 Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC. Defective glycosylation in muscular dystrophy. Lancet 2002; 360 (9343): 1419-1421
• 4 Stevens E, Carss KJ, Cirak S. , et al; UK10K Consortium. Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. Am J Hum Genet 2013; 92 (03) 354-365
• 5 Godfrey C, Clement E, Mein R. , et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 2007; 130 (Pt 10): 2725-2735
• 6 Bouchet-Séraphin C, Chelbi-Viallon M, Vuillaumier-Barrot S, Seta N. [Genes of alpha-dystroglycanopathies in 2016] [Article in French]. Med Sci (Paris) 2016; 32 Hors série n°2( (02) 40-45
• 7 Hiruma T, Togayachi A, Okamura K. , et al. A novel human beta1,3-N-acetylgalactosaminyltransferase that synthesizes a unique carbohydrate structure, GalNAcbeta1-3GlcNAc. J Biol Chem 2004; 279 (14) 14087-14095
• 8 Yoshida-Moriguchi T, Willer T, Anderson ME. , et al. SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. Science 2013; 341 (6148): 896-899
• 9 Hedberg C, Oldfors A, Darin N. B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations. Eur J Hum Genet 2014; 22 (05) 707-710
• 10 Ho ML, Glenn OA, Sherr EH, Strober JB. Serial prenatal and postnatal MRI of dystroglycanopathy in a patient with familial B3GALNT2 mutation. Pediatr Radiol 2017; 47 (07) 884-888
• 11 Clement E, Mercuri E, Godfrey C. , et al. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann Neurol 2008; 64 (05) 573-582
• 12 Godfrey C, Foley AR, Clement E, Muntoni F. Dystroglycanopathies: coming into focus. Curr Opin Genet Dev 2011; 21 (03) 278-285
• 13 Cormand B, Pihko H, Bayés M. , et al. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 2001; 56 (08) 1059-1069
• 14 Taniguchi K, Kobayashi K, Saito K. , et al. Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum Mol Genet 2003; 12 (05) 527-534
• 15 Alabdullatif MA, Al Dhaibani MA, Khassawneh MY, El-Hattab AW. Chromosomal microarray in a highly consanguineous population: diagnostic yield, utility of regions of homozygosity, and novel mutations. Clin Genet 2017; 91 (04) 616-622