X-linked CNM (myotubular myopathy)
Thought to be the most common form of centronuclear myopathy, myotubular myopathy (XLMTM) is caused by a mutation in the myotubularin (MTM1) gene, which produces a protein called myotubularin. This protein, which is lacking in patients with XLMTM, is required in muscle development for the formation of adult muscle and for muscle maintenance.
Myotubular myopathy gets its name from the appearance of the muscle biopsies under the microscope. They show the presence of structures that look like ‘myotubes’ or immature muscle cells.
The MTM1 gene is located on the X chromosome. All individuals have 46 chromosomes, two of which are the sex chromosomes. Females have two copies of the X chromosome, while males have one copy of X and one copy of the Y chromosome. If a male’s X chromosome has the MTM1 mutation, he will have the condition.
If a female has the mutation on one of her X chromosomes, usually her other X chromosome will compensate and she will not have the condition. She will, however, be a carrier of the condition and could pass the mutated X chromosome on to her children. It is also possible for female carriers to have symptoms of XLMTM (known as ‘manifesting carriers’), although this is quite rare.
Autosomal dominant CNM
Our genes are inherited in pairs, with one copy coming from each parent. ‘Autosomal dominant inheritance’ means that a mutation on one copy of the gene will cause the condition. The other, healthy copy cannot compensate. This form of CNM is rare and affects both males and females, often in different generations within the same family.
A large proportion of cases of autosomal dominant CNM result from mutations in the dynamin 2 (DNM2) gene. Alterations in DNM2 have also been implicated in two different neuromuscular conditions where the peripheral nerves are affected. These are called dominant intermediate Charcot Marie Tooth neuropathy (CMT) and CMT type 2M.
Autosomal recessive CNM
‘Autosomal recessive inheritance’ means that two copies of the mutated gene are needed to cause the condition. In other words, each parent carries a copy of the mutated gene. In contrast to autosomal dominant inheritance, however, the parents don’t usually show any signs of the condition. This form of the condition is rare and affects both males and females.
Several genes are known to be associated with autosomal recessive forms of CNM. This includes the BIN1 gene, encoding a protein called amphiphysin 2, and the RYR1 gene, encoding a protein called ryanodine receptor 1. Mutations in the RYR1 gene have also been implicated in other congenital myopathies, namely central core disease (CCD), multi-minicore disease (MmD) and congenital fibre type disproportion (CFTD).
Recently, recessive forms of centronuclear myopathy have also been attributed to mutations in the TTN gene, which is implicated in several other congenital myopathies but also cardiac muscle disease (cardiomyopathy). Another rare form associated with cardiac involvement is due to mutations of the SPEG10 gene. As genetic research moves forward, it is likely that other genes responsible for centronuclear myopathies are going to be identified.