X-linked myotubular myopathy

Developmental Malformations

Updated 12.21.2023
Released 04.26.1994
Expires For CME 12.21.2026

X-linked myotubular myopathy

Authors: Haluk Topaloglu MD, Gulcin Akinci MD

See Contributor Disclosures

Editor: Harvey B Sarnat MD FRCPC MS

X-linked myotubular myopathy

In This Article

Quick Link

Introduction

Overview

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.

Clinical manifestations

Presentation and course

Onset is perinatal. Polyhydramnios and premature birth are common features. The affected, most often male, newborn presents with severe generalized muscle hypotonia and weakness associated with respiratory insufficiency (13). Many of these boys lack spontaneous antigravity movements at birth, and many fail to establish spontaneous respiration. Feeding difficulties and ophthalmoplegia are common. The affected boys are often long for their gestational age and have relatively low birth weights; large heads, an uncommon characteristic among other congenital myopathies; and long fingers. Tendon reflexes are mostly absent. There may be contractures of the hips or knees. Some boys have cryptorchidism.

X-linked myotubular myopathy in an infant (face)

Male infant aged 6 months with X-linked myotubular myopathy. Note myopathic facies and nasogastric feeding tube. (Contributed by Dr. Carina Wallgren-Pettersson.)
X-linked myotubular myopathy in an infant (supine)

Male infant aged 6 months with X-linked myotubular myopathy. Note frog posture in the supine position. (Contributed by Dr. Carina Wallgren-Pettersson.)
X-linked myotubular myopathy in an infant (prone floppiness)

Male infant aged 6 months with X-linked myotubular myopathy. Note floppiness on handling. (Contributed by Dr. Carina Wallgren-Pettersson.)
X-linked myotubular myopathy in an infant (supine floppiness)

Male infant aged 6 months with X-linked myotubular myopathy. Note floppiness on handling. (Contributed by Dr. Carina Wallgren-Pettersson.)

Patients diagnosed with X-linked myotubular myopathy are categorized into mild (no ventilation support), intermediate (ventilation support < 12 hours/day), or severe (ventilation support ≥12 hours/day) phenotypes depending on the extent of ventilator assistance needed (155).

Insights from natural history studies unveiled that most patients encounter the severe form of this condition, often displaying profound hypotonia, significant respiratory insufficiency, and difficulties in swallowing at birth.

Most patients exhibit a low Apgar score within the first minute after birth. One of the main initial signs of X-linked myotubular myopathy is the inability to establish spontaneous breathing, resulting in an immediate requirement for respiratory support of patients from birth onwards (16; 155). Some individuals may achieve independent breathing shortly after birth, yet some might lose this capacity around the median age of 6 months, particularly in the severe phenotype group (09). Achieving motor milestones is typically delayed across different phenotypes, and achieved milestones are often lost in patients with the severe phenotype (09).

There is usually no primary cardiac involvement, but a report describes complete atrioventricular block in the absence of cardiomyopathy in a patient confirmed by mutation analysis to have the X-linked form of myotubular myopathy (107). A report described cardiac aneurysms in a patient with an MTM1 mutation; the causal relationship between the mutation and the cardiac disorder, however, was uncertain (20). An exceptional patient showed progressive dementia (154), and a twin pair presented with hypoxic encephalopathy (44).

A few affected boys have been described as showing abnormalities in neuromuscular transmission, and some have responded to pyridostigmine treatment (176).

Usually, but not invariably, the disease follows a fatal course. Formal clinical and histologic criteria for the diagnosis have been defined by the International Consortium on Myotubular Myopathy (233). Clinical reviews are available (232; 117; 140), and McEntagart and colleagues addressed genotype-phenotype correlations (155). Clinical papers describe Danish, German, and Dutch series (237; 82; 175).

There are less severe forms of X-linked myotubular myopathy, with symptom onset ranging from birth to later in childhood (09; 25). Reports highlight varying combinations of signs and symptoms in these patients, encompassing neonatal hypotonia, feeding difficulties that may improve in time, delayed motor milestones, mild to moderate weakness, gait abnormalities, speech difficulties characterized by a weak voice, and recurrent respiratory tract infections (25; 11). In about 20% of all X-linked myotubular myopathy cases with milder presentations, ventilatory support may not be necessary during childhood. However, some patients may experience nocturnal hypoventilation and may require BiPAP (25; 06; 09).

In some of the patients surviving long-term despite neonatally severe disease, involvement of organs other than muscle may ensue. Reports of such manifestations have included pyloric stenosis, spherocytosis, gallstones, hepatic peliosis, intrahepatic cholestasis, kidney stones, vitamin K–responsive bleeding diathesis, nontraumatic subdural or intracranial hemorrhage, and recurrent pneumothorax (105; 125; 144; 161; 158; 239). Among these, hepatic peliosis and other hepatobiliary diseases have been repeatedly reported (98; 159; 81; 55; 158). In one case, peliosis was successfully treated using hepatic artery embolization (213) and in another by liver transplantation (167). There are, however, a number of reports of patients in whom no long-term complications have been noted (237; 06; 09).

Many female cases have been described, with or without evidence of skewed X inactivation (232; 208; 100; 230; 205; 115; 128; 190; 94; 74; 189) and may be late (169; 103). Female patients, who may be regarded as being mosaic in that they have one normal MTM1 allele and one carrying the mutation, mutually exclusively active in any single cell, may show asymmetry and local involvement without showing detectable skewing of their X-inactivation. This is evident not only in terms of muscle weakness but also in terms of growth of the left and right side of the body, including the face and limbs (27; 242; 48). Quite often, the manifestations are milder than in affected males carrying the same mutation (27; 174). Killer cell immunoglobulin-like receptor variants were suggested as possible genetic modifiers of manifestation in female carriers (201). Cocanougher and coworkers developed a clinical classification for manifesting female carriers (48).

Prognosis and complications

The prognosis is usually poor, and most affected boys die in infancy. A number of patients with severe neonatal floppiness and serious respiratory problems have, however, survived. Some of these have even done well, without any residual respiratory difficulty or severe disability (155).

Historically, it was estimated that nearly half of infants did not survive beyond 18 months (155; 16; 92). However, subsequent reports suggest a lower mortality rate, around 10% per year, emphasizing the relative stability in the disease course and the pivotal role of intensive medical intervention in determining survival. The majority of infants necessitate prolonged stays in the neonatal intensive care unit, with about 30% to 50% of their first year spent within hospital. About a quarter of male infants do not survive beyond their first year of life (65).

A considerable number of individuals who survive X-linked myotubular myopathy often contend with disabilities, exhibiting a significant reliance on technology. Nearly 80% of these individuals depend on forms of technology, including 24-hour ventilatory support via tracheostomy, gastrostomy feeding tube, and wheelchair support (06).

The duration of ventilator support is a reliable, consistent, and clinically significant measurement for assessing disability among patients with X-linked myotubular myopathy (06; 66).

The persistent risk of premature death, primarily due to respiratory complications, remains notably high at about 10% annually after infancy. Episodes of hypoxia can arise, potentially resulting in hypoxic-ischemic encephalopathy (65).

Patients with X-linked myotubular myopathy experience frequent hospitalizations, often linked to respiratory failure, respiratory distress, infections (particularly lower respiratory tract infections), as well as various surgical and medical procedures (16; 91).

Patients often undergo various surgeries, including esophagogastric fundoplasty, tracheostomy, myringotomy (with or without ear tube insertion), bronchoscopy, laryngoscopy, orchidopexy, spinal fusion, adenotonsillectomy, and laparoscopy. Gastrointestinal tube insertion is reported to be more prevalent among patients under 18 months old. Procedures, such as gastrostomy, circumcision, muscle biopsy, myringotomy, inguinal hernia repair, and ventriculoperitoneal shunt, are reported at similar rates across both age groups (16).

Scoliosis commonly emerges during later childhood, affecting around 75% of individuals with X-linked myotubular myopathy (65). Long-term survivors have been reported to experience complications, such as pyloric stenosis and cavernous hemangiomas of the liver (105).

Hepatobiliary problems, particularly cholestasis, are common comorbidities among individuals with X-linked myotubular myopathy and require close observation (89). These issues might appear early, particularly after infections or vaccinations, and manifest as elevated liver enzymes and irregularities detected in liver ultrasound, such as hepatic peliosis or gallstones. In the INCEPTUS natural history study, 91% of 34 patients diagnosed with X-linked myotubular myopathy either had a history of liver disease at enrollment (eg, hyperbilirubinemia and intermittent or persistent cholestasis) or exhibited at least one sign of hepatic disease throughout the study period, ranging from 0.5 to 32.9 months (66). Half of the patients required treatment for cholestatic or other liver conditions, and one patient died due to hepatic peliosis. Among the complications associated with X-linked myotubular myopathy, hepatic peliosis emerges as one of the most serious issues not directly related to muscle involvement (16; 158). It is characterized by multiple sinusoidal blood-filled cysts within the liver (159). This complication may affect up to 5% to 10% of individuals (105; 16). Liver hemorrhage or bleeding to the peritoneal cavity caused by this vascular lesion could potentially lead to fatal outcomes.

Rare patients have shown mild disease since the neonatal period (25; 43; 240), and some patients have been diagnosed only as adults (109). Care is to be taken in prognosticating based on the mutation alone (52).

A follow-up study and a few case reports suggest that long-term survivors may be at risk for medical complications involving organ systems other than muscle tissue (see above) (105; 144; 125; 158; 239), but a number of adult patients have been described not showing any of these (12; 25; 240). A mouse model with a lifespan of more than 50 weeks also does not show extra-muscular manifestations (170).

The cause of death is usually respiratory failure, sometimes in combination with pneumonia or cardiac failure.

Clinical vignette

This fictitious but representative patient was born as the third child of a couple with a history of two male miscarriages. The pregnancy was complicated by polyhydramnios. The male, floppy infant was delivered at term. Birthweight was 3000 g, length was 53 cm, and head circumference was 37 cm. The neonate failed to establish spontaneous respiration, and antigravity movements were few and feeble. An ultrasound scan of the child’s head failed to reveal a central cause for the floppiness. An EMG showed spontaneous fibrillations, and a clinical diagnosis of spinal muscular atrophy was made. A muscle biopsy, however, showed changes compatible with myotubular myopathy, and genetic testing for spinal muscular atrophy was negative. Myotonic dystrophy was excluded by molecular genetic testing. The diagnosis of myotubular myopathy was made. A mutation identified in the MTM1 gene confirmed that the disorder in this family was X-linked. The mother, grandmother, and an aunt were later found to be carriers of the disease-causing mutation. The infant was mechanically ventilated and showed temporary improvement by establishing antigravity movements of the limbs. Doctors weaned him off the ventilator for 2 weeks, but he died at the age of 2 months of pneumonia and respiratory insufficiency. Prenatal diagnosis based on mutation detection could be offered in any future pregnancy of this couple.

