Other Names: X-linked centronuclear myopathy; XLCNM; XLMTM

X-linked myotubular myopathy (XLMTM) a life-threatening, rare neuromuscular disease characterized by myopathy and hypotonia. Development of motor skills such as sitting, standing, and walking are impaired as a result of muscle weakness. Breathing and feeding may also be disrupted. Mortality rates are estimated to be 50 percent in the first 18 months of life, and for those patients who survive past infancy, approximately 75 percent will live to the age of 10. XLMTM is caused by mutations in the MTM1 gene and is inherited in an X-linked recessive manner. 

 

Pathophysiology and Epidemiology

XLMTM is caused by mutations in the MTM1 gene. These mutations cause a lack or dysfunction of myotubularin, a protein involved in the development, maturation, and function of skeletal muscle cells. The disease affects approximately 1 in 40,000 to 50,000 newborn males. 

 

Signs and Symptoms

The specific symptoms and severity of XLMTM can vary greatly from one person to another, though the majority of individuals with XLMTM have a severe presentation. While the disorder may be fatal during infancy or childhood, some affected individuals will only develop mild to moderate symptoms.

In the severe form of XLMTM, affected male infants exhibit extreme muscle weakness and hypotonia at or shortly after birth. Weakness of the muscles used to breathe and swallow can cause respiratory distress and feeding difficulties during infancy often noticeable within the first few days or weeks of life. Respiratory distress can be present at birth and can cause affected infants to require constant, prolonged ventilation during infancy. Affected infants may be unable to suck, swallow or breathe on their own. 

Affected infants often have distinctive facial features including a high forehead, midface hypoplasia, weakness of facial muscles, and dolichocephaly with a long face. Some infants have a narrow, high-arched palate and later on develop severe malocclusion. Partial or complete ophthalmoparesis is also common. Ptosis and myopia may also occur.

 

Diagnosis

XLMTM should be suspected in newborns with hypotonia and muscle weakness and older male children with weakness in the arms and legs and diminished muscle bulk. A diagnosis is based upon identification of additional characteristic symptoms (e.g. cryptorchidism, long fingers and toes, macrocephaly), a detailed family history, a thorough clinical evaluation, and a variety of specialized tests.

Clinical Testing and Workup

A muscle biopsy may be performed to aid in obtaining a diagnosis. A diagnosis of XLMTM is confirmed through molecular genetic testing, which can detect mutations in the MTM1 gene causative of the disorder. 

 

Management and Treatment

The treatment of XLMTM is directed toward the specific symptoms apparent in each individual. Treatment will require the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. This team may include pediatricians, pulmonologists, neurologists, orthopedists, eye specialists, dental specialists, and other healthcare professionals.

The treatment of affected individuals usually requires intensive medical intervention. Some affected individuals will require prolonged, constant ventilation support. In some individuals feeding difficulties will require gastrostomy. 

Physical and occupational therapy is recommended to improve muscle strength and prevent contractures. Special measures may be necessary to allow ventilator-dependent individuals to communicate. Additional therapies are symptomatic and supportive. For example, scoliosis may require surgical intervention.

There are a number of investigational therapies being studied including gene therapies, protein replacement therapies, and treatments aimed at the neuromuscular junction. One gene therapy of particular interest is AT132, being developed by Astellas Gene Therapies. AT132 is an AAV8 vector containing a functional copy of the MTM1 gene.

 

Clinical Trials:

For a full list of clinical trials relating to XLMTM, go here.

 

Resources:

Joshua Frase Foundation

Myotubular Trust

X-Linked Myotubular Myopathy – NORD

X-Linked Myotubular Myopathy – NIH