Myotubular myopathy (MTM1)

What is myotubular myopathy?

Myotubular myopathy (MTM) is the most common and also usually the most severe centronuclear myopathy and usually only affects boys due to x-linked inheritance. The frequency is estimated at 1:50,000 male newborns. Before birth, the disease usually only manifests itself as a lot of amniotic fluid (polyhydramnios) and reduced fetal movements. However, these symptoms usually go unnoticed and it is only after birth that the low muscle strength (hypotonia, “floppy infant”) and inadequate breathing (respiratory insufficiency) are noticed.
The symptoms of myotubular myopathy can vary greatly in their severity. The low muscle strength usually leads to problems with breathing and swallowing/food intake. Many of those affected therefore require ventilation and are dependent on tube feeding. An (electric) wheelchair is also required. Many boys with myotubular myopathy exhibit one or more of the following characteristics: a long, narrow head shape, a high palate, immobility of the eyes (ophthalmoparesis), drooping eyelids (ptosis), undescended testicles (maldescensus testis), height greater than 90% of boys of the same age. In addition to myopathy, other symptoms may also occur. For example, the literature describes gastric outlet stenosis (only in infants), kidney problems (kidney stones and renal calcification), liver problems (bleeding tendency, vascular anomalies), orthodontic problems, scoliosis and frequent spontaneous bone fractures. Myopia can also occur.
Treatment and therapy options are only supportive and are based on a multidisciplinary approach (neuropaediatrics/neurologist, human geneticist, pulmonologist, internist, orthopaedist, ophthalmologist). Children should also be examined regularly for the possible concomitant diseases mentioned above.
Regular physiotherapy is also important to maintain muscle strength and muscle function and prevent contractures. Trunk-stabilizing exercises appear to be particularly helpful here. Swimming/exercises in water and riding therapy are particularly recommended.

How is myotubular myopathy inherited?

Myotubular myopathy follows an X-linked recessive inheritance, which means that the MTM1 gene with the mutation is located on one of the mother’s X chromosomes, specifically on the long arm of an X chromosome in position Xq28.
In 10-20% of cases, however, there is a de novo mutation in the MTM1 gene, which means that the mother is not a carrier.

How is myotubular myopathy diagnosed?

In most cases, a muscle biopsy is taken after other diseases have been ruled out. A small part of the muscle is removed and examined under the microscope. This reveals differences to the “normal image”: In people with centronuclear myopathy, the cell nuclei are not located at the edge of the muscle cells, but in the middle (see also explanation by J. Böhm). After the muscle biopsy, only 3 to 5 genes (MTM1, DNM2, BIN, RYR1… – the genes for centronuclear myopathies) remain as possible causes for the muscle weakness. If the child’s symptoms are very severe and visible from birth and if it is an affected boy, there is a very high probability that the mutation is in the MTM1 gene. This gene is therefore the first to be examined. Due to advances in the field of genetic analysis, in some cases a genetic test for individual genes is also initiated following a suspected diagnosis, or a panel diagnosis is used, in which many myopathy genes are tested for a causative mutation in one run. Subsequently, it can also be tested whether the mother is a carrier or not.

Are there therapeutic approaches to cure myotubular myopathy?

Preclinical research funded by many patient organizations has led to two international clinical trials in the last ten years. Until then, there was no cure for ZNM and treatment was symptomatic and supportive. The ASPIRO trial to test gene therapy in children with X-linked myotubular myopathy (MTM1) was conducted at seven centers in Canada, France, Germany and the USA. 24 boys (aged <5 years) with MTM1 and ventilation were enrolled in the study (NCT03199469).

In parallel, the Unite-CNM study was conducted to test the efficacy of a new drug called DYN101 to increase muscle strength. The study involved 18 patients (over the age of 16) with MTM1 or autosomal dominant DNM2-related CNM (NCT04033159).

Unfortunately, both studies were terminated prematurely due to severe side effects on the liver, ranging from reversible liver dysfunction to fatal liver failure.

New therapies are now being developed. Some of them are financed by our association. Read more…

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