Biological basis

Etiology and pathogenesis

Biological basis. This disorder follows X-linked inheritance, with mutations found in the MTM1 gene encoding a lipid phosphatase, myotubularin (MTM1) (135; 59; 134; 63; 163; 207; 36; 60; 131). Hitherto, no other X-chromosomal gene has been implicated.

Note: Autosomal forms with similar histology, and female patients with MTM1 mutation, have been described, and the X-linked mode of inheritance needs to be confirmed by mutation detection. The first gene for an autosomal form was published in 2005 (29) and was followed by three more (120; 162; 42).

Our understanding of X-linked myotubular myopathy is increasing based on the identification of the disease-causing gene, mutation detection in a great number of patients and observed genotype-phenotype correlations. At the same time, basic scientific advances and animal models are clarifying the pathogenetic mechanisms for both the X-linked and the autosomal forms of centronuclear myopathy characterized to date, with a number of molecular links being identified between these disorders (04; 67; 118; 219; 07; 138; 08; 75; 114; 87; 10; 89).

A number of patients with or without MTM1 mutations have been described as showing electrophysiological findings suggestive of a neuromuscular transmission defect, leading to a clinical suspicion of myasthenia (147; 176). Some of these patients showed a response to treatment with acetylcholinesterase.

Pathology. Histologic criteria for X-linked myotubular myopathy include the presence of numerous small muscle fibers, many of which contain rows of regularly spaced central nuclei resembling normal fetal myotubes (118). A study addressed the relationship between nuclear mislocalization and fiber contractility in X-linked myotubular myopathy (180). Type 1 slowly contracting fiber predominance is common, and type 1 fiber hypotrophy is observed in some, but not all, cases (Imoto and Nonaka 2001; 118). The myotube-like fibers show a central aggregation of mitochondria, resulting in a highly dense oxidative enzyme staining centrally. The ATPase reaction demonstrates a corresponding lack of central staining. Protein- and cDNA-based methods have identified absence or low levels of myotubularin expression in most patients tested (132; 137; 178; 218). A study described cellular, biochemical, and molecular changes as likely consequences of epigenetic modifications in muscles from patients with X-linked myotubular myopathy (10).

The presence of necklace fibers has been observed in certain cases of late-onset X-linked myotubular myopathy (22) and female carriers (27). These patients initially show mild symptoms during childhood but experience a worsening of symptoms during the first and second decades of life. Necklace fibers, observed through periodic acid–Schiff, oxidative staining, and electron microscopy, are basophilic rings beneath the sarcolemma that follow the cell's contour and align with internal nuclei.

Genetics. The gene for X-linked myotubular myopathy was assigned in 1987 to the proximal Xq28 region (214; 57; 145; 203; 215; 146; 111). The determination of the breakpoints of a deletion in a female patient with X-linked myotubular myopathy (54) and the physical mapping of deletions in two male patients with myotubular myopathy and ambiguous external genitalia helped to narrow down the region likely to contain the disease gene (110). These two male patients were later found to have unusually large deletions, including an alternatively spliced gene in proximal Xq28 (136). Bartsch and colleagues published a description of a familial deletion associated with male hypogenitalism (14). A further patient with a well-characterized deletion in this region had hypospadias and scrotal hypoplasia (189). In contrast, another patient described with a big deletion had normal genitalia (221).

This led to the characterization of a gene in this region (MTM1) showing mutations in affected males (135; 59; 134; 63; 163; 207; 36; 60; 209; 131; 24; 05). The gene encodes a lipid phosphatase, myotubularin. The MTM1 gene has 15 exons, and various disease-specific alterations have been found in most of them (209; 131; 106; 152; 221). The first exon of the MTM1 gene does not consist of coding sequences and serves as a putative promoter region. The start codon is located in exon 2. The complete genomic structure of the human myotubularin gene has been determined (133), and the corresponding sequences are available in GenBank under the accession number AH006018.2.

The incidence of new mutations appears not to be as high as previously thought, and a majority of mothers of affected boys will be found on genetic testing to be carriers (134; 131; 106; 21; 24; 119; 149; 189). It has also become evident that many female carriers manifest symptoms (174) and may present as index patients (128; 27; 242).

Grandpaternal inheritance of X-linked myotubular myopathy from a mosaic maternal grandfather has been described (104).

Genotype-phenotype correlations. X-linked myotubular myopathy predominantly arises from nonsense, frameshift, and splice site mutations in the MTM1 gene that typically result in loss of function. These pathogenic variations distribute across the gene without any specific concentration in particular domains (36; 131; 106; 25; 221). All males who carry pathogenic variants in the MTM1 gene will show symptoms of the disease. However, the severity of the illness can differ, ranging from mild to severe. In addition to small mutations, further reports present large deletions and duplications (24; 220; 05; 166; 189; 126; 88). Most point mutations are truncating, but approximately 30% are missense mutations that affect conserved residues (131; 21). Some of these are associated with a milder phenotype, although no strong correlation appears to exist between the nature of the mutation and the clinical picture, and severity varies even within families (131; 106; 155; 52; 204). In an Italian series of patients with autosomal and X-linked forms, the MTM1 gene was the most commonly mutated gene in the early-onset forms (74). In a few families, manifestations have been mild from the outset, and a 67-year-old grandfather was still mildly affected (12; 25; 240). An exceptional patient with progressive dementia had a mutation removing the start signal of exon 2 (154). In two studies, eighty-five percent of mothers were carriers, and approximately 5% of index cases were female (24; 119). The latter figure is, however, likely to be an underestimate because females with this X-linked disorder presenting as index cases may go undiagnosed (27; 242).

Pathogenesis. The emergence of pathological changes and distinct phenotypes in centronuclear myopathies can be attributed to the lack or insufficiency of proteins, including MTM1, BIN1 and DNM2. These proteins are functionally related to each other and are involved in autophagy, membrane fission, and vesicle trafficking (181). MTM1 plays a role in bringing BIN1 and DNM2 to the membranes of muscles, which helps enhance the formation of BIN1 tubules. Mutations in MTM1 affect the structure of the triad (182; 51). It has been shown that the proper balance of expression levels of BIN1, DNM2, and MTM1 is essential for muscle physiology. Furthermore, DNM2 appears to hold a significant position in the development of the condition and shows elevated levels in cases of centronuclear myopathy linked to BIN1, DNM2, and MTM1.

Myotubularins, a group of proteins associated with variety of diseases, have been found to be conserved throughout evolution and have similarities to phosphatases. Within the human system, there are 14 distinct paralogs of myotubularins; MTM1 absence being related to X-linked myotubular myopathy was the first one discovered and was followed by other myotubularin-related proteins, MTMR1 to MTMR13 (135; 172).

Mutations in two of these myotubularin-related genes, namely MTMR2 and MTMR13/SBF2, have been found to cause separate neuromuscular disorders: Charcot-Marie-Tooth disease type 4B1 (31; 18) and type 4B2 (193), respectively. Gomez-Oca and colleagues provide a review on the subject (89).

A boy with a big deletion involving both the MTM1 gene and the homologous MTMR1 gene did not differ clinically from other patients with myotubular myopathy in any significant way, indicating that the MTMR1 gene has little clinical significance during early postnatal life (241). Members of the myotubularin protein family form homodimers and also heterodimers in which an active and an inactive protein binding to each other may produce conformational changes affecting substrate affinity, hydrolysis, and binding to associated proteins (19; 123; 160; 47; 17).

MTM1 does not have the N-terminal extension (172). Interestingly, only a short version of MTMR2, which lacks this extension, shows a similar behavior to MTM1 in both yeast and mice. The production of MTMR2 isoforms using AAV vectors has been shown to improve myopathic characteristics in mice that lack MTM1 (56), suggesting that therapeutic interventions through MTMR2 may serve as a potential treatment for X-linked myotubular myopathy. Myotubularin is thought to be involved in the intracellular pathways necessary for myogenesis. Disease-causing mutations have been identified in all four active sites: GRAM, RID, PTP/DSP, and SID (106; 25; 21). These domains are implicated in substrate recognition, appropriate targeting to cellular compartments, and interaction with other proteins. Myotubularin was initially thought mainly to be a dual-specificity phosphatase acting on proteins but was later shown to be primarily a lipid phosphatase acting on phosphatidylinositol 3-monophosphate. It is involved in regulating intracellular and endosomal trafficking and vesicular transport processes (134; 53; 133; 30; 212; 132; 137; 222; 177; 41; 89). Gene expression analysis suggests that remodeling of the cytoskeletal and extracellular architecture may contribute to atrophy and disorganization of organelles in affected myofibers (164; 08).

A defect in muscle fiber maturation has been suggested as a pathogenetic mechanism in X-linked myotubular myopathy (196). However, studies have demonstrated the presence in muscle fibers of mature isoforms of myofibrillar proteins (194). A transgenic knockout mouse model confirmed these findings (38). This model also showed that in mice, myotubularin is necessary for the maintenance of skeletal muscle but not for myogenesis, including muscle fiber differentiation. A case report indicates that myofiber maintenance is the crucial problem in humans also (99).

Studies of a knockdown zebrafish model of myotubular myopathy confirmed the lipid phosphatase activity of myotubularin by showing high levels of its substrate phosphoinositide-3-phosphate in myotubularin-deficient muscle tissue (67). In other tissues, and in an experimental setting where myotubularin homologs were upregulated, the phosphatase function of myotubularin was found to be taken by homologous proteins. This provided an explanation for the specific involvement of muscle tissue in myotubular myopathy and suggested a possible route to future therapies.

The muscle tissue of the zebrafish model shows morphologic and functional abnormalities of the tubuloreticular system, paralleled by T-tubule abnormalities in patient muscle, suggesting that the pathogenetic mechanism in myotubular myopathy may be one of impaired excitation-contraction coupling. These results implicated a pathogenetic link not only to the other centronuclear myopathies (219; 182), but also to central core disease and multi-minicore disease. Impaired calcium homeostasis could, thus, be a possible common explanation for the known clinical and histologic similarities between these different congenital myopathies (67; 89; 140). These findings were further corroborated by studies on myotubularin-deficient fibers in the mouse model, showing fewer triads and ryanodine receptors than normal muscle fibers, as well as abnormal T-tubules and depressed calcium release from the sarcoplasmic reticulum (04). Altered calcium release has later been further corroborated as part of the pathogenetic pathway (130). Studies in human muscle suggest epigenetic modifications (10).

