Brain involvement in muscular dystrophies with defective dystroglycan glycosylation

Clement, Emma; Mercuri, Eugenio; Godfrey, Caroline; Smith, Janine; Robb, Stephanie; Kinali, Maria; Straub, Volker; Bushby, Kate; Manzur, Adnan; Talim, Beril; Cowan, Frances; Quinlivan, R.; Klein, Andrea; Longman, Cheryl; McWilliam, Robert; Topaloǧlu, Haluk; Mein, R.; Abbs, Stephen; North, Klaus; Barkovich, A. James; Rutherford, Mary; Muntoni, F.

doi:10.1002/ana.21482

Cited by 172 publications

(158 citation statements)

References 55 publications

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“…[1][2][3][4] Such disorders are caused by mutations in genes coding for glycosyltransferases or accessory proteins of glycosyltransferases including protein O-mannosyltransferase 1 (POMT1, MIM 607423), protein O-mannosyltransferase 2 (POMT2, MIM 607439), protein O-mannose b-1,2-N-acetylglucosaminyltransferase (POMGNT1, MIM 606822), fukutin (FKTN; MIM 607440), fukitin-related protein (FKRP, MIM 606596), acetylglucosaminyltransferase-like protein (LARGE, MIM 603590), isoprenoid synthase domaincontaining protein (ISPD, MIM 614631), glycosyltransferase-like domain-containing protein 2 (GTDC2, MIM 147730), b-1,3-Nacetylglucosaminyltransferase 1 (B3GNT1, MIM 605517), GDP-mannose pyrophosphorylase B (GMPPB, MIM 615320), protein kinase-like protein sgk196 (SGK196, MIM 615247) and transmembrane protein 5 (TMEM5, MIM 605862). Additional genes link congenital muscular dystrophy with congenital disorders of glycosylation (DOLK, MIM 610746; DPM1, MIM 603503; DPM2, MIM 603564; and DPM3, MIM 605951).…”

Section: Introductionmentioning

confidence: 99%

B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations

2013

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Congenital muscular dystrophies associated with brain malformations are a group of disorders frequently associated with aberrant glycosylation of a-dystroglycan. They include disease entities such a Walker-Warburg syndrome, muscle-eye-brain disease and various other clinical phenotypes. Different genes involved in glycosylation of a-dystroglycan are associated with these dystroglycanopathies. We describe a 5-year-old girl with psychomotor retardation, ataxia, spasticity, muscle weakness and increased serum creatine kinase levels. Immunhistochemistry of skeletal muscle revealed reduced glycosylated a-dystroglycan. Magnetic resonance imaging of the brain at 3.5 years of age showed increased T2 signal from supratentorial and infratentorial white matter, a hypoplastic pons and subcortical cerebellar cysts. By whole exome sequencing, the patient was identified to be compound heterozygous for a one-base duplication and a missense mutation in the gene B3GALNT2 (b-1,3-N-acetylgalactosaminyltransferase 2; B3GalNAc-T2). This patient showed a milder phenotype than previously described patients with mutations in the B3GALNT2 gene.

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Section: Introductionmentioning

confidence: 99%

B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations

2013

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“…15 These phenotypes were also found to be among the most frequent in the large UK study. [16][17][18] All the cases identified as dystroglycanopathies were further subdivided according to the gene mutations. POMT1 mutations were the most frequent, followed by FKRP, POMGnT1, and POMT2.…”

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confidence: 99%

Prevalence of congenital muscular dystrophy in Italy

et al. 2015

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Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy.Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results:The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with a-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin a2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions:Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. The term congenital muscular dystrophy (CMD) classically includes a group of genetically, clinically, and biochemically distinct entities sharing clinical and pathologic features such as early presentation of weakness and hypotonia and dystrophic features on muscle biopsy. 1 The rapidly increasing identification of several genes responsible for different forms of CMD has dramatically expanded the spectrum of the known forms, allowing a better understanding of the individual forms and different underlying pathomechanisms. 2 The incidence and prevalence of CMD in populations is not sufficiently known with only a few studies reporting incidence or point prevalence in relatively small regions. 3-5 Furthermore, several new genes have only been described in the last few years and the subtyping and classification in those reports is therefore not updated.

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“…The myopathy, which in the latter is pronounced, congenital and global, is understandably milder in our patient, who has limited myopathic signs in her leg muscle (as shown by the histopathology of her muscle biopsy), frank muscle weakness only in her face and possibly postural muscles, and a chronically elevated serum CK level. Of the brain malformations observed in MEB/WWS, our patient has subcortical white matter abnormalities and ventricular dilatation, 9,10 but not the more severe structural anomalies such as lissencephaly. She also has considerable learning difficulties, with significant speech delay compounded by oral-motor dyspraxia.…”

Section: Discussionmentioning

confidence: 66%

“…7 Although the milder disorders result in an apparently simple myopathy reminiscent of the DMD-BMD spectrum, 8 FCMD, MEB and WWS also have a variety of ocular and brain defects (including cobblestone lissencephaly, white matter abnormalities, learning difficulties, agenesis of the corpus callosum, myopia, cataracts and microphthalmia). 9,10 The relationship between degree of dystroglycan hypoglycosylation and phenotypic severity is significant but complex. 11 Dystroglycan is known to bind to a number of intracellular and extracellular partners.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities

et al. 2010

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Dystroglycan is a protein which binds directly to two proteins defective in muscular dystrophies (dystrophin and laminin a2) and whose own aberrant post-translational modification is the common aetiological route of neuromuscular diseases associated with mutations in genes encoding at least six other proteins (POMT1, POMT2, POMGnT1, LARGE, FKTN and FKRP). It is surprising, therefore, that to our knowledge no mutations of the human dystroglycan gene itself have yet been reported. In this study, we describe a patient with a heterozygous de novo deletion of a B2-Mb region of chromosome 3, which includes the dystroglycan gene (DAG1). The patient is a 16-year-old female with learning difficulties, white matter abnormalities, elevated serum creatine kinase, oral-motor dyspraxia and facial hypotonia but minimal clinically significant involvement of other muscles. As these symptoms are a subset of those observed in disorders of dystroglycan glycosylation (muscle-eye-brain disease and WarkerWarburg syndrome), we assess the likely contribution to her phenotype of her heterogosity for a null mutation of DAG1. We also show that the transcriptional compensation observed in the Dag1 +/À mouse is not observed in the patient. Although we cannot show that haploinsufficiency of DAG1 is the sole cause of this patient's myopathy and white matter changes, this case serves to constrain our ideas of the severity of the phenotypic consequences of heterozygosity for null DAG1 mutations.

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Brain involvement in muscular dystrophies with defective dystroglycan glycosylation

Cited by 172 publications

References 55 publications

B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations

B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations

Prevalence of congenital muscular dystrophy in Italy

Heterozygous deletion of a 2-Mb region including the dystroglycan gene in a patient with mild myopathy, facial hypotonia, oral-motor dyspraxia and white matter abnormalities

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