Congenital muscle disease characterized by generalized
hypotonia, muscle weakness, and central nuclei on muscle biopsy
XMTM; X-Linked Myotubular Myopathy; XLMTM; Centronuclear
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.
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.
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.
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 ...