Myotubularin has been shown to be a desmin-binding protein with effects of the altered myotubularin on desmin-myotubularin interactions. Myotubularin deficiency also affects mitochondrial positioning, shape, dynamics, and function (108). Thus, an association of myotubularin was discovered with both sarcomeric thin filament abnormalities and mitochondrial abnormalities. Another study suggested that muscle atrophy may be induced by loss of myotubularin, leading to impaired Akt-dependent survival signaling (173). Apoptosis is also impaired (138).

Myotubularin phosphatases (eg, MTM1) play a crucial role in hydrolyzing cell membrane phospholipid phosphatidylinositol 3-phosphate (PI3P), which is necessary for autophagosome formation and endosome recycling to the cell surface to facilitate exocytosis in hepatocytes (122). Additionally, the accumulation of PI3P disrupts activity of phosphatidylinositol 3-kinase, an essential enzyme involved in the translocation of bile salt export pump (157). The inadequate activity of MTM1 within hepatocytes in patients with X-linked myotubular myopathy may impair the transportation of bile acids through the canalicular membrane. A direct link between liver abnormalities observed in X-linked myotubular myopathy and the MTM1 mutations has been suggested based on findings in a preclinical model. In this study, loss-of-function mutations in MTM1 led to notable liver abnormalities, such as disrupted bile flux and improper trafficking of transporters through endosomes in the zebrafish model (121). Additionally, the use of a DNM2 inhibitor was able to restore bile flow.

Studies towards treatment opportunities. Myotubularin appears to be required for the proper function of skeletal muscle in adulthood, which suggests long-term demands for the development of treatment (114).

Currently, Drosophila and zebrafish models provide further prospects for pathogenetic studies aiming toward identifying future therapeutic possibilities (118; 67; 96).

Myostatin has been proposed as a circulating biomarker in an Mtm1 mouse model (124). A study of the effects of inducing myostatin inhibition in myotubularin-deficient knock-out mice showed transiently better muscle strength and longer lifespan in the mice injected with the hypertrophy-inducing agent, ActRIIB-mfC, than in wild-type mice (141). The mice showed selective hypertrophy of type 2B fibers. A method for studying sarcomere structure and function in vivo in mice has been developed (156), and the proteomics of different mouse models have been studied (62).

Buj-Bello and coworkers reported successful viral transfer of myotubularin to selected murine muscles (37). Myotubularin replacement led to corrected positions of nuclei and mitochondria and to an increase in muscle volume as well as force. In the same report, results of overexpression of myotubularin in wild-type muscle indicated that myotubularin is involved in the plasma membrane homeostasis of muscle fibers.

This initial knockout mouse model, however, did not survive long enough for reliable preclinical testing of potential therapeutic modalities. A later knock-in mouse model with a longer lifespan and nonprogressive myopathy has been used for preclinical studies (170; 143; 148). Childers and colleagues described successful systemic AAV myotubularin gene delivery in both mice and dogs (46; 73). Further articles report improvement in MTM1-deficient mice by downregulation of dynamin 2 expression (50; 211; 45). Two trials of tamoxifen, previously used in mdx mice, in mouse models of X-linked myotubular myopathy showed promising results through the reduction of DNM2 and P13KC2B (84; 150). This exploration suggests the potential repurposing of tamoxifen for the treatment of individuals affected by X-linked myotubular myopathy. Currently, this potential repurposing is being studied in a clinical trial called TAM4MTM (NCT04915846).

AAV delivery of the mtm1 homolog mtmr2 also appears to have an ameliorating effect in mice (171; 56).

A study has presented initial evidence of epigenetic changes in X-linked myotubular myopathy (228). This abnormality, which was also observed in a mouse model, was effectively reversed by using a HDAC inhibitor.

Labrador, Rottweiler, and Boykin spaniel disorders resembling centronuclear myopathies in humans have been described, the natural course of the disease in dogs has been studied, outcome measures have been defined, and the canine models are being used for testing potential treatment modalities (216; 168; 118; 15; 93; 46; 86; 188; 87; 199; 200; 165). A 4-year follow-up study of dogs treated with gene therapy showed that the dogs are doing well; however, their muscle strength started to decline 3 years after the gene transfer (73; 71). AAV gene transfer appeared to correct fiber properties in these dogs (180).

In preparation for clinical trials, now ongoing, natural history studies have been reported (06; 16; 09; 92; 82). Of these, only one is truly prospective and longitudinal, albeit with a limited follow-up time of 1 year at the time of the first published report (09). The INCEPTUS natural history study focused on the findings of 34 children under the age of 4 years diagnosed with X-linked myotubular myopathy (66). Their median follow-up duration was reported as 13.0 months (ranging from 0.5 to 32.9 months). A paper suggested using the Bayesian statistical model for comparing each patient’s possible treatment response with the progression expected from their own natural history data (80). Outcome measures have been defined (70).

In many infants with this disorder, a strong fetal expression of vimentin and desmin has been found to persist in the muscle fibers of affected boys (186; 187; 196), but this is not a consistent feature. These intermediate filament cytoskeletal proteins attach to the membranes of the sarcolemma, nuclei, and mitochondria.

Vimentin in myotubular myopathy (photomicrograph)

In myotubular myopathy, vimentin is overexpressed or upregulated in all myofibers. In a term neonate, vimentin should be limited in muscle to fibroblasts and to endothelial cells and smooth muscular walls of blood vessels. (x250) ...
Desmin in myotubular myopathy (photomicrograph)

In myotubular myopathy, desmin is upregulated in all myofibers; it should no longer be demonstrated as strong immunoreactivity after 38 weeks gestation. (x400) (Used with permission. Sarnat HB. Myotubular myopathy: arrest of morph...
Nucleus and mitochondria in myotubular myopathy (electron micrograph)

Longitudinal section of a centronuclear fiber in a term neonate with myotubular myopathy.
X-linked myotubular myopathy muscle (photomicrograph)

Frozen section showing large central nuclei. (Hematoxylin-eosin; x330)(Photomicrographs by courtesy of Juhani Rapola MD) (Used with permission. Sarnat HB. Myotubular myopathy: arrest of morphogenesis of myofibers associated with p...
NADH histochemistry in X-linked myotubular myopathy (photomicrograph)

Frozen section stained with NADH, showing central aggregation of mitochondrial enzyme activity. (Used with permission. Sarnat HB. Myotubular myopathy: arrest of morphogenesis of myofibers associated with persistence of fetal vimen...

Differential diagnosis

Confusing conditions

Myotonic dystrophy in the neonate is clinically and histologically similar to X-linked myotubular myopathy, and myotonic dystrophy, being more common, is the more likely diagnosis in a female infant with this presentation. However, it has been recognized that female carriers of X-linked myotubular myopathy may manifest muscle disease, in at least a proportion due to skewed X-inactivation (208; 100; 230; 205; 115; 128; 190; 94; 169; 119; 189; 174). In a family, female carriers manifested spastic paraplegia (127). In all cases of X-linked myotubular myopathy in which a mutation has not been found in the MTM1 gene, it is necessary to exclude myotonic dystrophy. For this differential diagnosis, immunohistochemical testing for muscleblind-like 1 protein may be a more rapid method (195) than molecular genetic studies (34).

Profoundly affected boys with clinical features indistinguishable from those of X-linked myotubular myopathy have been diagnosed with RYR1-caused centronuclear myopathy (119).

Other disorders causing severe floppiness in combination with muscle weakness are the other congenital myopathies, severe childhood spinal muscular atrophy and other anterior horn cell disorders, myasthenia, and motor neuropathies. Prader-Willi syndrome with severe hypotonia and feeding difficulties can be excluded by molecular genetic methods.

In the case of a surviving male patient, it is important to differentiate between the X-linked and the autosomal forms of myotubular myopathy, the latter of which usually follow a milder course (232; 112). Four genes for autosomal forms have been characterized (29; 120; 162; 42), and muscle biopsy findings may provide clues for directing mutation detection (22; 118; 179). One workshop report provides a diagnostic algorithm for distinguishing between the various forms of centronuclear myopathy (118).

Diagnostic workup

In many cases, there will be a family history of miscarriages or neonatal deaths of male infants in the maternal line. Pregnancy may have been complicated by polyhydramnios, and birth may have been premature. The floppy male infant is often long and light for his gestational age and has a large head. Spontaneous movements and respiration may be lacking. Ophthalmoplegia may be a feature but is not always apparent at birth.

Once clinical examination has shown muscle weakness and severe hypotonia not explained by abnormalities of the central nervous system, muscle biopsy is essential to confirm the diagnosis. Myotonic dystrophy may need to be excluded by molecular genetic methods, but other myopathies are excluded primarily by histopathologic differences in the muscle biopsy. Characteristic findings include centrally placed nuclei with a surrounding central zone deficient in oxidative enzyme activity, and some patients show so-called necklace fibers (22; 97).

Electromyography may yield normal findings or small polyphasic motor unit potentials, and sometimes even so-called neurogenic features. Serum concentrations of creatine kinase are usually normal, but sometimes they are slightly elevated.

The diagnosis of X-linked myotubular myopathy can be confirmed by direct molecular genetic testing of genomic DNA (135; 134; 207; 209; 230; 79; 106; 21; 74; 113), some cases requiring analyses of copy number variation (220; 24; 05; 166; 189; 126; 88). In a further subset of patients, RNA- or protein-based methods may be needed (178; 218; 226; 153; 02; 77; 35). In the absence of such confirmation, the autosomal forms should be considered (22; 118; 179; 119).

In all new families, a clinical geneticist should be involved in the workup, and the family should have access to genetic counseling. Muscle biopsy as a method for carrier detection has been replaced molecular genetic testing (135; 134; 207; 230; 21). It is to be noted that female carriers may show clinical symptoms, easily mistaken for manifestations of autosomal forms of the disorder (208; 100; 230; 205; 115; 128; 190; 103; 74; 189; 174). Carrier females with unilateral weakness have been described (68), and in one family, female patients had a clinical picture of hereditary spastic paraplegia (127). Of note, one affected boy with type 1 fiber predominance and unspecific myopathic changes was diagnosed only after the identification of a maternal relative with the same disorder (58).

Management

At this time, no specific, curative treatment is commonly available, although therapy trials are underway. Nevertheless, much can be done for boys with X-linked myotubular myopathy (116; 206). No reliable prognostic indicators have been established (155), and active treatment of the neonate is indicated, at least initially, in view of the good outcome in some patients. It is recommended that any decision to refrain from active treatment should not be based on diagnosis alone but should be taken individually, using the same criteria as for children with other neonatally severe conditions (206).

For children who survive, management should be entrusted to a multidisciplinary team with experience of treatment of children with neuromuscular disorders. In particular, patients need regular evaluation of their respiratory capacity, and they are likely to benefit from early intervention including intermittent use of a mechanical ventilator (231; 234; 198; 206). Based on studies of four essentially nonambulant patients, Cahill and colleagues make recommendations for the orthopedic treatment of scoliosis by long posterior fusion, and of metaphyseal fractures of long bones by brief periods of immobilization, while suggesting conservative treatment for contractures (40).

