Mutations in TPM3 are a common cause of congenital fiber type disproportion

Authors

  • Nigel F. Clarke MBChB, PhD,

    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
    Search for more papers by this author
  • Hanna Kolski MD,

    1. Division of Pediatric Neurology, Department of Pediatrics, Stollery Children's Hospital, University of Alberta Hospital, Edmonton, Canada
    Search for more papers by this author
  • Danielle E. Dye BSc (Hons),

    1. Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, QEII Medical Centre, Perth
    Search for more papers by this author
  • Esther Lim BSc,

    1. Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, QEII Medical Centre, Perth
    Search for more papers by this author
  • Robert L. L. Smith FRACP,

    1. John Hunter Children's Hospital and University Discipline of Paediatrics and Child Health, Newcastle, Australia
    Search for more papers by this author
  • Rakesh Patel FRACP,

    1. Starship Children's Hospital, University of Auckland, Auckland, New Zealand
    Search for more papers by this author
  • Michael C. Fahey FRACP,

    1. Monash Neurology, Monash Medical Centre, Melbourne, Australia
    Search for more papers by this author
  • Rémi Bellance MD,

    1. Centre de Référence Maladies Rares Neurologiques et Neuromusculaires, Centre Hospitalier Universitaire de Fort-de-France, Martinique
    Search for more papers by this author
  • Norma B. Romero MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    Search for more papers by this author
  • Edward S. Johnson MD,

    1. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
    Search for more papers by this author
  • Annick Labarre-Vila MD,

    1. Centre de Référence des Maladies Neuromusculaires, Pôle de Psychiatrie et Neurologie, Centre Hospitalier Universitaire Grenoble
    Search for more papers by this author
  • Nicole Monnier PhD,

    1. Biochimie et Génétique Moléculaire, Centre Hospitalier Universitaire Grenoble/Institut National de la Sante et de la Recherche Médicale U836, Grenoble, France
    Search for more papers by this author
  • Nigel G. Laing PhD,

    1. Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, QEII Medical Centre, Perth
    Search for more papers by this author
  • Kathryn N. North MBBS, MD

    Corresponding author
    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
    • Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia
    Search for more papers by this author

Abstract

Objective

Congenital fiber type disproportion (CFTD) is a rare form of congenital myopathy in which the principal histological abnormality is hypotrophy of type 1 (slow-twitch) fibers compared with type 2 (fast-twitch) fibers. To date, mutation of ACTA1 and SEPN1 has been associated with CFTD, but the genetic basis in most patients is unclear. The gene encoding α-tropomyosinslow(TPM3) is a rare cause of nemaline myopathy, previously reported in only five families. We investigated whether mutation of TPM3 is a cause of CFTD.

Methods and Results

We sequenced TPM3 in 23 unrelated probands with CFTD or CFTD-like presentations of unknown cause and identified novel heterozygous missense mutations in five CFTD families (p. Leu100Met, p.Arg168Cys, p.Arg168Gly, p.Lys169Glu, p.Arg245Gly). All affected family members that underwent biopsy had typical histological features of CFTD, with type 1 fibers, on average, at least 50% smaller than type 2 fibers. We also report a sixth family in which a recurrent TPM3 mutation (p.Arg168His) was associated with histological features of CFTD and nemaline myopathy in different family members. We describe the clinical features of 11 affected patients. Typically, there was proximal limb girdle weakness, prominent weakness of neck flexion and ankle dorsiflexion, mild facial weakness, and mild ptosis. The age of onset and severity varied, even within the same family. Many patients required nocturnal noninvasive ventilation despite remaining ambulant.

Interpretation

Mutation of TPM3 is the most common cause of CFTD reported to date. Ann Neurol 2008

Ancillary