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X-linked centronuclear myopathy
A rare X-linked congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and that presents at birth with marked weakness, hypotonia and respiratory failure.
ORPHA:596Classification level: Disorder
The birth prevalence of X-linked centronuclear myopathy (XLMTM) is estimated at 1/50,000 males.
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.
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.
The main differential diagnoses include congenital myotonic dystrophy and other conditions characterized by severe neonatal hypotonia.
Prenatal diagnosis is possible where the mutation has been previously identified in a family member.
The pattern of inheritance is x-linked recessive. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%; female offspring have a 50% risk of being carriers. The degree of disease penetrance depends on skewed X-inactivation; the majority of female disease carriers are asymptomatic but may show signs of only mild muscle weakness or urinary incontinence may, indicating smooth muscle involvement. Genetic counseling should be offered to all patients and families.
Management and treatment
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.
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