Increasing evidence indicates that hepatobiliary issues are linked to the natural progression of X-linked myotubular myopathy and are unrelated to any particular treatments. The evidence emphasizes the significance of monitoring liver parameters, potentially consulting a pediatric hepatologist, as a crucial facet of ongoing clinical care. Assessing liver-related laboratory values, such as ALT, AST, GGT, and total and direct bilirubin, alongside examining serum bile acid levels, could aid in detecting cholestatic episodes among individuals with X-linked myotubular myopathy (66). The families should be provided with access to genetic counseling.

Proof of concept has been achieved for several different therapy modalities using replacement of MTM1 through viral transfer of a normal gene or a homolog, enzyme replacement therapy, reduction of the interacting protein dynamin or drugs acting on the neuromuscular junction or the use of tamoxifen, or modification of the autophagy pathway. Several studies provide reviews on the subject (89; 140; 85). This brightens the outlook for future therapeutic trials, and preparations are in progress, covering many aspects of the disorder (37; 176; 03; 75; 139; 46; 50; 61; 86; 129; 183; 73; 172; 84; 150; 56; 210; 180; 62; 70; 175). The first human trial, ASPIRO, testing resamirigene bilparvovec as AAV-mediated gene therapy for X-linked myotubular myopathy, took the form of an open-label dose-escalation study (197). Within this trial, 17 patients with X-linked myotubular myopathy were allocated to the higher dose group, seven patients to the lower dose group, and 14 individuals to a control group. The median ages at the time of dosing or enrollment were recorded as 12.1, 31.1, and 18.7 months for the lower dose, higher dose, and control groups, respectively. The study documented improvements in both ventilatory capacity and motor function. However, the deaths of four participants imposed a clinical hold on the trial in September 2021; this hold persisted as of December 2023. Among the four participants who were administered doses and later deceased (three receiving the higher dose and one receiving the lower dose), each experienced severe cholestatic liver injury and decompensated liver failure. Additionally, five participants experienced nonfatal, treatment-associated serious adverse events related to the hepatobiliary system. Myocarditis is another concern that has emerged in some patients after treatment with resamirigene bilparvovec.

Although histopathological endpoints, such as fiber type distributions, numbers of triad structures, the degree of internal/central nucleation, fiber type distributions, and numbers of satellite cells, did not demonstrate statistically significant changes following treatment with resamirigene bilparvovec, muscle biopsies taken at 24 weeks post-treatment showed marked improvements in organelle localization, without apparent increases in myofiber size among most participants (142). However, statistically significant increases in myofiber size were detected in nine biopsies obtained at 48 weeks.

The economic disease burden of X-linked myotubular myopathy has been studied in the United States (184), but the results may not be applicable to other countries as both health economy and treatment policies vary between countries (155).

