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 cells, in which it is normally found at the periphery. Myotubular Myopathy normally refers to the X-linked form described here, but we also provide information about other manifistantions of the condition.
X-linked Myotubular Myopathy (XLMTM)
This is the most common of the myotubular myopathies affecting 1 in 50,000 new-born males worldwide. This is usually the most severe form with profound muscle weakness (myopathy) and decreased muscle tone (hypotonia) present at birth. Primarily affecting the skeletal muscle, motor skills are predominantly affected, causing difficulties with sitting, standing and walking. In addition, there are associated breathing and swallowing difficulties as the muscles involved in taking a breath, and in swallowing are also involved. Curvature of the spine (scoliosis) and contractures of the hips and knees can also be problematic. Cognitive function is not thought to be affected.
Muscle weakness affecting breathing can often result in the need for mechanical ventilation, sometimes periodically, during sleep or continuously. Due to these severe breathing problems, individuals with X linked myotubular myopathy (XLMTM) usually survive only into early childhood, however some have lived into adulthood. It is generally not thought to be progressive condition.
Autosomal-dominant Centronuclear Myopathy (AD-CNM)
Autosomal-dominant centronuclear myopathy also predominantly affects the skeletal muscles. Individuals with this form of myopathy often do have normal early development. However, even in those with normal early development muscle weakness usually becomes evident during adolescence or early adulthood.
Presenting symptoms are usually difficulty walking and, sometimes, muscle pain during exercise. Weakness often progressively deteriorates 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.
Autosomal-recessive Centronuclear Myopathy (AR-CNM)
This condition also presents as progressive weakness, usually beginning at birth or childhood. Symptoms may include foot abnormalities, high arched palate (roof of the mouth) and abnormal side to side curvature of the spine (scoliosis). Mild to severe breathing problems may also be present. Much less commonly the heart muscle may also be weakened, although this has not been reported in any of the genetically resolved forms to date.
The Genetics of MTM-CNM
X-linked Myotubular Myopathy (XLMTM)
The X-linked form is of Myotubular Myopathy (XLMTM) caused by a mutation in the MTM1 gene. MTM1 is needed to produce myotublarin an enzyme thought to be involved in the development and maintenance of muscle cells.
MTM1 gene mutations are thought to disrupt myotubularin’s normal role in muscle cell development and maintenance. This then causes muscle weakness and other signs and symptoms of X-linked Myotubular Myopathy (XLMTM). This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. 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. Because it is highly unlikely that females will have two altered copies of this gene, it is only males that are affected by X-linked recessive disorders. A characteristic of X-linked inheritance is that affected fathers cannot pass X-linked traits to their sons, but all their daughters will be carriers of the condition.
In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the gene, but generally does not experience signs and symptoms of the disorder. In rare cases, however, carrier females have experienced some muscle weakness associated with X-linked Myotubular Myopathy.
This is often associated with a mechanism called “skewed X-inactivation”: As females don’t need both of their X chromosomes, in any given cell half of all X chromosomes are switched off, in a process called “X inactivation” (or “lyonization”). This process usually occurs randomly but very rarely, one copy of the X chromosome may be active much more than the other (“skewed X-inctivation”); if this copy happens to carry a gene fault, females may develop symptoms of conditions that usually only affect males.
Autosomal Centronuclear Myopathy (dominant and recessive)
The majority of described Centronuclear Myopathy cases have been attributed to mutations in the DNM2 and BIN1 genes, and more recently mutations in the RYR1 gene. More recently, mutations in the TTN gene have also been associated with centronuclear Myopathy, but the frequency of this form is currently not certain. However some cases still remain unknown.
Mutations in the DNM2 gene causing CNM are usually associated with dominant inheritance, mutations in the RYR1 gene are usually associated with recessive inheritance, whereas mutations in the BIN1 gene have been associated with both dominant and recessive inheritance.
The DNM2 gene provides instructions for making a protein called dynamin 2 and the BIN1 gene encodes a protein called amphiphysin 2. Both proteins are involved in trafficking of cell membranes and do interact with each other. The RYR1 gene encodes the skeletal muscle ryanodine receptor, which is involved in intramuscular calcium release and excitation-contraction coupling, the process whereby the nerve impulse from the brain is translated into muscle contraction. The TTN gene encodes Titin, a giant protein that is fundamental in giving muscle its structure.
Normally, the nucleus is found at the edges of muscle cells, however, in people with centronuclear Myopathy, the nucleus is located in the centre of these cells. It is not well understood how mutations in the DNM2, BIN1, RYR1 or TTN genes lead to muscle weakness and the other specific features of centronuclear Myopathy, however, there is likely to be more than one mechanism in place, including disturbances of muscle membrane trafficking, muscle fibre integrity and/or excitation-contraction coupling.
Patient organisationsFederacion Española de Enfermedades Neuromusculares (Federación ASEM) – Spain Joshua Frase Foundation – United States of America MTM-CNM Family Connection – United States of America Myotubular Trust – United Kingdom The Information Point – ZNM- Zusammen Stark! e. V. – United Kingdom
About clinical research
Clinical research is medical research that is carried out on humans. Individuals volunteer to participate in studies that aim to uncover better ways to treat, prevent, diagnose and understand human disease.
Clinical research includes both clinical trials that test new treatments and natural history studies, which provide valuable information about how diseases progress.
If you are considering taking part in a clinical trial, the doctor in charge of the trial will give you a lot of information about the treatment being tested, the possible results and the possible side-effects. It is always worth finding out as much as you can before you agree to take part.
Even before you get to the stage of talking to a doctor about a specific trial, you can read a lot about the general principles of clinical trials online.
Two useful resources providing general information about clinical research created by the US National Institutes of Health (NIH) are provided below.
How does clinical research work?
Finding out information about clinical trials
The most comprehensive online listing of trials is at www.clinicaltrials.gov: you can search for trials for a particular condition. We have also collected the listings of trials for specific diseases and you can find this in the “current trials” section in the menu on the left.
The UK Muscular Dystrophy Campaign also has a listing of neuromuscular-related clinical trials in the UK and across the world available from the following link: