Centronuclear myopathy

History

In 1966, Dr. Spiro, a New York City neurologist, published a medical report of a boy with myopathy whose muscle biopsy showed nuclei located in the center of muscle cells instead of the periphery. More than three decades later, it remains uncertain whether the theory of halted or delayed embryonic muscle development is correct. Some research suggests this theory may apply to infant-onset myotubular myopathy (MTM1 mutations) but not to autosomal forms, while other research suggests the growth arrest mechanism may be responsible for all forms of MTM and CNM. Regardless, the name myotubular myopathy persists for historical reasons.

Presentation

Centronuclear myopathies are primarily marked by muscle weakness and the disabilities that follow. In congenital cases, babies often have low muscle tone at birth, significant weakness, and delays in reaching gross motor milestones like holding up their head, crawling, or walking. Respiratory muscles can be affected, leading to lung complications. Facial muscle weakness may cause drooping eyelids or limited eye movement.

A mutation in the RYR1 gene can also raise the risk of malignant hyperthermia, a dangerous reaction to anesthesia. The degree of impairment varies widely: some people stay able to walk throughout life, while others never crawl or walk and may need a wheelchair. Though only voluntary muscles are involved, some children have experienced cardiac arrest, possibly from extra strain on the heart. The X-linked form, myotubular myopathy, was once usually fatal in infancy, with survival typically under two years.

Severity can differ even among people with different mutations in the same MTM1 gene, and even among relatives sharing the same mutation. Most truncating MTM1 mutations lead to severe, early lethal disease, but some missense mutations allow milder forms and survival into the 50s. Centronuclear myopathies generally have a milder course and better outlook. Autosomal dominant CNM is usually less severe than the recessive type.

Mutations in the DNM2 gene cause the autosomal dominant form, now called DNM2-CNM, which features slowly progressive weakness that typically starts between ages 12 and 74.

Genetic

The X-linked form of myotubular myopathy (XLMTM) was localized in 1990 to Xq28. The MTM1 gene codes for myotubularin, a lipid phosphatase involved in cellular transport and signalling. About 80% of males diagnosed with myotubular myopathy by muscle biopsy have MTM1 mutations, and about 7% of these are deletions. Centronuclear myopathies not sex-linked are autosomal, either dominant (AD) or recessive (AR).

Epidemiology

Myotubular myopathy occurs in about one of every fifty thousand male births. Other centronuclear myopathies are far rarer, with only nineteen families known globally.

Most affected individuals need walking aids like a cane or walker. Severe cases requiring full-time wheelchair or stand aid use are exceptionally uncommon, with just two documented within the CNM community. For roughly eighty percent of males diagnosed with myotubular myopathy via muscle biopsy, genetic testing reveals a mutation in the MTM1 gene.

Did You Know?

• Centronuclear myopathy is diagnosed when typical histological findings on muscle biopsy are combined with suggestive clinical symptoms; muscle MR imaging may supplement assessment and inform genetic testing.
• On muscle biopsy, centronuclear myopathy shows centrally located nuclei encircled by a perinuclear halo filled with aggregates of glycogen and mitochondria but without myofilaments.
• All muscles, including extra-ocular muscles, have the distinctive central nucleus, which can affect up to 90% of the fibers.