Media

References

01: Agrawal PB, Pierson CR, Joshi M, et al. SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet 2014;95(2):218-26. PMID 25087613
02: Al-Hashim A, Gonorazky HD, Amburgey K, Das S, Dowling JJ. A novel intronic mutation in MTM1 detected by RNA analysis in a case of X-linked myotubular myopathy. Neurol Genet 2017;3(5):e182. PMID 28852708
03: Al-Qusairi L, Prokic I, Amoasii L, et al. Lack of myotubularin (MTM1) leads to muscle hypotrophy through unbalanced regulation of the autophagy and ubiquitin-proteasome pathways. FASEB J 2013;27(8):3384-94. PMID 23695157
04: Al-Qusairi L, Weiss N, Toussaint A, et al. T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. Proc Natl Acad Sci USA 2009;(106)44:18763-8. PMID 19846786
05: Amburgey K, Lawlor MW, Del Gaudio D, et al. Large duplication in MTM1 associated with myotubular myopathy. Neuromuscul Disord 2013;23(3):214-8. PMID 23273872
06: Amburgey K, Tsuchiya E, de Chastonay S, et al. A natural history study of X-linked myotubular myopathy. Neurology 2017;89(13):1355-64. PMID 28842446
07: Amoasii L, Bertazzi DL, Tronchere H, et al. Phosphatase-dead myotubularin ameliorates X-linked centronuclear myopathy phenotypes in mice. PLoS Genet 2012;8(10):e1002965. PMID 23071445
08: Amoasii L, Hnia K, Chicanne G, et al. Myotubularin and PtdIns3P remodel the sarcoplasmic reticulum in muscle in vivo. J Cell Sci 2013;126(Pt 8):1806-19. PMID 23444364
09: Annoussamy M, Lilien C, Gidaro T, et al. X-linked myotubular myopathy: a prospective international natural history study. Neurology 2019;92(16):e1852-67. PMID 30902907
10: Bachmann C, Jungbluth H, Muntoni F, Manzur AY, Zorzato F, Treves S. Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations. Hum Mol Genet 2017;26(2):320-32. PMID 28007904
11: Barreto-Mota R, Figueirinha J, Quental R, et al. X-linked myotubular myopathy: a clinical report and a review of the mild phenotype. Rev Neurol 2023;76(7):243-6. PMID 36973888
12: Barth PG, Dubowitz V. X-linked myotubular myopathy: a long-term follow-up study. Europ J Paediatr Neurol 1998;1:49-56. PMID 10726846
13: Barth PG, Van Wijngaarden GK, Bethlem J. X-linked myotubular myopathy with fatal neonatal asphyxia. Neurology 1975;25:531-6. PMID 1168872
14: Bartsch O, Kress W, Wagner A, Seemanova E. The novel contiguous gene syndrome of myotubular myopathy (MTM1), male hypogenitalism and deletion in Xq28: report of the first familial case. Cytogenet Cell Genet 1999;85(3-4):310-14. PMID 10449925
15: Beggs AH, Bohm J, Snead E, et al. MTM1 mutation associated with X-linked myotubular myopathy in labrador retrievers. Proc Natl Acad Sci U S A 2010;107(33):14697-702. PMID 20682747
16: Beggs AH, Byrne BJ, De Chastonay S, et al. A multicenter, retrospective medical record review of X-linked myotubular myopathy: the recensus study. Muscle Nerve 2018;57(4):550-60. PMID 29149770
17: Begley MJ, Taylor GS, Brock MA, et al. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc Natl Acad USA 2006;103:927-32. PMID 16410353
18: Berger P, Bonneick S, Willi S, Wymann M, Suter U. Loss of phosphatase activity in Myotubularin-Related-Protein-2 is associated with Charcot-Marie-Tooth disease type 4B1. Hum Mol Genet 2002;11:1569-79. PMID 12045210
19: Berger P, Schaffitzel C, Berger I, Ban N, Suter U. Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module. Proc Natl Acad Sci USA 2003;100(21):12177-82. PMID 14530412
20: Bermudez-Jimenez FJ, Jiménez-Jáimez J, González Molina M, Tercedor L. Giant biventricular aneurysms: a novel cardiac phenotype in myotubular/centronuclear myopathy. Eur Heart J 2018;39(48):4289-90. PMID 29668875
21: Bertini E, Biancalana V, Bolino A, et al. 118th ENMC International Workshop on Advances in Myotubular Myopathy. 26-28 September 2003, Naarden, The Netherlands. (5th Workshop of the International Consortium on Myotubular Myopathy). Neuromuscul Disord 2004;14:387-96. PMID 15145343
22: Bevilacqua JA, Bitoun M, Biancalana V, et al. “Necklace" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy. Acta Neuropathol 2009;117(3):283-91. PMID 19084976
23: Bevilacqua JA, Monnier N, Bitoun M, et al. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol 2011;37(3):271-84. PMID 21062345
24: Biancalana V, Beggs AH, Das S, et al. Clinical utility gene card for: centronuclear and myotubular myopathies. Eur J Hum Genet 2012;20(10). PMID 22617344
25: Biancalana V, Caron O, Gallati S, et al. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet 2003;112(2):135-42. PMID 12522554
26: Biancalana V, Romero NB, Thuestad IJ, et al. Some DNM2 mutations cause extremely severe congenital myopathy and phenocopy myotubular myopathy. Acta Neuropathol Commun 2018;6(1):93. PMID 30208955
27: Biancalana V, Scheidecker S, Miguet M, et al. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues. Acta Neuropathol 2017;134(6):889-904. PMID 28685322
28: Bitoun M, Bevilacqua JA, Prudhon B, et al. Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. Ann Neurol 2007;62(6):666-70. PMID 17932957
29: Bitoun M, Maugenre S, Jeannet PY, et al. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nature Genetics 2005;37(11):1207-9. PMID 16227997
30: Blondeau F, Laporte J, Bodin S, Superti-Furga G, Payrastre B, Mandel J-L. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum Molec Genet 2000;15:2223-9. PMID 11001925
31: Bolino A, Muglia M, Conforti FL, et al. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 2000;25(1):17-9. PMID 10802647
32: Breningstall GN, Grover WD, Marks HG. Maternal muscle biopsy in X-linked recessive centronuclear (myotubular) myopathy. Am J Hum Genet 1991;39:13-8. PMID 1867257
33: Breslin D, Reid J, Hayes A, Mirakhur RK. Anaesthesia in myotubular (centronuclear) myopathy. Anaesthesia 2000;55:471-4. PMID 10792141
34: Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of myotonic muscular dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 1992;68(4):799-808. PMID 1310900
35: Bryen S, Oates EC, Evesson FJ, et al. Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy. Eur J Hum Genet 2021;29(1):61-6. PMID 32862205
36: Buj-Bello A, Biancalana V, Moutou C, Laporte J, Mandel JL. Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy. Hum Mutat 1999;14(4):320-5. PMID 10502779
37: Buj-Bello A, Fougerousse F, Schwab Y, et al. AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis. Hum Mol Genet 2008;17(14):2132-43. PMID 18434328
38: Buj-Bello A, Laugel V, Messaddeq N, et al. The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc Natl Acad Sci U S A 2002;99(23):15060-5. PMID 12391329
39: Bullivant J, Sen A, Page J, et al. The myotubular and centronuclear myopathy patient registry: a multifunctional tool for translational research. Neuromuscul Disord 2023. [Epub ahead of print] PMID 38061948
40: Cahill PJ, Rinella AS, Bielski RJ. Orthopaedic complications of myotubular myopathy. J Pediatr Orthop 2007;27(1):98-103. PMID 17195806
41: Cao C, Backer JM, Laporte J, Bedrick EJ, Wandinger-Ness A. Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking. Molec Biol Cell 2008;19(8):3334-46. PMID 18524850
42: Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, et al. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 2013;81(14):1205-14. PMID 23975875
43: Chanzy S, Routon MC, Moretti S, de Gennes C, Mselati JC. [Unusual good prognosis for X-linked myotubular myopathy]. [French]. Archives De Pediatrie 2003;10:707-9. PMID 12922003
44: Chaudhari T, Todd DA, Kent AL, et al. Bilateral subdural hygromas and cephalhaematomas in male twins with severe myotubular myopathy caused by a Novel c.431delT (p.Leu144fs) mutation in MTM1 gene. J Paediatr Child Health 2011;47(1-2):64-5. PMID 20500434
45: Chen X, Gao YQ, Zheng YY, et al. The intragenic microRNA miR199A1 in the dynamin 2 gene contributes to the pathology of X-linked centronuclear myopathy. J Biol Chem 2020;295(26):8656-67. PMID 32354746
46: Childers MK, Joubert R, Poulard K, et al. Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy. Sci Transl Med 2014;6(220):220ra10. PMID 24452262
47: Clague MJ, Dove SK, Barr FA. I-proteins - a proposed switch in myotubularin function. Trends Biochem Sci 2004;29(2):58-61. PMID 15102431
48: Cocanougher BT, Flynn L, Yun P, et al. Adult MTM1-related myopathy carriers: classification based on deep phenotyping. Neurology 2019;93(16):e1535-42. PMID 31541013
49: Costi D, van der Walt JH. General anesthesia in an infant with X-linked myotubular myopathy. Ped Anest 2004;14:964-8. PMID 15500500
50: Cowling BS, Chevremont T, Prokic I, et al. Reducing dynamin 2 expression rescues X-linked centronuclear myopathy. J Clin Invest 2014;124(3):1350-63. PMID 24569376
51: Cowling BS, Prokic I, Tasfaout H, et al. Amphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturation. J Clin Invest 2017;127(12):4477-87. PMID 29130937
52: Cox K, Gattas M, Harvey P, Doplhin C, Friend K, Yu S. X-linked myotubular myopathy: mutation R69C identified in a family with neonatal deaths. Clin Genet 2005;67:441-2. PMID 15811014
53: Cui X, De Vivo I, Slany R, Miyamoto A, Firestein R, Cleary ML. Association of SET domain and myotubularin-related proteins modulates growth control. Nat Genet 1998;18:331-7. PMID 9537414
54: Dahl N, Hu LJ, Chery M, et al. Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X-inactivation assigns the gene to a 600 kb region. Am J Hum Genet 1995;56(5):1108-15. PMID 7726166
55: D'Amico A, Longo A, Fattori F, et al. Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies. Orphanet J Rare Dis 2021;16(1):425. PMID 34641930
56: Daniele N, Moal C, Julien L, et al. Intravenous administration of a MTMR2-encoding AAV vector ameliorates the phenotype of myotubular myopathy in mice. J Neuropathol Exp Neurol 2018;77(4):282-95. PMID 29408998
57: Darnfors C, Larsson HE, Oldfors A, et al. X-linked myotubular myopathy: a linkage study. Clin Genet 1990;37(5):335-40. PMID 1972354
58: de Goede C, Kelsey A, Kingston H, Tomlin PI, Hughes MI. Muscle biopsy without central nuclei in a male child with mild X-linked myotubular myopathy. Dev Med Child Neurol 2005;47:835-7. PMID 16288675
59: de Gouyon B, Zhao W, Laporte J, Mandel JL, Metzenberg A, Herman G. Characterization of mutations in the recently identified myotubularin gene in twenty-six patients with X-linked myotubular myopathy. Hum Mol Genet 1997;6:1499-504. PMID 9285787
60: De Luca A, Torrente I, Mangino M, Bertini E, Dallapiccola B, Novelli G. A novel mutation (R27 1X) in the myotubularin gene causes a severe myotubular myopathy. Hum Hered 1999;49:59-60. PMID 9858861
61: Demonbreun AR, McNally EM. Dynamin 2 the rescue for centronuclear myopathy. J Clin Invest 2014;124(3):976-8. PMID 24569368
62: Djeddi S, Reiss D, Menuet A, et al. Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies. Mol Ther 2021;29(8):2514-34. PMID 33940157
63: Donnelly A, Haan E, Manson J, Mulley J. A novel mutation in exon b (R259C) of the MTM1 gene is associated with a mild myotubular myopathy. Mutations in brief no. 125. Online. Hum Mutat 1998;11:334. PMID 10215413
64: Dowling JJ. Titin and centronuclear myopathy: The tip of the iceberg for TTN-ic mutations. Neurology 2013;81(14):1189-90. PMID 23975873
65: Dowling JJ, Lawlor MW, Das S. X-linked myotubular myopathy. In: GeneReviews ® [Internet]. Seattle, WA: University of Washington, Seattle. Accessed 2002. PMID 20301605
66: Dowling JJ, Muller-Felber W, Smith BK, et al. INCEPTUS natural history, run-in study for gene replacement clinical trial in X-linked myotubular myopathy. J Neuromuscul Dis 2022;9(4):503-16. PMID 35694931
67: Dowling JJ, Vreede AP, Low SE, et al. Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy. PLoS Genet 2009;5(2):e1000372. PMID 19197364
68: Drouet A, Ollagnon-Roman E, Streichenberger N, et al. Unilateral presentation of X-linked myotubular myopathy (XLMTM) in two out of three female carriers in a family with no affected male. Rev Neurol (Paris) 2008;164(2):169-76. PMID 18358876
69: Dubowitz V. Muscle biopsy. A practical approach. London: Balliére-Tindall, 1985.
70: Duong T, Harding G, Mannix S, et al. Use of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-linked myotubular myopathy: content validity and psychometric performance. J Neuromuscul Dis 2021;8(1):63-77. PMID 32925083
71: Dupont JB, Guo J, Renaud-Gabardos E, et al. AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy. Mol Ther 2020;28(2):382-93. PMID 31784415
72: Echaniz-Laguna A, Nicot AS, Carre S, et al. Subtle central and peripheral nervous system abnormalities in a family with centronuclear myopathy and a novel dynamin 2 gene mutation. 2007;17(11-12):955-9. PMID 17825552
73: Elverman M, Goddard MA, Mack D, et al. Long-term effects of systemic gene therapy in a canine model of myotubular myopathy. Muscle Nerve 2017;56(5):943-53. PMID 28370029
74: Fattori F, Maggi L, Bruno C, et al. Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort. J Neurol 2015;262(7):1728-40. PMID 25957634
75: Fetalvero KM, Yu Y, Goetschkes M, et al. Defective autophagy and mTORC1 signaling in myotubularin null mice. Mol Cell Biol 2013;33(1):98-110. PMID 23109424
76: Fischer D, Herasse M, Bitoun M, et al. Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy. Brain 2006;129:1463-9. PMID 16585051
77: Fitzgerald J, Feist C, Dietz P, Moore S, Basel D. A deep intronic variant activates a pseudoexon in the MTM1 gene in a family with X-linked myotubular myopathy. Mol Syndromol 2020;11(5-6):264-70. PMID 33505229
78: Flaherty DC, Lonner B, Gal JS. Successful management of a patient with X-linked myotubular myopathy for scoliosis surgery and previous cardiac arrest after prone positioning: a case report. A A Pract 2018;10(12):340-2. PMID 29634567
79: Flex E, De Luca A, D’Apice MR, Buccino A, Dallapiccola B, Novelli G. Rapid scanning of the myotubularin (MTM1) gene by denaturing high-performance liquid chromatography (DHPLC). Neuromuscul Disord 2002;12:501-5. PMID 12031625
80: Fouarge E, Monseur A, Boulanger B, et al. Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy. Orphanet J Rare Dis 2021;16(1):3. PMID 33407688
81: Funayama K, Shimizu H, Tanaka H, et al. An autopsy case of peliosis hepatis with X-linked myotubular myopathy. Leg Med (Tokyo) 2019:38;77-82. PMID 31030121
82: Gangfuss A, Schmitt D, Roos A, et al. Diagnosing X-linked myotubular myopathy - a German 20-year follow up experience. J Neuromuscul Dis 2021;8(1):79-90. PMID 33164942
