Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene

Received 5 August 2009; received in revised form 6 December 2009; accepted 15 December 2009.

Abstract

The skeletal muscle ryanodine receptor plays a crucial role in excitation–contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca2+ release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.

Keywords: Multi-minicore disease (MmD), Periodic paralysis, Excitation–contraction coupling (ECC), Skeletal muscle ryanodine receptor (RYR1) gene

a Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital for Children, London, UK

b DNA Laboratory, GSTS Pathology, Guy’s Hospital, London, UK

c University of Rochester Medical Center, Department of Pharmacology and Physiology, Rochester, New York, USA

d University of North Carolina, Department of Biochemistry and Biophysics, Chapel Hill, North Carolina, USA

e Department of Neurology, King’s College Hospital, London, UK

f Department of Neurophysiology, King’s College Hospital, London, UK

g Department of Clinical Neuropathology, King’s College Hospital, London, UK

h Department of Clinical Neurosciences, Charing Cross Hospital, London, UK

i MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

j Centre for Inherited Neuromuscular Disorders, RJAH Orthopaedic Hospital, Oswestry, UK

k Departments of Anaesthesia and Research, Basel University Hospital, 4031 Basel, Switzerland

l Department of Paediatric Neurology, Evelina Children’s Hospital, St. Thomas’ Hospital, London, UK

m Clinical Neuroscience Division, King’s College, London, UK

Corresponding author. Address: Clinical Neuroscience Division, King’s College London, and Department of Paediatric Neurology, Evelina Children’s Hospital, Guy’s & St. Thomas’ NHS Foundation Trust, Lambeth Palace Road, London SE1 7EH, UK.

PII: S0960-8966(09)00716-0

doi:10.1016/j.nmd.2009.12.005

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