Clinical characteristics: X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), is characterized by muscle weakness that ranges from severe to mild.
Approximately 80% of affected males present with severe (classic) X-MTM characterized by polyhydramnios, decreased fetal movement, and neonatal weakness, hypotonia, and respiratory failure. Motor milestones are significantly delayed and most individuals fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most individuals requiring 24-hour ventilatory assistance. It is estimated that at least 25% of boys with severe X-MTM die in the first year of life, and those who survive rarely live into adulthood.
Males with mild or moderate X-MTM (~20%) achieve motor milestones more quickly than males with the severe form; many ambulate independently, and may live into adulthood. Most require gastrostomy tubes and/or ventilator support. In all subtypes of X-MTM, the muscle disease is not obviously progressive. Female carriers of X-MTM are generally asymptomatic, although manifesting heterozygotes are increasingly being identified. In affected females, symptoms range from severe, generalized weakness presenting in childhood, with infantile onset similar to affected male patients, to mild (often asymmetric) weakness manifesting in adulthood. Affected adult females may experience progressive respiratory decline and ultimately require ventilatory support.
Diagnosis/testing: The diagnosis of X-MTM is established in a proband with suggestive clinical findings and identification of a hemizygous pathogenic variant in MTM1 by molecular genetic testing.
Management: Treatment of manifestations: Treatment is supportive. Management optimally involves a team of specialists with expertise in the long-term care of children and/or adults with neuromuscular disorders, often including a pulmonologist, neurologist, physical therapist and/or rehabilitation medicine specialist, and clinical geneticist. Tracheostomy, G-tube feeding, and assistive communication devices are often required. Ophthalmologists, orthopedists, and orthodontists should address specific medical complications related to the underlying myopathy.
Surveillance: Annual pulmonary assessment; polysomnography every one to three years; routine examination for scoliosis; annual ophthalmologic examinations to evaluate for ophthalmoplegia, ptosis, and myopia; routine assessment for dental malocclusion.
Genetic counseling: X-MTM is inherited in an X-linked manner. The risk to sibs of a male proband depends on the carrier status of the mother. If the mother is a carrier, each sib has a 50% chance of inheriting the MTM1 pathogenic variant. Males who inherit the variant will be affected; females who inherit the variant will be carriers and will generally not be affected. To date, there are no reported males with incomplete penetrance. In simplex cases (i.e., a single occurrence in a family), there is a probability of 80%-90% that a woman is a carrier if her son has a confirmed MTM1 pathogenic variant. Thus, about 10%-20% of males who represent simplex cases have a de novo pathogenic variant in MTM1 and a mother who is not a carrier. Germline mosaicism has been reported. Carrier testing of at-risk female relatives and prenatal testing for a pregnancy at risk are possible if the MTM1 pathogenic variant has been identified in an affected male relative.
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