83: Garcia-Garcia J, Fernández-García MA, Blanco-Arias P, et al. Non-compaction cardiomyopathy and early respiratory failure in an adult symptomatic female carrier of centronuclear myopathy caused by a MTM1 mutation. Neuromuscul Disord 2018;28(11):952-5. PMID 30241883
84: Gayi E, Neff LA, Massana Muñoz X, et al. Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy. Nat Commun 2018;9(1):4848. PMID 30451843
85: Gineste C, Laporte J. Therapeutic approaches in different congenital myopathies. Curr Opin Pharmacol 2023;68:102328. PMID 36512981
86: Goddard MA, Burlingame E, Beggs AH, et al. Gait characteristics in a canine model of X-linked myotubular myopathy. J Neurol Sci 2014;346(1-2):221-6. PMID 25281397
87: Goddard MA, Mack DL, Czerniecki SM, et al. Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy. Ann Transl Med 2015;3(18):262. PMID 26605308
88: Gomez-Gonzalez C, Rosas-Alonso R, Rodríguez-Antolín C, et al. Symptomatic heterozygous X-Linked myotubular myopathy female patient with a large deletion at Xq28 and decrease expression of normal allele. Eur J Med Genet 2021;64(4):104170. PMID 33618039
89: Gomez-Oca R, Cowling BS, Laporte J. Common pathogenic mechanisms in centronuclear and myotubular myopathies and latest treatment advances. Int J Mol Sci 2021;22(21):11377. PMID 34768808
90: Gottschalk A, Heiman-Patterson T, deQuevedo R, Quinn PD. General anesthesia for a patient with centronuclear (myotubular) myopathy. Anesthesiology 1998;89:1018-20. PMID 9778019
91: Graham RJ, Darras BT, Haselkorn T, et al. Real-world analysis of healthcare resource utilization by patients with X-linked myotubular myopathy (XLMTM) in the United States. Orphanet J Rare Dis 2023;18(1):138. PMID 37280644
92: Graham RJ, Muntoni F, Hughes I, et al. Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis. Arch Dis Child 2020;105(4):332-8. PMID 31484632
93: Grange RW, Doering J, Mitchell E, et al. Muscle function in a canine model of X-linked myotubular myopathy. Muscle Nerve 2012;46(4):588-91. PMID 22987702
94: Grogan PM, Tanner SM, Orstavik KH, et al. Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations. Neurology 2005;64(9):1638-40. PMID 15883335
95: Guiraud-Chaumeil C, Vincent MC, Laporte J, Fardeau M, Samson F, Mandel JL. A mutation in the MTM1 gene invalidates a previous suggestion of nonallelic heterogeneity in X-linked myotubular myopathy [letter]. Am J Hum Genet 1997;60(6):1542-4. PMID 9199578
96: Gupta VA, Hnia K, Smith LL, et al. Loss of catalytically inactive lipid phosphatase myotubularin-related protein 12 impairs myotubularin stability and promotes centronuclear myopathy in zebrafish. PLoS Genet 2013;9(6):e1003583. PMID 23818870
97: Gurgel-Giannetti J, Zanoteli E, de Castro Concentino EL, et al. Necklace fibers as histopathological marker in a patient with severe form of X-linked myotubular myopathy. Neuromuscul Disord 2012;22:541-5. PMID 22264517
98: Hagiwara SI, Kubota M, Sakaguchi K, Hiwatari E, Kishimoto H, Kagimoto S. Fatal hepatic hemorrhage from peliosis hepatis with X-linked myotubular myopathy: a case report. J Pediatr Gastroenterol Nutr 2013;23(11):917-21. PMID 24011703
99: Hamanaka K, Inami I, Wada T, et al. Muscle from a 20-week-old myotubular myopathy fetus is not myotubular. Neuromuscul Disord 2016;26(3):234-5. PMID 26898940
100: Hammans SR, Robinson DO, Moutou C, et al. A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy. Neuromuscul Disord 2000;10(2):133-7. PMID 10714588
101: Hane BG, Rogers RC, Schwartz CE. Germline mosaicism in X-linked myotubular myopathy. Clin Genet 1999;56:77-81. PMID 10466421
102: Heckmatt JZ, Sewry CA, Hodes D, Dubowitz V. Congenital centronuclear (myotubular) myopathy. A clinical, pathological and genetic study in eight children. Brain 1985;108(Pt 4):941-64. PMID 4075080
103: Hedberg C, Lindberg C, Máthé G, Moslemi A-R, Oldfors A. Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation. Neuromusc. Disord. 2012;22:244-51. PMID 22101172
104: Hedberg-Oldfors C, Visuttijai K, Topa A, Tulinius M, Oldfors A. Grand paternal inheritance of X-linked myotubular myopathy due to mosaicism, and identification of necklace fibers in an asymptomatic male. Neuromuscul Disord 2017;27(9):843-7. PMID 28622964
105: Herman GE, Finegold M, Zhao W, de Gouyon B, Metzenberg A. Medical complications in long-term survivors with X-linked myotubular myopathy. J Pediatr 1999;134(2):206-14. PMID 9931531
106: Herman GE, Kopacz K, Zhao W, Mills PL, Metzenberg A, Das S. Characterization of mutations in fifty North American patients with X-linked myotubular myopathy. Hum Mutat 2002;19(2):114-21. PMID 11793470
107: Hikita T, Wakita S, Mori Y, et al. Severe infantile myotubular myopathy with complete atrioventricular block. Pediatr Int 2008;50(5):698-700. PMID 19261124
108: Hnia K, Tronchere H, Tomczak KK, et al. Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle. J Clin Invest 2011;121(1):70-85. PMID 21135508
109: Hoffjan S, Thiels C, Vorgerd M, Neuen-Jacob E, Epplen JT, Kress W. Extreme phenotypic variability in a German family with X-linked myotubular myopathy associated with E404K mutation in MTM1. Neuromuscul Disord 2006;16:749-53. PMID 17005396
110: Hu LJ, Laporte J, Kress W, et al. Deletions in Xq28 in two boys with myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430 kb region. Hum Mol Genet 1996;5(1):139-43. PMID 8789451
111: Janssen EA, Hensels GW, van Oost BA, et al. The gene for X-linked myotubular myopathy is located in a 8 Mb region at the border of Xq27.3 and Xq28. Neuromuscul Disord 1994;4(5-6):455-61. PMID 7881289
112: Jeannet PY, Bassez G, Eymard B, et al. Clinical and histologic findings in autosomal centronuclear myopathy. Neurology 2004;62(9):1484-90. PMID 15136669
113: Johannsen J, Hempel M, Diehl T, Haack TB, Denecke J. Exome sequencing is a valuable approach in critically ill patients with suspected monogenic disease: diagnosis of X-linked centronuclear myopathy in preterm twins. Pediatr Neonatol 2017;58(5):458-9. PMID 27989427
114: Joubert R, Vignaud A, Le M, Moal C, Messaddeq N, Buj-Bello A. Site-specific MTM1 mutagenesis by an AAV-Cre vector reveals that myotubularin is essential in adult muscle. Hum Mol Genet 2013;22(9):1856-66. PMID 23390130
115: Jungbluth H, Sewry CA, Buj-Bello A, et al. Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation. Neuromuscul Disord 2003;13(1):55-9. PMID 12899873
116: Jungbluth H, Wallgren-Pettersson C. Congenital/structural myopathies. In: Rimoin D, Pyeritz R, Korf B, editors: Principles and Practice of Medical Genetics. 6th edition. London: Elsevier, 2014.
117: Jungbluth H, Wallgren-Pettersson C, Laporte J. Centronuclear (myotubular) myopathy. Orphanet J Rare Dis 2008;3:26. PMID 18817572
118: Jungbluth H, Wallgren-Pettersson C, Laporte JF; for the Centronuclear (Myotubular) Myopathy Consortium. 164th ENMC International workshop: 6th workshop on centronuclear (myotubular) myopathies, 16-18th January 2009, Naarden, The Netherlands. Neuromuscul Disord 2009;19(10):721-9. PMID 19683444
119: Jungbluth H, Wallgren-Pettersson C, Laporte JF, Centronuclear (Myotubular) myopathy Consortium. 198th ENMC International Workshop: 7th Workshop on Centronuclear (Myotubular) myopathies, 31st May - 2nd June 2013, Naarden, The Netherlands. Neuromuscul Disord 2013;23(12):1033-43. PMID 24070817
120: Jungbluth H, Zhou H, Sewry CA, et al. Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord 2007;17:338-45. PMID 17376685
121: Karolczak S, Deshwar AR, Aristegui E, et al. Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy. J Clin Invest 2023;133(18):e166275. PMID 37490339
122: Ketel K, Krauss M, Nicot AS, et al. A phosphoinositide conversion mechanism for exit from endosomes. Nature 2016;529(7586):408-12. PMID 26760201
123: Kim SA, Vacratsis PO, Firestein R, Cleary ML, Dixon JE. Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proc Natl Acad Sci USA 2003;100(8):4492-7. PMID 12668758
124: Koch C, Buono S, Menuet A, et al. Myostatin: a circulating biomarker correlating with disease in myotubular myopathy mice and patients. Mol Ther Methods Clin Dev 2020;17:1178-89. PMID 32514412
125: Koga H, Miyako K, Suga N, Hidaka T, Takahashi N. Predisposition to subdural hemorrhage in X-linked myotubular myopathy. Pediatr Neurol 2012;46:332-4. PMID 22520358
126: Kosma K, Mitrakos A, Sofokleous C, et al. A female patient with Xq28 microduplication presenting with myotubular myopathy, confirmed with a custom-designed X-array. Neuropediatrics 2019;50(1):61-3. PMID 30541163
127: Kraatari M, Tuominen H, Haapaniemi T, Moilanen J, Rahikkala E. X-linked myotubular myopathy mimics hereditary spastic paraplegia in two female manifesting carriers of pathogenic MTM1 variant. Eur J Hum Genet 2020;63(11):104040. PMID 32805447
128: Kristiansen M, Knudsen GP, Tanner SM, et al. X-inactivation patterns in carriers of X-linked myotubular myopathy. Neuromuscul Disord 2003;13(6):468-71. PMID 12899873
129: Kutchukian C, Lo Scrudato M, Tourneur Y, et al. Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice. Proc Natl Acad Sci U S A 2016;113(50):14432-7. PMID 27911767
130: Kutchukian C, Szentesi P, Allard B, Buj-Bello A, Csernoch L, Jacquemond V. Ca2+-induced sarcoplasmic reticulum Ca2+ release in myotubularin-deficient muscle fibers. Cell Calcium 2019;80:91-100. PMID 30999217
131: Laporte J, Biancalana V, Tanner SM, et al. MTM1 mutations in X-linked myotubular myopathy. Hum Mutat 2000;15(5):393-409. PMID 10790201
132: Laporte J, Blondeau F, Buj-Bello A, Mandel JL. The myotubularin phosphatase family: from genetic diseases to phosphoinositide metabolism. Trends Genet 2001a;4:221-8. PMID 11275328
133: Laporte J, Guiraud-Chaumeil C, Tanner SM, et al. Genomic organization of the MTM1 gene implicated in X-linked myotubular myopathy. Eur J Hum Genet 1998;6(4):325-30. PMID 9781038
134: Laporte J, Guiraud-Chaumeil C, Vincent MC, et al. Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuromuscular Center. Hum Mol Genet 1997b;6(9):1505-11. PMID 9305655
135: Laporte J, Hu LJ, Kretz C, et al. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 1996;13(2):175-82. PMID 8640223
136: Laporte J, Kioschis P, Hu LJ, et al. Cloning and characterization of an alternatively spliced gene in proximal Xq28 deleted in two patients with intersexual genitalia and myotubular myopathy. Genomics 1997a;41(3):458-62. PMID 9169146
137: Laporte J, Kress W, Mandel JL. Diagnosis of X-linked myotubular myopathy by detection of myotubularin. Ann Neurol 2001b;50(1):42-6. PMID 11456308
138: Lawlor MW, Alexander MS, Viola MG, et al. Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment. Am J Pathol 2012;181(3):961-8. PMID 22841819
139: Lawlor MW, Armstrong D, Viola MG, et al. Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy. Hum Mol Genet 2013;22(8):1525-38. PMID 23307925
140: Lawlor MW, Dowling JJ. X-linked myotubular myopathy. Neuromuscul Disord 2021;31(10):1004-12. PMID 34736623
141: Lawlor MW, Read BP, Edelstein R, et al. Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice. Am J Pathol 2011;178(2):784-93. PMID 21281811
142: Lawlor MW, Schoser B, Margeta M, et al. Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial. EBioMedicine 2023;99:104894. PMID 38086156
143: Lawlor MW, Viola MG, Meng H, et al. Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following activin type IIB receptor inhibition in MTM1 p.R69C mice. Am J Pathol 2014;184(6):1831-42. PMID 24726641
144: Lee IC, Su PH, Chen JY, Hu JM, Lu JJ, Ng YY. Congenital myotubular myopathy with a novel MTM1 gene mutation in a premature infant presenting with ventilator dependency and intrahepatic cholestasis. J Child Neurol 2012;27:99-104. PMID 21881007
145: Lehesjoki AE, Sankila EM, Miao J, et al. X linked neonatal myotubular myopathy: one recombination detected with polymorphic DNA markers from Xq28. J Med Genet 1990;27(5):288-91. PMID 1972196
146: Liechti-Gallati S, Muller B, Grimm T, et al. X-linked centronuclear myopathy: mapping the gene to Xq28. Neuromuscul Disord 1991;1(4):239-45. PMID 1822801
147: Liewluck T, Shen XM, Milone M, Engel AG. Endplate structure and parameters of neuromuscular transmission in sporadic centronuclear myopathy associated with myasthenia. Neuromuscul Disord 2011;21(6):387-95. PMID 21482111
148: Lim HJ, Joo S, Oh SH, et al. Syngeneic myoblast transplantation improves muscle function in a murine model of X-linked myotubular myopathy. Cell Transplant 2015;24(9):1887-900. PMID 25197964
149: Longo G, Russo S, Novelli G, Sangiuolo F, D'Apice MR. Mutation spectrum of the MTM1 gene in XLMTM patients: 10 years of experience in prenatal and postnatal diagnosis. Clin Genet 2016;89(1):93-8. PMID 26338224
150: Maani N, Sabha N, Rezai K, et al. Tamoxifen therapy in a murine model of myotubular myopathy.Nat Commun 2018;9(1):4849. PMID 30451841
151: Majczenko K, Davidson AE, Camelo-Piragua S, et al. Dominant mutation of CCDC78 in a unique congenital myopathy with prominent internal nuclei and atypical cores. Am J Hum Genet 2021;91(2):365-71. PMID 22818856
152: Mandel JL, Laporte J, Buj-Bello A, Sewry C, Wallgren-Pettersson C. X-linked myotubular myopathy. In: Karpati G, editor. Structural and Molecular Basis of Skeletal Muscle Diseases. Basel: ISN Neuropath Press, 2002:124-9.
153: Mansour R, Severin S, Xuereb JM, et al. Expression of myotubularins in blood platelets: Characterization and potential diagnostic of X-linked myotubular myopathy. Biochem Biophys Res Commun 2016;476(3):167-73. PMID 27155155
154: McCrea HJ, Kretz C, Laporte J, Ment LR. Dementia in a child with myotubular myopathy. Pediatr Neurol 2009;40(6):483-5. PMID 19433289
155: McEntagart M, Parsons G, Buj-Bello A, et al. Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord 2002;12(10):939-46. PMID 12467749
156: Mercier L, Böhm J, Fekonja N, et al. In vivo imaging of skeletal muscle in mice highlights muscle defects in a model of myotubular myopathy. Intravital 2016;5(1). PMID 28243519
157: Misra S, Ujhazy P, Gatmaitan Z, Varticovski L, Arias IM. The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver. J Biol Chem 1998;273(41):26638-44. PMID 9756904
158: Molera C, Sarishvili T, Nascimento A, et al. Intrahepatic cholestasis is a clinically significant feature associated with natural history of X-linked myotubular myopathy (XLMTM): a case series and biopsy report. J Neuromuscul Dis 2022;9(1):73-82. PMID 34366366
159: Motoki T, Fukuda M, Nakano T, et al. Fatal hepatic hemorrhage by peliosis hepatis in X-linked myotubular myopathy: a case report. Neuromuscul Disord 2013;23(11):917-21. PMID 24011703
