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  • Updated 12.21.2023
  • Released 04.26.1994
  • Expires For CME 12.21.2026

X-linked myotubular myopathy



X-linked myotubular myopathy is a form of centronuclear myopathy mainly affecting newborn boys, but it can sometimes also affect girls and adults. Diagnostic methods have improved so that the majority of patients and carriers may now have their diagnosis verified by molecular methods. Currently, the complex pathogenetic mechanisms are better understood and include defects in membrane tubulation and excitation-contraction coupling, providing evidence towards a common basis for the X-linked and autosomal forms of centronuclear myopathy. Several studies of potential therapeutic modalities aimed at ameliorating disease severity have reached proof of concept, natural history studies have been completed, a number of animal models have been established and experimental trials carried out, outcome measures have been defined, and therapeutic trials are being planned. These trials have investigated inventive methods, such as therapies based on antisense oligonucleotides, gene therapy, and drug repurposing. Although the first in-human gene transfer study was affected by a major drawback, these innovative initiatives are leading the way towards a future of hope.

Key points

• X-linked myotubular myopathy is caused by mutations in the myotubularin gene MTM1.

• Molecular genetic verification is often possible through sequencing, but it should be noted that copy number variations may also be causative, as may intronic alterations, and this may require other analytic methods.

• Female carriers may present with overt disease.

• Although no curative treatment exists to date for this usually very severe disorder, active treatment is indicated, at least initially, because of the favorable course in some neonatally severe cases.

• Hepatobiliary disease is quite common and should be carefully monitored.

• Prognosis cannot be based solely on the nature of the mutation, and decisions about treatment have to be taken on an individual basis.

• Differential diagnoses include the autosomal forms of centronuclear myopathy and myotonic dystrophy.

• Most, but not all, mothers of affected boys are mutation carriers; mosaicism has been reported.

Historical note and terminology

X-linked myotubular or centronuclear myopathy is assigned to the group of congenital myopathies (OMIM #310400) (69). These myopathies were defined after the advent of histochemical staining methods of muscle biopsy sections on the basis of structural abnormalities in the muscle fibers.

Centronuclear myopathies are characterized by the presence of centrally located nuclei in muscle fibers. This term is used to describe a diverse collection of individually rare congenital myopathies. These conditions are primarily caused by pathogenic variants in MTM1 (approximately 50%), DNM2 (approximately 15%), or BIN1 (approximately 3%). Although a significant percentage (approximately 20%) of centronuclear myopathy cases have an unknown genetic basis, another portion (approximately 12%) involves other genes (24). The centronuclear myopathy–like phenotype has been reported to be associated with pathogenic variants in genes, such as ryanodine receptor 1 (RYR1) (238), titin (TTN) (42), SPEG (01), ZAK (225), DHPR (CACNA1S) (191), and potentially CCDC78 (151) and myotubularin-related protein 14 (MTMR14) (217). Centronuclear myopathies, despite their diverse presentations and modes of inheritance, often show noticeable weakness in the eye muscles, such as ptosis and ophthalmoparesis.

X-linked myotubular myopathy typically represents the most severe manifestation within the spectrum of centronuclear myopathies (39).

In 1966, findings of muscle pathology were reported in a 12-year-old boy who exhibited generalized muscle wasting and facial weakness, including ptosis (202). The authors of this report were surprised to find that the images of the affected muscle fibers closely resembled fetal myotubes. These myotubes appeared slightly elongated, having a central nucleus with one or a few myofibrils. The authors hypothesized that this condition arose from an interruption in the development of muscle fibers and proposed the term “myotubular myopathy” to describe the condition. Although the exact nature of this disease is not yet fully understood, "myotubular myopathy" remains the designated term for the X-linked inherited type of centronuclear myopathy.

In 1969, the X-linked form of myotubular myopathy was described in a large Dutch pedigree in which the affected males showed muscle fibers resembling fetal myotubes (224). A long-term follow-up study of this and another Dutch family shows wide variability in the clinical picture (12), confirmed by reports of patients diagnosed as adults (109; 169).

Myotubes in fetal muscle (photomicrographs)
Transverse sections of quadriceps femoris muscle of a 14-week human fetus (left) and a term neonate with X-linked myotubular myopathy (right). In the fetal muscle, both early and late myotubes are seen; the early fibers have scant...

The coining of the alternative name "centronuclear" myopathy reflects the argument about whether the basic defect in this disorder is an arrest of maturation of the fetal muscle fibers or whether the central nuclei constitute the main histologic feature.

Central nuclei in muscle fiber (photomicrographs)
Longitudinal sections of quadriceps femoris muscle of a 14-week human fetus (left) and a term neonate with X-linked myotubular myopathy (right). In both true fetal myotubes and the centronuclear fibers of myotubular myopathy, the ...

In 1985, eight patients with muscle biopsies showing a centronuclear myopathy pattern were reported (102). The authors of this report proposed three inheritance patterns in this group of patients. They observed that the individuals they identified as having X-linked inheritance were male and displayed a severe phenotype, including neonatal asphyxia, difficulties with breathing and feeding shortly after birth, as well as weakness in the face and limbs during the neonatal period, often leading to early mortality.

In 1996, a consortium of three groups found mutations within the MTM1 gene located on the X chromosome as the underlying cause of this condition (135). The final product of this gene, known as myotubularin (MTM1), is recognized as an enzyme found in endosomes. It plays a role as endosomal lipid phosphatase, which regulates membrane trafficking by modulating phosphoinositide (PI) dephosphorylation and contributes to the structure and function of muscle fibers.

The first disease model of X-linked myotubular myopathy using knockout mice was established in 2002 (38), followed by the development of other animal models (67; 170) and natural disease models in canines (15; 87; 165). These initiatives have led to a better understanding of disease pathogenesis and treatment targets.

Autosomal forms with similar histology have been described (OMIM #60150, #255200). They usually present later and follow a milder course than the X-linked form (232; 112), in dogs also (199), but exceptionally severe cases similar to the X-linked form have also been reported (119; 26). Mutations in the dynamin 2 gene (29) are a common cause of the dominantly inherited form (76; 28; 72; 192), whereas mutations in the ryanodine receptor gene RYR1 have also been identified, including recessively inherited mutations (120; 238; 23; 119).

The first causative gene for autosomal recessive centronuclear myopathy was identified as amphiphysin 2 (BIN1) (162). Subsequently, a patient with internalized nuclei, the histopathology resembling centronuclear myopathy, was found to have compound heterozygous mutations in the titin gene TTN (42; 64). A further differential diagnosis may be myopathy caused by SPEG mutations, often accompanied by cardiomyopathy (01; 235; 236).

It is to be noted that female carriers of the X-linked form can manifest muscle disease, as index patients, also, with no affected males known in the family (100; 230; 205; 115; 128; 190; 94; 169; 24; 103; 119; 74; 189; 27; 83; 242; 48; 126). A female patient described with cardiomyopathy requiring heart transplantation had not undergone analysis of the myotubularin gene.

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