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NEUROLOGY 2005;65:1930-1935
© 2005 American Academy of Neurology

Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene

H. Jungbluth, MD, PhD, H. Zhou, MD, PhD, L. Hartley, B. Halliger-Keller, S. Messina, MD, C. Longman, M. Brockington, S. A. Robb, MD, V. Straub, MD, PhD, T. Voit, MD, PhD, M. Swash, MD, A. Ferreiro, MD, PhD, G. Bydder, PhD, C. A. Sewry, PhD, C. Müller, PhD and F. Muntoni, MD

From Dubowitz Neuromuscular Centre (Drs. Jungbluth, Zhou, Messina, Sewry, and Muntoni, and L. Hartley, C. Longman, and M. Brockington) and Robert Steiner MRI Unit (Dr. Bydder), Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK; Department of Paediatric Neurology (Drs. Jungbluth and Robb), Guy’s Hospital, London, UK; Institut für Humangenetik (B. Halliger-Keller and Dr. Müller), Universität Würzburg, Biozentrum am Hubland, Würzburg, Germany; Institute for Human Genetics (Dr. Straub), International Centre for Life, University of Newcastle upon Tyne, UK; Department of Pediatrics and Pediatric Neurology (Dr. Voit), University Hospital Essen, Germany; Department of Neurology (Dr. Swash), The Royal London Hospital, London, UK; Institut de Myologie (Dr. Ferreiro), Bâtiment Babinski, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; and Department of Histopathology (Dr. Sewry), Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK.

Address correspondence and reprint requests to Dr. Heinz Jungbluth, Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; e-mail: h.jungbluth{at}imperial.ac.uk

Background: Minicore myopathy (multi-minicore disease [MmD]) is a congenital myopathy characterized by multifocal areas with loss of oxidative activity on muscle biopsy. MmD is clinically heterogeneous and distinct phenotypes have been associated with recessive mutations in either the selenoprotein N (SEPN1) or the skeletal muscle ryanodine receptor (RYR1) gene, also implicated in central core disease and malignant hyperthermia. External ophthalmoplegia is an additional finding in a subset of patients with MmD.

Objective: To clinically and genetically examine families with MmD and external ophthalmoplegia.

Methods: The authors investigated 11 affected individuals from 5 unrelated families. Clinical, histopathologic, and imaging studies were performed and RYR1 haplotyping and mutational analysis were carried out.

Results: All patients had multiple cores involving the entire fiber diameter on longitudinal sections. Weakness and wasting in the shoulder girdle, scoliosis, moderate respiratory impairment, and feeding difficulties were prominent. In contrast to SEPN1-related myopathies, soleus was more severely affected than gastrocnemius on muscle MRI. Haplotyping suggested linkage to the RYR1 locus in informative families and mutational screening revealed four novel RYR1 mutations in three unrelated families; in addition, functional haploinsufficiency was found in one allele of two recessive cases.

Conclusion: These findings expand the phenotypic spectrum associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Recessive mutations of domains commonly affected in malignant hyperthermia appear to be particularly prevalent in multi-minicore disease with external ophthalmoplegia and might suggest a different pathomechanism from that involved in central core disease.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 27 issue to find the title link for this article.

Supported by the Muscular Dystrophy Campaign of Great Britain and the European Neuromuscular Consortium.

Disclosure: The authors report no conflicts of interest.

Received June 2, 2004. Accepted in final form September 2, 2005.




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H. Zhou, H. Jungbluth, C. A. Sewry, L. Feng, E. Bertini, K. Bushby, V. Straub, H. Roper, M. R. Rose, M. Brockington, et al.
Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies
Brain, August 1, 2007; 130(8): 2024 - 2036.
[Abstract] [Full Text] [PDF]


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