160: Nandurkar HH, Layton M, Laporte J, et al. Identification of myotubularin as the lipid phosphatase catalytic subunit associated with the 3-phosphatase adapter protein, 3-PAP. Proc Natl Acad Sci USA 2003;100(15):8660-5. PMID 12847286
161: Neese JM, Yum S, Matesanz S, et al. Intracranial hemorrhage secondary to vitamin K deficiency in X-linked myotubular myopathy. Neuromuscul Disord 2021;31(7):651-5. PMID 34120822
162: Nicot AS, Toussaint A, Tosch V, et al. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet 2007;39(9):1134-9. PMID 17676042
163: Nishino I, Minami N, Kobayashi O, et al. MTM1 gene mutations in Japanese patients with the severe infantile form of myotubular myopathy. Neuromuscul Disord 1998;8(7):453-8. PMID 9829274
164: Noguchi S, Fujita M, Murayama K, et al. Gene expression analysis in X-linked myotubular myopathy. Neurology 2005;65:732-7. PMID 16157907
165: Olby NJ, Friedenberg S, Meurs K, et al. A mutation in MTM1 causes X-linked myotubular myopathy in Boykin spaniels. Neuromuscul Disord 2020;30(5):353-9. PMID 32417001
166: Oliveira J, Oliveira ME, Kress W, et al. Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database. Eur J Hum Genet 2013;21(5):540-9. PMID 22968136
167: Omata K, Okada N, Miyahara G, et al. Peliosis hepatis in a child with X-linked myotubular myopathy treated with living-donor liver transplant: a case report. Transplant Proc 2021;53(4):1317-21. PMID 33468339
168: Pele M, Tiret L, Kessler JL, Blot S, Panthier JJ. SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal centronuclear myopathy in dogs. Hum Molec Genet 2005;14:1417-27. PMID 15829503
169: Penisson-Besnier I, Biancalana V, Reynier P, Cossee M, Dubas F. Diagnosis of myotubular myopathy in the oldest known manifesting female carrier: A clinical and genetic study. Neuromuscul Disord 2007;17:180-5. PMID 17251023
170: Pierson CR, Dulin-Smith AN, Durban AN, et al. Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype. Hum Mol Genet 2012;21(4):811-25. PMID 22068590
171: Raess MA, Cowling BS, Bertazzi DL, et al. Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy. Hum Mol Genet 2017a;26(19):3736-48. PMID 28934386
172: Raess MA, Friant S, Cowling BS, Laporte J. WANTED - Dead or alive: myotubularins, a large disease-associated protein family. Adv Biol Regul 2017b;63:49-58. PMID 27666502
173: Razidlo GL, Katafiasz D, Taylor GS. Myotubularin regulates Akt-dependent survival signaling via phosphatidylinositol 3-phosphate. J Biol Chem 2011;286(22):20005-19. PMID 21478156
174: Reumers SFI, Braun F, Spillane JE, et al. Spectrum of clinical features in X-linked myotubular myopathy carriers: an international questionnaire study. Neurology 2021a;97(5):e501-12. PMID 34011573
175: Reumers SFI, Erasmus CE, Bouman K, et al. Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands. Clin Genet 2021b;100(6):692-702. PMID 34463354
176: Robb SA, Sewry CA, Dowling JJ, et al. Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies. Neuromuscul Disord 2011;21(6):379-86. PMID 21440438
177: Robinson FI, Dixon JE. Myotubularin phosphatases: policing 3-phosphoinositides. Trends Cell Biol 2006;16(8):403-12. PMID 16828287
178: Rohde HM, Tronchere H, Payrastre B, Laporte J. Detection of myotubularin phosphatases activity on phosphoinositides in vitro and ex vivo. Methods Mol Biol 2009;462:265-78. PMID 19160676
179: Romero NB. Centronuclear myopathies: a widening concept. Neuromuscul Disord 2010;20(4):223-8. PMID 20181480
180: Ross JA, Tasfaout H, Levy Y, et al. rAAV-related therapy fully rescues myonuclear and myofilament function in X-linked myotubular myopathy. Acta Neuropathol Commun 2020;8(1):167. PMID 33076971
181: Rossi D, Catallo MR, Pierantozzi E, Sorrentino V. Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies. J Gen Physiol 2022;154(9):e202213115. PMID 35980353
182: Royer B, Hnia K, Gavriilidis C, Tronchere H, Tosch V, Laporte J. The myotubularin-amphiphysin 2 complex in membrane tubulation and centronuclear myopathies. EMBO Rep 2013;14(10):907-15. PMID 23917616
183: Sabha N, Volpatti JR, Gonorazky H, et al. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models. J Clin Invest 2016;126(9):3613-25. PMID 27548528
184: Sacks NC, Healey BE, Cyr PL, et al. Costs and health resource use in patients with X-linked myotubular myopathy: insights from US commercial claims. J Manag Care Spec Pharm 2021;27(8):1019-26. PMID 33843254
185: Samson F, Mesnard L, Heimburger M, et al. Genetic linkage heterogeneity in myotubular myopathy. Am J Hum Genet 1995;57(1):120-6. PMID 7611280
186: Sarnat HB. Myotubular myopathy: arrest of morphogenesis of myofibres associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle. Can J Neurol Sci 1990;17:109-23. PMID 2357647
187: Sarnat HB. Vimentin and desmin in maturing skeletal muscle and developmental myopathies. Neurology 1992;42:1616-24. PMID 1641160
188: Sarwal A, Cartwright MS, Walker FO, et al. Ultrasound assessment of the diaphragm: preliminary study of a canine model of x-linked myotubular myopathy. Muscle Nerve 2014;50(4):607-9. PMID 24861988
189: Savarese M, Musumeci O, Giugliano T, et al. Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers. Neuromuscul Disord 2016;26(4-5):292-9. PMID 27017278
190: Schara U, Kress W, Tucke J, Mortier W. X-linked myotubular myopathy in a female infant caused by a new MTM1 gene mutation. Neurology 2003;60:1363-5. PMID 12707446
191: Schartner V, Romero NB, Donkervoort S, et al. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathol 2017;133(4):517-33. PMID 28012042
192: Schessl J, Medne L, Hu Y, et al. MRI in DNM2-related centronuclear myopathy: evidence for highly selective muscle involvement. Neuromuscul Disord 2007;17(1):28-32. PMID 17134899
193: Senderek J, Bergmann C, Weber S, et al. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet 2003;12(3):349-56. PMID 12554688
194: Sewry CA. The role of immunocytochemistry in congenital myopathies. Neuromuscul Disord 1998;8(6):394-400. PMID 9713857
195: Sewry CA, Quinlivan RC, Squier W, Morris GE, Holt I. A rapid immunohistochemical test to distinguish congenital myotonic dystrophy from X-linked myotubular myopathy. Neuromuscul Disord 2012;22:225-30. PMID 22113158
196: Shichiji M, Biancalana V, Fardeau M, et al. Extensive morphological and immunohistochemical characterization in myotubular myopathy. Brain Behav 2013;3(4):476-86. PMID 24381816
197: Shieh PB, Kuntz NL, Dowling JJ, et al. Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial. Lancet Neurol 2023;22(12):1125-39. PMID 37977713
198: Smith BK, Goddard M, Childers MK. Respiratory assessment in centronuclear myopathies. Muscle Nerve 2014;50(3):315-26. PMID 24668768
199: Snead EC, Taylor SM, van der Kooij M, Cosford K, Beggs AH, Shelton GD. Clinical phenotype of X-linked myotubular myopathy in Labrador Retriever puppies. J Vet Intern Med 2015;29(1):254-60. PMID 25581576
200: Snyder JM, Meisner A, Mack D, et al. Validity of a neurological scoring system for canine X-linked myotubular myopathy. Hum Gene Ther Clin Dev 2015;26(2):131-7. PMID 26086764
201: Souza LS, Almeida CF, Yamamoto GL, et al. Manifesting carriers of X-linked myotubular myopathy: genetic modifiers modulating the phenotype. Neurol Genet 2020;6(5):e513. PMID 33062893
202: Spiro AJ, Shy GM, Gonatas NK. Myotubular myopathy. Persistence of fetal muscle in an adolescent boy. Arch Neurol 1996;14(1):1-14. PMID 4954227
203: Starr J, Lamont M, Iselius J, Harvey J, Heckmatt J. A linkage study of a large pedigree with X linked centronuclear myopathy. J Med Genet 1990;27:284-7. PMID 2352255
204: Sustersic B, Neubauer D. Letter to the editor. Dev Med Child Neurol 2005;47:358-9.
205: Sutton IJ, Winer JB, Norman AN, Liechti-Gallati S, MacDonald F. Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations. Neurology 2001;5:900-2. PMID 11552027
206: Tan HL, Chan E. Respiratory care in myotubular myopathy. ERJ Open Res 2021;7(1):00641-2020. PMID 33778049
207: Tanner SM, Laporte J, Guiraud-Chaumeil C, Liechti-Gallati S. Confirmation of prenatal diagnosis results of X-linked recessive myotubular myopathy by mutational screening, and description of three new mutations in the MTM1 gene. Hum Mutat 1998;11:62-8. PMID 9450905
208: Tanner SM, Orstavik KH, Kristiansen M, et al. Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother. Hum Genet 1999a;104(3):249-53. PMID 10323249
209: Tanner SM, Schneider V, Thomas NS, Clarke A, Lazarou L, Liechti-Gallati S. Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients. Neuromuscul Disord 1999b;9:41-9. PMID 10063835
210: Tasfaout H, Cowling BS, Laporte J. Centronuclear myopathies under attack: a plethora of therapeutic targets. J Neuromuscul Dis 2018b;5(4):387-406. PMID 30103348
211: Tasfaout H, Lionello VM, Kretz C, et al. Single intramuscular injection of aav-shrna reduces DNM2 and prevents myotubular myopathy in mice. Mol Ther 2018a;26(4):1082-92. PMID 29506908
212: Taylor GS, Maehama T, Dixon JE. Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc Natl Acad Sci USA 2000;97:8910-5. PMID 10900271
213: Terlizzi JP, Azizi R, Chow MD, et al. Peliosis hepatis in a child with myotubular myopathy: successful treatment using hepatic artery embolization. J Pediatr Surg 2013;48(8):e9-e12. PMID 23932635
214: Thomas NS, Sarfarazi M, Roberts K, et al. X-linked myotubular myopathy (MTM1): evidence for linkage to Xq28 DNA markers [abstract]. Cytogenet Cell Genet 1987;46:704.
215: Thomas NS, Williams H, Cole G, et al. X linked neonatal centronuclear/myotubular myopathy: evidence for linkage to Xq28 marker loci. J Med Genet 1990;27(5):284-7. PMID 2352256
216: Tiret L, Blot S, Kessler JL, Gaillot H, Breen M, Panthier JJ. The cnm locus, a canine homologue of human autosomal forms of centronuclear myopathy, maps to chromosome 2. Hum Genet 2003;113(4):297-306. PMID 12884002
217: Tosch V, Rohde HM, Tronchere H, et al. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum Mol Genet 2006;15(21):3098-106. PMID 17008356
218: Tosch V, Vasli N, Kretz C, et al. Novel molecular diagnostic approaches for X-linked centronuclear (myotubular) myopathy reveal intronic mutations. Neuromuscul Disord 2010;20(6):375-81. PMID 20434914
219: Toussaint A, Cowling BS, Hnia K, et al. Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies. Acta Neuropathol 2011;121(2):253-66. PMID 20927630
220: Trump N, Cullup T, Verheij JB, et al. X-linked myotubular myopathy due to a complex rearrangement involving a duplication of MTM1 exon 10. Neuromuscul Disord 2012;22:384-8. PMID 22153990
221: Tsai TC, Horinouchi H, Noguchi S, et al. Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240 kb deletion in Xq28 without male hypogenitalism. Neuromuscul Disord 2005;15(3):245-52. PMID 15725586
222: Tsujita K, Itoh T, Ijuin T, et al. Myotubularin regulates the function of the late endosome through the gram domain-phosphatidylinositol 3,5-bisphosphate interaction. J Biol Chem 2004;279(14):13817-24. PMID 14722070
223: Vandersmissen I, Biancalana V, Servais L, et al. An integrated modelling methodology for estimating the prevalence of centronuclear myopathy. Neuromuscul Disord 2018;28(9):766-77. PMID 30122513
224: Van Wijngaarden GK, Fleury P, Bethlem J, Meijer AE. Familial "myotubular" myopathy. Neurology 1969;19:901-8. PMID 5816884
225: Vasli N, Harris E, Karamchandani J, et al. Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion. Brain 2017;140(1):37-48. PMID 27816943
226: Vasli N, Laugel V, Bohm J, Lannes B, Biancalana V, Laporte J. Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype. Eur J Hum Genet 2012;20:701-4. PMID 22258523
227: Vincent MC, Guiraud-Chaumeil C, Laporte J, Manouvrier-Hanu S, Mandel JL. Extensive germinal mosaicism in X-linked myotubular myopathy simulates genetic heterogeneity. J Med Genet 1998;35:241-3. PMID 9541111
228: Volpatti JR, Ghahramani-Seno MM, Mansat M, et al. X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition. Acta Neuropathol 2022;144(3):537-63. PMID 35844027
229: Wallgren-Pettersson C. 58th ENMC Workshop: Myotubular Myopathy, 20-22 March 1998, Naarden, The Netherlands. Neuromusc Disord 1998;8:521-5. PMID 9829284
230: Wallgren-Pettersson C. 72nd International Workshop: myotubular myopathy 1-3 October 1999, Hilversum, The Netherlands. Neuromuscul Disord 2000;10:525-9. PMID 10996786
231: Wallgren-Pettersson C, Bushby K, Mellies U, Simonds A. 117th ENMC workshop: Ventilatory Support in Congenital Neuromuscular Disorders: Congenital Myopathies, Congenital Muscular Dystrophies, Congenital Myotonic Dystrophy and SMA (II). April 4-6th 2003, Naarden, the Netherlands. Neuromuscul Disord 2004;14:56-69. PMID 14659414
232: Wallgren-Pettersson C, Clarke A, Samson F, et al. The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. J Med Genet 1995;32(9):673-9. PMID 8544184
233: Wallgren-Pettersson C, Thomas NS. Report on the 20th ENMC sponsored international workshop: myotubular/centronuclear myopathy. Neuromuscul Disord 1994;4:71-4. PMID 8173354
234: Wang CH, Dowling JJ, North K, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol 2012;27(3):363-82. PMID 22431881
235: Wang H, Castiglioni C, Kaçar Bayram A, et al. Insights from genotype-phenotype correlations by novel SPEG mutations causing centronuclear myopathy. Neuromuscul Disord 2017;27(9):836-42. PMID 28624463
236: Wang H, Schänzer A, Kampschulte B, et ak. A novel SPEG mutation causes non-compaction cardiomyopathy and neuropathy in a floppy infant with centronuclear myopathy. Acta Neuropathol Commun 2018;6(1):83. PMID 30157964
237: Werlauff U, Petri H, Witting N, Vissing J. Frequency and phenotype of myotubular myopathy amongst Danish patients with congenital myopathy older than 5 years. J Neuromuscul Dis 2015;2(2):167-74. PMID 27858727
238: Wilmshurst JM, Lillis S, Zhou H, et al. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol 2010;68(5):717-26. PMID 20839240
239: Yabe T, Itonaga T, Kuga S, et al. An autopsy case of recurrent pneumothorax and peliosis-like intrapulmonary hematoma with X-linked myotubular myopathy. Bran Dev 2022;44(3):234-8. PMID 34830057
240: Yu S, Manson J, White S, et al. X-linked myotubular myopathy in a family with three adult survivors. Clin Genet 2003;64(2):148-52. PMID 12859411
241: Zanoteli E, Oliveira A, Gabbai AA, et al. Deletion of both MTM1 and MTMR1 genes in a boy with myotubular myopathy. Am J Med Genet 2005;134A:338-40. PMID 15690409
242: Zhao Y, Zhao Z, Shen H, Bing Q, Hu J. Characterization and genetic diagnosis of centronuclear myopathies in seven Chinese patients. Neurol Sci 2018;39(12):2043-51. PMID 30232666

