This section of soleus muscle demonstrates the striations characteristic of skeletal muscle. However, the myocyte nuclei are located centrally within the fiber in 25 - 50% of fibers, rather than in the peripheral location normally seen in skeletal muscle.

Centronuclear myopathy (also known as myotubular myopathy) is a congenital disorder with 3 subtypes based on the age of onset of clinical disease. The early or infantile form presents as a floppy infant at birth. The juvenile form is the most common and presents in late infancy with slowly progressive muscle weakness. The adult form has a relatively benign course.

The infantile form of centronuclear myopathy is rare, with only 15 families described in the literature by 1990 (Darnfors et al. Clin. Genetics 37:335-340, 1990). It has an X-linked recessive form of inheritance. Affected infants are severely hypotonic with respiratory distress. Prenatally, these infants exhibit polyhydramnios and weak fetal movements (Donders et al. Eur. J. Obstet. Gynecol. Reprod. Biol. 24:33-38, 1987). The neonatal mortality is 80%. The major histologic findings are muscle fibers with centrally placed nuclei in 10-50% of fibers, with perinuclear halos (Sasaki et al. Brain Develop. 11:26-32, 1989). All of these features were present in the current case.

The gene for this disorder was localized by positional cloning to Xq28, corresponding to the myotubularin locus. Myotubularin has a tyrosine phosphatase (PTP) domain and is highly conserved through evolution. A variety of mutations were discovered in patients with X-linked centronuclear myopathy, including point mutations, deletions, and splice mutations. Five point mutations were found in multiple unrelated patients, accounting for 27% of the observed mutations. The possibility of detecting mutations and determining carrier status in a disease with a high proportion of sporadic cases is of importance for genetic counselling. More than half of these mutations are expected to inactivate the putative enzymatic activity of myotubularin, either by truncation or by missense mutations affecting the predicted PTP domain.

de Gouyon BM . Zhao W. Laporte J. Mandel JL. Metzenberg A. Herman GE. Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy. Human Mol Genet 6:1499-1504, 1997.

Laporte J. Guiraud-Chaumeil C. Vincent MC. Mandel JL. Tanner SM. Liechti-Gallati S. Wallgren-Pettersson C. Dahl N. Kress W. Bolhuis PA. Fardeau M. Samson F. Bertini E. Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. Human Molecular Genetics. 6(9):1505-1511, 1997