# X-Linked Myotubular Myopathy in a Female Patient with a Pathogenic Variant in the _Mtm1_ Gene
## 1 Introduction  
Centronuclear myopathy (CNM) is a genetically heterogeneous group of neuromuscular disorders characterized by muscular weakness and hypotonia. Histochemical analysis of muscular tissue biopsy shows abnormally positioned nuclei in skeletal muscle cells. Centronuclear myopathies are subdivided into three forms: X-linked CNM or myotubular myopathy 1 (caused by variants in the _MTM1_ gene), autosomal-dominant CNM (genes _DNM2_ and _CCDC78_), and autosomal-recessive CNM (genes _BINI, MAP3K20_, and _SPEG_).  
Myotubular myopathy 1 (myopathy, centronuclear, X-linked, OMIM 310400, XLMTM) is one of the most common and severe forms of CNM. Its frequency is estimated to be 1 case per 50,000 male newborns [1]. This form of congenital myopathy is caused by disruptions in the structure of myotubularin, which is a phosphatidylcholine 3-phosphate (PI3P) phosphatase and is essential for the differentiation of muscle cells [1; 2; 3]. The MTM1 protein consists of 603 amino acids and has 5 domains: PH-GRAM (Pleckstrin Homology-Glucosyltransferase, Rablike GTPase Activator and Myotubularin), RID (Rac1-Induced recruitment Domain), PTP/DSP (protein tyrosine phosphatase/dual-specificity phosphatase), SID (SET-protein Interaction Domain), and C-terminal coiled-coil motif (PDZ binding domain) (Figure 1) [4]. Myotubularin is coded by the _MTM1_ gene, which is mapped on the long arm of the X chromosome (Xq28) and consists of 15 exons. To date, according to the data presented in HGMD [5], there are 366 described pathogenic variants in the _MTM1_ gene. Among these variants, 32% are missense mutations, 16.7% are deletions, 15% are splice site mutations, 13.1% are nonsense mutations, 10.6% are gross deletions, 8.7% are duplications, 2.5% are indels, 0.8% are gross duplications, and 0.6% are complex rearrangements.  
XLMTM has three forms distinguished by the severity of symptoms: mild, moderate, and severe. The disease is characterized by an early age of onset, diffuse weakness, and generalized muscular hypotonia [3]. Other possible symptoms include weakness in sucking and swallowing muscles, ophthalmoplegia, respiratory failure, diaphragmatic eventration, hepatic failure, cryptochism, and joint contractures. Tendon reflexes are decreased or absent [6]. Muscle biopsy examination shows muscle fibers of reduced size with large vesicular nuclei localized in the center of the cell (normal muscle cell nuclei are peripheral) and positioned in one straight line. The predominance of slow contracting type 1 fibersand the absence of oxidative activity in the periphery of the fibers are also detected [6; 7]. High vimentin and desmin immunoreactivity is detected in muscle fibers of an affected individual, whereas in muscles of a healthy full-term newborn, these enzymes will be inactive [6]. Laboratory analysis shows creatine phosphokinase levels within the norm. Electromyography results are usually normal; however, minimal non-specific symptoms may be detected in infancy. Nerve conduction velocity may be decreased, although usually within the norm. The disease predominantly affects males [8]. Female carriers are divided into two groups: manifesting carriers (includes mild (muscle weakness and independent ambulation), moderate (muscle weakness and assisted ambulation), and severe phenotypes (muscle weakness and wheelchair dependence) and non-manifesting carriers (they have no muscle weakness and can be independently ambulant). Non-manifesting carriers may present with clinical symptoms such as fatigue, intolerance to physical activity, myalgia, and cramps. The development of clinical symptoms in manifesting carriers may be related to skewed X chromosomal inactivation [8; 9]. At the same time, manifest carriers with a mild phenotype may not seek medical attention, so they may not be diagnosed and will be detected by chance. Manifest carriers with a moderate or severe phenotype may seek medical attention, but they may be diagnosed with a diagnosis other than XLMTM, as XLMTM is not usually suspected in women [9].