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Haluk Topaloglu MD

Dr. Topaloglu of Hacettepe Children's Hospital in Ankara, Turkey, has no relevant financial relationships to disclose.
See Profile
Gulcin Akinci MD

Dr. Akinci of Izmir Faculty of Medicine and Dr. Behcet Uz Children's Hospital has no relevant financial relationships to disclose.
See Profile

Editor

Harvey B Sarnat MD FRCPC MS

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.
See Profile

Former Authors

Carina Wallgren-Pettersson MD

Patient Profile

Age range of presentation: 0-01 month
Sex preponderance: male>female, >2:1
Heredity: heredity typical

X-linked
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Centronuclear myopathy: 359.0
ICD-10: Centronuclear myopathy: G71.2
OMIM: Myotubular myopathy 1: #310400

Centronuclear myopathy, autosomal dominant: #160150

Centronuclear myopathy, autosomal recessive: #255200

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

X-linked myotubular myopathy

Differential Diagnosis

myotonic dystrophy
congenital myopathies
congenital muscular dystrophy
severe childhood spinal muscular atrophy
anterior horn cell disorders
- myasthenia
- motor neuropathies
- Prader-Willi syndrome
- autosomal centronuclear (myotubular) myopathy

Also Relevant

Congenital muscle fiber-type disproportion
Congenital muscular dystrophies
Core myopathies
Desmin body myofibrillar myopathy
Nemaline myopathy
- Neuromuscular pathology: overview

X-linked myotubular myopathy

X-linked myotubular myopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Distal myopathies

Epileptic lesions due to malformation of cortical development

Amyotrophic lateral sclerosis

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

ALS-like disorders of the Western Pacific

Norrie disease

X-linked myotubular myopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Distal myopathies

Epileptic lesions due to malformation of cortical development

Amyotrophic lateral sclerosis

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

ALS-like disorders of the Western Pacific

Norrie disease

This is an article preview.
Start a Free Account
to access the full version.