X-Linked Myotubular Myopathy
X-linked myotubular myopathy is a condition that primarily affects muscles used for movement (skeletal muscles) and occurs almost exclusively in males.
Because of their severe breathing problems, individuals with X-linked myotubular myopathy usually survive only into early childhood; however, some people with this condition have lived into adulthood.
X-linked myotubular myopathy is a member of a group of disorders called centronuclear myopathies. In centronuclear myopathies, the nucleus is found at the center of many rod-shaped muscle cells instead of at either end, where it is normally located.
The incidence of X-linked myotubular myopathy is estimated to be 1 in 50,000 newborn males worldwide.
People with this condition have muscle weakness (myopathy) and decreased muscle tone (hypotonia) that are usually evident at birth. These muscle problems impair the development of motor skills such as sitting, standing, and walking. Affected infants may also have difficulties with feeding due to muscle weakness. Individuals with X-linked myotubular myopathy frequently do not have the muscle strength to breathe unassisted and must be supported with a machine to help them breathe (mechanical ventilation). Some individuals need breathing assistance only periodically, typically during sleep, while others require it continuously. Affected individuals may also have weakness in the muscles that control eye movement (ophthalmoplegia), weakness in other muscles of the face, absent reflexes (areflexia), an abnormal curvature of the spine (scoliosis), joint deformities (contractures) of the hips and knees, and a large head with a narrow and elongated face.
Mutations in the MTM1 gene cause X-linked myotubular myopathy. The MTM1 gene provides instructions for producing an enzyme called myotubularin. Myotubularin is thought to be involved in the development and maintenance of muscle cells.
MTM1 gene mutations probably disrupt myotubularin's role in muscle cell development and maintenance, causing muscle weakness and other signs and symptoms of X-linked myotubular myopathy.
This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the gene, but generally does not experience signs and symptoms of the disorder. In rare cases, however, carrier females have experienced some muscle weakness associated with X-linked myotubular myopathy.
Braga et al. (1990) reported 7 cases from 3 families, calling attention to the prenatal onset and rapid progression of the disorder. They concluded that needle biopsy of muscle, showing an increased number of centrally located nuclei with perinuclear halos, is a 'powerful tool for early diagnosis.'
Sarnat (1990) found by immunohistochemical studies persistence of desmin and vimentin in 2 female carriers of the X-linked form, which they thought might be useful in carrier detection. In 3 mothers of boys with X-linked centronuclear myopathy, one of them an obligate carrier, Breningstall et al. (1991) found abnormalities of nonspecific character on muscle biopsy. They reviewed other experience with muscle biopsy in possible carriers and concluded that a more specific tissue marker is required before muscle biopsy can facilitate carrier identification.
Laporte et al. (2001) found that 87% (21/24) of patients with known MTM1 mutations showed reduced myotubularin levels in a variety of cell lines, as detected by immunoprecipitation followed by Western blot analysis. Four patients were diagnosed by immunoprecipitation before mutations in the MTM1 gene were identified. The authors suggested that this would be a rapid and helpful method for initial diagnosis of XLMTM.
Heckmatt et al. (1985) reported in detail on 8 unrelated children. They pointed out that the severity, mode of presentation and pedigree pattern permit definition of 3 types: a severe neonatal X-linked recessive type, a less severe infantile or juvenile autosomal recessive type (255200), and a yet milder autosomal dominant type (160150).
Wallgren-Pettersson et al. (1995) reviewed data relevant to the differential diagnosis of the X-linked, autosomal dominant, and autosomal recessive forms of myotubular myopathy. Whereas the X-linked recessive form is well documented, information is scantier on the autosomal dominant and autosomal recessive forms. No clear consensus exists regarding the use of the alternative names myotubular or central nuclear myopathy. Quantitative clinical differences existed between the 3 types, in regard to age at onset, severity of the disease, and prognosis, and also regarding some of the clinical characteristics. The autosomal dominant form had a later onset and milder course than the X-linked form, and the autosomal recessive form was intermediate in both respects. Wallgren-Pettersson et al. (1995) noted that determining the mode of inheritance and prognosis in individual families, especially those with a single male patient, poses a problem.
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Myotubular myopathy: arrest of morphogenesis of myofibres associated with persistence of fetal vimentin and desmin: four cases compared with fetal and neonatal muscle. Can. J. Neurol. Sci. 17: 109-123, 1990.
Maternal muscle biopsy in X-linked recessive centronuclear (myotubular) myopathy.Am. J. Med. Genet. 39: 13-18, 1991.
Diagnosis of X-linked myotubular myopathy by detection of myotubularin. Ann. Neurol. 50: 42-46, 2001.
Congenital centronuclear (myotubular) myopathy: a clinical, pathological and genetic study in eight children. Brain 108: 941-964, 1985.
The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. J. Med. Genet. 32: 673-679, 1995.
X-linked myotubular myopathy (XLMTM) is a severe muscle disease caused by an absence of a protein called myotubularin. There is currently no treatment for this disorder, and most patients die in infancy or childhood. The overall incidence of myotubular myopathy is 1 in 50,000 live male births.
Michael W. Lawlor, MD, PhD, assistant professor of pathology at MCW, researcher at the Children’s Hospital of Wisconsin Research Institute, and director of the pediatric pathology neuromuscular laboratory in MCW’s division of pediatric pathology, coordinated a study at Boston Children’s Hospital and MCW that used targeted enzyme replacement therapy to deliver myotubularin to muscles of mice with XLMTM. After two weeks of treatment, the mice showed marked improvement in muscle function and pathology.
“These promising findings suggest that even low levels of myotubularin protein replacement can not only improve weakness in patients, but also at least partially reverse the structural abnormalities seen in XLMTM,” said Dr. Lawlor. “The next step is to determine appropriate dosage, and toxicity, before we venture into human trials,” he continued.
The study was supported by the National Institutes of Health, the Muscular Dystrophy Association, the Joshua Frase Foundation, and the Lee and Penny Anderson Family Foundation.