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Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation

From the Department of Neuromuscular Research (I.S., S.W., C.A.I.M., Y.K.H., I.N., S.N., I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Department of Pediatrics (I.S.), Tohoku University School of Medicine, Sendai, Department of Pediatrics (H.F.), Hirosaki University School of Medicine, Department of Pediatrics (M.T.), Niigata Prefecture Hamagumi Medical Rehabilitation Center for Handicapped Children, Japan; and Department of Neurology (S.J.O.), University of Alabama at Birmingham.

Address correspondence and reprint requests to Dr. I. Nishino, Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan nishino{at}ncnp.go.jp

Background: Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is a rare form of congenital myopathy, which is pathologically diagnosed by the presence of more than 99% of type 1 fiber, with no specific structural changes. Its pathogenic mechanism is still unknown. We recently reported that almost all patients with central core disease (CCD) with ryanodine receptor 1 gene (RYR1) mutations in the C-terminal domain had type 1 fibers, nearly exclusively, in addition to typical central cores.

Objective: To investigate whether CNMDU1 is associated with RYR1 mutation.

Methods: We studied 10 unrelated Japanese patients who were diagnosed to have CNMDU1 based on clinical features and muscle pathology showing more than 99% type 1 muscle fibers. We extracted genomic DNA from frozen muscles and directly sequenced all 106 exons and their flanking intron–exon boundaries of RYR1.

Results: Four of 10 patients had a heterozygous mutation, three missense and one deletion, all in the C-terminal domain of RYR1. Two missense mutations were previously reported in CCD patients. Clinically, patients with mutations in RYR1 showed milder phenotype compared with those without mutations.

Conclusion: Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) in 40% of patients is associated with mutations in the C-terminal domain of RYR1, suggesting that CNMDU1 is allelic to central core disease at least in some patients.

Editorial, see page 99

e-Pub ahead of print on May 30, 2007, at www.neurology.org.

Supported by "Research on Psychiatric and Neurological Diseases and Mental Health" from Health and Labor Sciences Research Grants; "Research on Health Sciences Focusing on Drug Innovation" from the Japanese Health Sciences Foundation; "Research Grant (16B-2, 17A-10) for Nervous and Mental Disorders" from the Ministry of Health, Labor, and Welfare; and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO).

Disclosure: The authors report no conflicts of interest.

Received December 4, 2006. Accepted in final form February 26, 2007.

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