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Brain involvement in muscular dystrophies with defective dystroglycan glycosylation

Authors

  • Emma Clement MBChB,

    1. Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom
    2. Department of Paediatrics, Hammersmith Hospital, Imperial College London, London, United Kingdom
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    • E.C. and E.M. contributed equally to this work.

  • Eugenio Mercuri MD,

    1. Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom
    2. Department of Pediatric Neurology, Catholic University, Rome, Italy
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    • E.C. and E.M. contributed equally to this work.

  • Caroline Godfrey BSc,

    1. Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom
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  • Janine Smith MBChB,

    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Faculty of Medicine, University of Sydney, Sydney, Australia
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  • Stephanie Robb MD,

    1. Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom
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  • Maria Kinali MRCPCH, MD,

    1. Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom
    2. Department of Paediatrics, Hammersmith Hospital, Imperial College London, London, United Kingdom
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  • Volker Straub MD,

    1. Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Newcastle upon Tyne, United Kingdom
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  • Kate Bushby MD,

    1. Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Newcastle upon Tyne, United Kingdom
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  • Adnan Manzur FRCPCH,

    1. Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom
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  • Beril Talim MD,

    1. Hacettepe Children's Hospital, Ankara, Turkey
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  • Frances Cowan MD, PhD,

    1. Department of Paediatrics, Hammersmith Hospital, Imperial College London, London, United Kingdom
    2. Department of Imaging Sciences, Imperial College, Hammersmith Hospital, London
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  • Ros Quinlivan FRCPCH,

    1. Centre for Inherited Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom
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  • Andrea Klein MD,

    1. Department of Neurology, University Children's Hospital Zurich, Zurich, Switzerland
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  • Cheryl Longman MD,

    1. Ferguson Smith Centre for Clinical Genetics, London, United Kingdom
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  • Robert McWilliam FRCPCH,

    1. Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children,Yorkhill Hospitals, Glasgow
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  • Haluk Topaloglu MD,

    1. Hacettepe Children's Hospital, Ankara, Turkey
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  • Rachael Mein BSc,

    1. DNA Laboratory, Genetics Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom
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  • Stephen Abbs PhD,

    1. DNA Laboratory, Genetics Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom
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  • Kathryn North MD,

    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Faculty of Medicine, University of Sydney, Sydney, Australia
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  • A. James Barkovich MD,

    1. Department of Radiology, University of California at San Francisco, San Francisco, CA
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  • Mary Rutherford MD, PhD,

    1. Robert Steiner Magnetic Resonance Unit, Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, United Kingdom
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  • Francesco Muntoni MD

    Corresponding author
    1. Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom
    2. Department of Paediatrics, Hammersmith Hospital, Imperial College London, London, United Kingdom
    • Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital for Children, 30 Guilford Street, London WC1N 1EH, United Kingdom
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  • Potential conflict of interest: Nothing to report.

Abstract

Objective

To assess the range and severity of brain involvement, as assessed by magnetic resonance imaging, in 27 patients with mutations in POMT1 (4), POMT2 (9), POMGnT1 (7), Fukutin (4), or LARGE (3), responsible for muscular dystrophies with abnormal glycosylation of dystroglycan (dystroglycanopathies).

Methods

Blinded review of magnetic resonance imaging brain scans from 27 patients with mutations in 1 of these 5 genes.

Results

Brain magnetic resonance images were normal in 3 of 27 patients; in another 5, only nonspecific abnormalities (ventricular dilatation, periventricular white matter abnormalities, or both) were seen. The remaining 19 patients had a spectrum of structural defects, ranging from complete lissencephaly in patients with Walker–Warburg syndrome to isolated cerebellar involvement. Cerebellar cysts and/or dysplasia and hypoplasia were the predominant features in four patients. Polymicrogyria (11/27) was more severe in the frontoparietal regions in 6, and had an occipitofrontal gradient in 2. Pontine clefts, with an unusual appearance to the corticospinal tracts, were seen in five patients with a muscle-eye-brain–like phenotype, three patients with POMGnT1, one with LARGE, and one with POMT2 mutations. Prominent cerebellar cysts were always seen with POMGnT1 mutations, but rarely seen in POMT1 and POMT2. Brainstem and pontine abnormalities were common in patients with POMT2, POMGnT1, and LARGE mutations.

Interpretation

Our results expand the spectrum of brain involvement associated with mutations in LARGE, POMGnT1, POMT1, and POMT2. Pontine clefts were visible in some dystroglycanopathy patients. Infratentorial structures were often affected in isolation, highlighting their susceptibility to involvement in these conditions. Ann Neurol 2008;64:573–582

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