Clinical Features and Molecular Characterization of a Patient With Muscle-Eye-Brain Disease

Abstract

Muscle-eye-brain disease is a congenital muscular dystrophy characterized by structural brain and eye defects. Here, we describe a 12-year-old boy with partial agenesis of corpus callosum, ventriculomegaly, flattened brain stem, diffuse pachygyria, blindness, profound cognitive deficiencies, and generalized muscle weakness, yet without a clear dystrophic pattern on muscle biopsy. There was no glycosylation of α-dystroglycan and the genetic screening revealed a novel truncating mutation, c.1545delC (p.Tyr516Thrfs*21), and a previously identified missense mutation, c.1469G>A (p.Cys490Tyr), in the protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) gene. These findings broaden the clinical spectrum of muscle-eye-brain disease to include pronounced hypotonia with severe brain and eye malformations, yet with mild histopathologic changes in the muscle specimen, despite the absence of glycosylated α-dystroglycan.

Keywords

dystroglycan dystroglycanopathy muscle-eye-brain disease POMGNT1 glycosylation

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References

Santavuori

Somer

Sainio

. Muscle-eye-brain disease (MEB). Brain Dev. 1989;11:147–153.

Mercuri

Messina

Bruno

. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009;72:1802–1809.

Taniguchi

Kobayashi

Saito

. Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum Mol Genet. 2003;12:527–534.

Clement

Godfrey

Tan

. Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant. Arch Neurol. 2008;65:137–141.

Raducu

Baets

Fano

. Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O. Eur J Hum Genet. 2012;20:945–952.

Barresi

Campbell

. Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci. 2006;119:199–207.

Chiba

Matsumura

Yamada

. Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve alpha-dystroglycan. The role of a novel O-mannosyl-type oligosaccharide in the binding of alpha-dystroglycan with laminin. J Biol Chem. 1997;272:2156–2162.

Yoshida-Moriguchi

Stalnaker

. O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding. Science. 2010;327:88–92.

Yoshida

Kobayashi

Manya

. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell. 2001;1:717–724.

10.

Biancheri

Bertini

Falace

. POMGnT1 mutations in congenital muscular dystrophy: genotype-phenotype correlation and expanded clinical spectrum. Arch Neurol. 2006;63:1491–1495.

11.

Dubowitz

Sewry

. Muscle Biopsy: A Practical Approach. 3 rd ed. Philadelphia PA: Saunders Elsevier; 2007.

12.

Godfrey

Escolar

Brockington

. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy. Ann Neurol. 2006;60:603–610.

13.

Prados

Pena

Cotarelo

. Expression of the murine Pomt1 gene in both the developing brain and adult muscle tissues and its relationship with clinical aspects of Walker-Warburg syndrome. Am J Pathol. 2007;170:1659–1668.

14.

Demir

Gucuyener

Akturk

. An unusual presentation of muscle-eye-brain disease: severe eye abnormalities with mild muscle and brain involvement. Neuromuscul Disord. 2009;19:692–695.

15.

Martin

. Mechanisms of disease: congenital muscular dystrophies-glycosylation takes center stage. Nat Clin Pract Neurol. 2006;2:222–230.

16.

Auranen

Rapola

Pihko

. Muscle membrane-skeleton protein changes and histopathological characterization of muscle-eye-brain disease. Neuromuscul Disord. 2000;10:16–23.

17.

Bertini

D'Amico

Gualandi

. Congenital muscular dystrophies: a brief review. Semin Pediatr Neurol. 2011;18:277–288.

18.

Jimenez-Mallebrera

Torelli

Feng

. A comparative study of alpha-dystroglycan glycosylation in dystroglycanopathies suggests that the hypoglycosylation of alpha-dystroglycan does not consistently correlate with clinical severity. Brain Pathol. 2009;19:596–611.

19.

Diesen

Saarinen

Pihko

. POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. J Med Genet. 2004;41: e115.

20.

Godfrey

Clement

Mein

. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007;130:2725–2735.

21.

Devisme

Bouchet

Gonzales

. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain. 2012;135:469–482.

22.

Voglmeir

Kaloo

Laurent

. Biochemical correlation of activity of the alpha-dystroglycan-modifying glycosyltransferase POMGnT1 with mutations in muscle-eye-brain disease. Biochem J. 2011;436:447–455.