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Congenital muscle disease characterized by generalized hypotonia, muscle weakness, and central nuclei on muscle biopsy (myotube-like aspect).

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XMTM; X-Linked Myotubular Myopathy; XLMTM; Centronuclear Myopathy.

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1:50,000 males births.

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Three types of myotubular myopathy are recognized based on the mode of inheritance: X-linked, autosomal recessive, and autosomal dominant. For the neonatal form, the gene has been localized on chromosome Xq28.

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The myotubular or centronuclear myopathies are a group of inherited myopathies defined by the presence of central nuclei in affected skeletal muscle. Males with XLMTM with identifiable mutations in MTM1 can be said to have MTM1. Typically, X-linked myotubular myopathy is the most severe form, presenting with hypotonia and respiratory distress in affected newborn males. It is associated with high neonatal mortality. Surviving patients typically have prolonged ventilator dependence and grossly delayed motor milestones. Female carriers of XLMTM are generally asymptomatic, although rare manifesting heterozygotes have been described. The autosomal dominant (or adult) form has a later onset and a milder course. The course and severity of the autosomal recessive (or infantile) form is intermediate between the X-linked and the autosomal dominant form. Intelligence is usually within the normal range.

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Creatine kinase level is normal or slightly increased. The diagnosis of XLMTM has traditionally relied upon the presence of characteristic pathology in muscle samples: atrophy predominantly of type I muscle fibers, which have centrally placed myofiber nuclei. The central areas of muscle fibers are devoid of myofibrils, with aggregation of mitochondria. Resemblance to fetal myotubes is thought to reflect an arrest in morphogenesis of the muscle fibers. The diagnosis of XLMTM should be considered in any male with significant neonatal hypotonia and/or muscle weakness. A positive family history suggestive of X-linked inheritance, found in approximately 30% of reported cases, provides further evidence for XLMTM. Although clinical features such as a length and head circumference greater than 90th percentile, cryptorchidism, and/or long fingers and toes are common, none is diagnostic of XLMTM. With the advent of molecular genetic testing, males with milder clinical phenotypes have been found to have mutations in the MTM1 gene.

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Neonatal Form: In males with the classic, severe, neonatal presentation, polyhydramnios with decreased fetal movement is often present. Hypotonia in the neonatal period appears to be a universal finding and, in the US series of Herman et al. (1999), 80% of patients required endotracheal intubation and ventilatory support at birth. Patients often have typical myopathic facies with dolichocephaly, a high forehead, long face with midface hypoplasia, and a narrow, high-arched palate with subsequent severe malocclusion. Additional features in the US series included length greater than 90th percentile with a proportionately lower weight (60%), long fingers and/or toes (43%), cryptorchidism (>50%), contractures including clubfeet (30%), and areflexia (60%). Many patients succumb during infancy to complications of the disorder or as a result of withdrawal of life support. For surviving patients in the United States, the average length of initial ...

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