What are myotubular and centronuclear myopathies?
Myotubular and centronuclear myopathies are a group of very rare conditions characterised by the central location of the nucleus in muscle fibres, rather than on the outer edges. Myotubular myopathy usually refers to the X-linked form (XLMTM) described below, but we also provide information about other forms of the condition.
X-linked myotubular myopathy (XLMTM) is the most common and usually the most severe form of the myotubular myopathies affecting 1 in 50,000 newborn males worldwide. This disease is characterised by profound muscle weakness (myopathy) and decreased muscle tone (hypotonia) present at birth.
Autosomal-dominant centronuclear myopathy (AD-CNM) is a disease that predominantly affects the skeletal muscles. Individuals with this form of myopathy often have normal early development. However, even in these patients, muscle weakness usually becomes evident during adolescence or early adulthood.
Autosomal-recessive centronuclear myopathy (AR-CNM) presents as progressive weakness, usually beginning at birth or childhood.
What causes myotubular and centronuclear myopathies?
XLMTM is caused by mutations in the MTM1 gene which is needed to produce the protein myotubularin – an enzyme required for muscle cell development and maintenance. The MTM1 gene is located on the X chromosome, and is inherited in an X-linked recessive pattern. As with other X-linked recessive conditions, in males (who have only one X chromosome, plus one Y chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), the mutation in one X chromosome is compensated for by their other X chromosome – a mutation would have to be present in both copies of the gene to cause the disorder. A female with one altered copy of the gene in each cell is called a carrier, and can pass on the gene, but generally does not experience signs and symptoms of the disorder.
The majority of AD-CNM and AR-CNM cases have been attributed to mutations in the DNM2, BIN1, RYR1, and more recently the TTN gene.
Mutations in the DNM2 gene causing CNM are usually associated with dominant inheritance, mutations in the RYR1 gene are usually associated with recessive inheritance, and mutations in the BIN1 gene can be associated with either dominant and recessive inheritance.
It is not well understood how mutations in these genes lead to muscle weakness and the other specific features of centronuclear myopathy. However the genes affected provide instructions for proteins that are involved in key muscle processes including muscle structure, muscle membrane trafficking, muscle fibre integrity or the process called excitation-contraction coupling which translated nerve impulses into muscle contraction.
What are the signs and symptoms of myotubular and centronuclear myopathies?
XLMTM is usually the most severe form of CNM. It usually only affects males and has the earliest onset. Often, but not always, there are signs of the disease even before birth which can include reduced foetal movement and an excess of amniotic fluid. Most babies with XLMTM are born with severe ‘floppiness’ (hypotonia) and muscle weakness. They may also experience problems with breathing (and often require mechanical ventilation) and swallowing. A child with XLMTM may appear to have a long face and their eyelids may be ‘puffy’ due to weakening of facial muscles. They may also experience tightening of the knee and ankle joints and curvature of the spine.
In AD-CNM presenting symptoms are usually difficulty walking and, in some cases, muscle pain during exercise. The condition mainly affects the skletal muscles and usually becomes evident during adolescence or early adulthood. Weakness is often progressive, and wheelchair assistance may be required in mid to late childhood. More severe presentations begin in childhood and these individuals walk later than their peers and typically need wheelchair assistance in childhood or adolescence.
In AR-CNM, symptoms may include foot abnormalities, a high-arched palate (roof of mouth) and curvature of the spine (scoliosis). Difficulties with breathing and/or feeding an also be present, which may require a feeding tube and/or assisted ventilation. More rarely, the cardiac disease can be weakened (cardiomyopathy).
How does the disease progress?
People living with XLMTM usually survive only into early childhood, however some have lived into adulthood. Some may show improvement in the first few years but may then become severely disabled. Many will require ventilation to support their breathing. Occasionally, some improve significantly and experience only mild weakness even into adulthood, however, for those requiring breathing support from birth or early in life, this is unlikely.
AD-CNM often has a gradual onset and is slowly progressive. It may not cause a person to seek medical attention until young adulthood. AR-CNM tends to begin earlier and is more severe.