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  • Updated 03.24.2021
  • Released 04.26.1994
  • Expires For CME 03.24.2024

X-linked myotubular myopathymyosin heavy

Introduction

Overview

X-linked myotubular (centronuclear) myopathy is a severe muscle disorder mainly affecting newborn boys, but sometimes it can 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 are underway, canine and other animal models have been established and experimental trials carried out, outcome measures have been defined, and therapeutic trials are being planned in terms of a variety of potentially disease-modifying interventions. The first-in-human gene transfer study is underway but was afflicted by a major drawback.

Key points

• X-linked myotubular (centronuclear) 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.

• 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) (64). 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. The X-linked form of myotubular myopathy was first described in a large Dutch pedigree in which the affected males showed muscle fibers resembling fetal myotubes (202). A long-term follow-up study of this and another Dutch family shows wide variability in the clinical picture (14), confirmed by 2 reports of patients diagnosed as adults (99; 154).

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 ...

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 (208; 103), in dogs also (180), but exceptionally severe cases have also been reported (110; 27). Mutations in the dynamin 2 gene (30) are a common cause of the dominantly inherited form (70; 29; 66; 172), whereas mutations in the ryanodine receptor gene RYR1 have also been identified, including recessively inherited mutations (111; 214; 24; 110).

The first causative gene for autosomal recessive myotubular/centronuclear myopathy was identified as amphiphysin 2 (BIN1) (147). Subsequently, a patient with internalized nuclei, the histopathology resembling centronuclear myopathy, was found to have compound heterozygous mutations in the titin gene TTN (42; 61). A further differential diagnosis may be myopathy caused by SPEG mutations, often accompanied by cardiomyopathy (01; 211; 212).

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 (91; 206; 185; 106; 118; 171; 85; 154; 25; 93; 110; 68; 170; 28; Zhao et al 2017; 77; 48; 116). A female patient described with cardiomyopathy requiring heart transplantation had not undergone analysis of the myotubularin gene.

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