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X-linked myotubular myopathy (XLMTM) is an inherited neuromuscular disorder defined by numerous centrally placed nuclei on muscle biopsy and clinical features of a congenital myopathy. The incidence of XLMTM is estimated at 1/50,000 male births. The disease is characterized by a severe phenotype in males presenting at birth with marked weakness, hypotonia and respiratory failure. Signs of antenatal onset are frequent and comprise reduced fetal movements and polyhydramnios. Thinning of the ribs is observed on chest radiographs of the newborn. Birth asphyxia may be the presenting feature. A family history of either male neonatal deaths or miscarriages is common. Affected infants are often macrosomic, with a body length above the 90th centile and large head circumference. External ophthalmoplegia is commonly associated. Testes are frequently undescended. Pyloric stenosis and cavernous hemangiomas of the liver have been reported in some long-term survivors. The majority of disease carriers are asymptomatic or show signs of only mild muscle weakness. Presentation may be overt in some females, especially if additional genetic abnormalities, such as skewed X-inactivation, are present. Urinary incontinence may be an additional feature in females, indicating smooth muscle involvement. XLMTM is caused by mutations in the myotubularin (MTM1; Xq27.3-q28) gene. Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features. Genetic testing confirms the diagnosis and genetic counseling should be offered to all patients and families. The main differential diagnoses include congenital myotonic dystrophy and other conditions characterized by severe neonatal hypotonia (see these terms). There is currently no curative treatment available. Management is supportive and based on a multidisciplinary approach. In the majority of cases, the course is fatal within the first months of life. A proportion of affected males may survive into their teens or beyond. In these cases, the survival depends on a substantial degree of medical intervention and often constant ventilation. |