Early prenatal diagnosis of XLR centronuclear myopathy using mutation analysis and early histopathological changes in an affected fetus. D. Cushing¹, S. Liechti-Gallati², A. Chan¹, V. Jay³, D. Chitayat¹. 1) Prenatal Diagnosis Program, University of Toronto, Toronto, Ontario, Canada; 2) Department of Human Molecular Genetics, Children's Hospital, Inselspital, Bern, Switzerland; 3) Department of Pathology, University of Toronto, Toronto, Ontario, Canada.

   X-linked centronuclear myopathy (XLR-CNM, OMIM #310400) is a myopathy resulting in severe hypotonia and respiratory failure. The disease is caused by a mutation in the MTM1 gene mapped to Xq28. We report early prenatal diagnosis in a family with XLR-CNM due to a 340insA mutation in exon 5 of the MTM1 gene and the fetal histopathological findings at 14 weeks gestation. The patient was a 34 year old woman whose first son was delivered at 28 weeks gestation with hypotonia and respiratory difficulties and died at 6 months of age. Muscle biopsy was consistent with CNM. Muscle biopsy on the patient demonstrated muscle fibres with increased central nuclei consistent with a carrier state for XLR-CNM. In her subsequent pregnancy the patient decided to pursue early prenatal diagnosis. Mutation analysis on the patient demonstrated she is a carrier of the 340insA mutation in exon 5 of the MTM1 gene(previously reported in XLR-CNM) and analysis of fetal DNA extracted from CVS showed the fetus to be an affected male. The pregnancy was terminated at 15 weeks gestation and histopathology confirmed prominent central nuclei and type 1 predominance consistent with CNM. Review of the family history showed that the patient had a brother and two maternal uncles who died in infancy of unknown etiology. To the best of our knowledge this is the first reported case of prenatal diagnosis of XLR-CNM by mutation analysis and the earliest fetal muscle histopathology showing that the muscle changes present very early in pregnancy. Since similar histological changes can be detected in normal fetuses, prenatal diagnosis is most reliable by mutation analysis.