Disorders of lipid metabolism
Apr. 08, 2022
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X-linked myotubular (centronuclear) myopathy is a severe muscle disorder mainly affecting newborn boys, but sometimes it can also affect girls and adults. Diagnostic methods have improved so that the majority of patients and carriers may now have their diagnosis verified by molecular methods. Currently, the complex pathogenetic mechanisms are better understood and include defects in membrane tubulation and excitation-contraction coupling, providing evidence towards a common basis for the X-linked and autosomal forms of centronuclear myopathy. Several studies of potential therapeutic modalities aimed at ameliorating disease severity have reached proof of concept, natural history studies have been completed, canine and other animal models have been established and experimental trials carried out, outcome measures have been defined, and therapeutic trials are being planned in terms of a variety of potentially disease-modifying interventions. The first in-human gene transfer study was afflicted by a major drawback.
• X-linked myotubular (centronuclear) myopathy is caused by mutations in the myotubularin gene MTM1.
• Molecular genetic verification is often possible through sequencing, but it should be noted that copy number variations may also be causative, as may intronic alterations, and this may require other analytic methods.
• Female carriers may present with overt disease.
• Although no curative treatment exists to date for this usually very severe disorder, active treatment is indicated, at least initially, because of the favorable course in some neonatally severe cases.
• Prognosis cannot be based solely on the nature of the mutation, and decisions about treatment have to be taken on an individual basis.
• Differential diagnoses include the autosomal forms of centronuclear myopathy and myotonic dystrophy.
• Most, but not all, mothers of affected boys are mutation carriers; mosaicism has been reported.
X-linked myotubular or centronuclear myopathy is assigned to the group of congenital myopathies (OMIM #310400) (66). These myopathies were defined after the advent of histochemical staining methods of muscle biopsy sections on the basis of structural abnormalities in the muscle fibers. The X-linked form of myotubular myopathy was first described in a large Dutch pedigree in which the affected males showed muscle fibers resembling fetal myotubes (212). A long-term follow-up study of this and another Dutch family shows wide variability in the clinical picture (14), confirmed by reports of patients diagnosed as adults (103; 160).
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.
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 (218; 107), in dogs also (189), but exceptionally severe cases similar to the X-linked form have also been reported (114; 27). Mutations in the dynamin 2 gene (30) are a common cause of the dominantly inherited form (73; 29; 69; 181), whereas mutations in the ryanodine receptor gene RYR1 have also been identified, including recessively inherited mutations (115; 224; 24; 114).
The first causative gene for autosomal recessive myotubular/centronuclear myopathy was identified as amphiphysin 2 (BIN1) (153). Subsequently, a patient with internalized nuclei, the histopathology resembling centronuclear myopathy, was found to have compound heterozygous mutations in the titin gene TTN (42; 63). A further differential diagnosis may be myopathy caused by SPEG mutations, often accompanied by cardiomyopathy (01; 221; 222).
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 (95; 216; 194; 110; 122; 180; 89; 160; 25; 97; 114; 71; 179; 28; 80; 229; 48; 120). A female patient described with cardiomyopathy requiring heart transplantation had not undergone analysis of the myotubularin gene.
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 ventilatory insufficiency (15). 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 and large heads. Tendon reflexes are mostly absent. There may be contractures of the hips or knees. Some boys have cryptorchidism.
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 (101). 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 (21). An exceptional patient showed progressive dementia (146), 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 (167).
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 (219). Clinical reviews are available (218; 112; 134), and McEntagart and colleagues addressed genotype-phenotype correlations (147). Clinical papers describe Danish, German, and Dutch series (223; 79; 166).
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 (99; 119; 137; 152; 149; 226). Among these, hepatic peliosis and other hepatobiliary diseases have been repeatedly reported (93; 150; 78; 54; 149). In one case, peliosis was successfully treated using hepatic artery embolization (202) and in another by liver transplantation (158). There are, however, a number of reports of patients in whom no long-term complications have been noted (223; 06; 09).
Many female cases have been described, with or without evidence of skewed X inactivation (218; 197; 95; 216; 194; 110; 122; 180; 89; 71; 179) and may be late (160; 97). 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 (28; 229; 48). Quite often, the manifestations are milder than in affected males carrying the same mutation (28; 165). Killer cell immunoglobulin-like receptor variants were suggested as possible genetic modifiers of manifestation in female carriers (191). Cocanougher and coworkers developed a clinical classification for manifesting female carriers (48).
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 (147). Rare patients have shown mild disease since the neonatal period (26; 43; 227), and some patients have been diagnosed only as adults (103). Care is to be taken in prognosticating based on the mutation alone (51).
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) (99; 137; 119; 149; 226), but a number of adult patients have been described not showing any of these (14; 26; 227). A mouse model with a lifespan of more than 50 weeks also does not show extra-muscular manifestations (161).
The cause of death is usually respiratory failure, sometimes in combination with pneumonia or cardiac failure.
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. This disorder follows X-linked inheritance, with mutations found in the MTM1 gene encoding a lipid phosphatase, myotubularin (129; 58; 128; 62; 154; 196; 37; 59; 125). 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 (30) and was followed by three more (115; 153; 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; 64; 113; 207; 07; 132; 08; 72; 109; 83; 12; 85).
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 (140; 167). Some of these patients showed a response to treatment with acetylcholinesterase.
Pathology. Histologic criteria for myotubular myopathy include the presence of numerous small muscle fibers, many of which contain rows of regularly spaced central nuclei resembling normal fetal myotubes (113). A study addressed the relationship between nuclear mislocalization and fiber contractility in X-linked myotubular myopathy (171). Type 1 fiber predominance is common, and type 1 fiber hypotrophy is observed in some, but not all, cases (105; 113). 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 (126; 131; 169; 206). A study described cellular, biochemical, and molecular changes as likely consequences of epigenetic modifications in muscles from patients with X-linked myotubular myopathy (12).
Genetics. The gene for X-linked myotubular myopathy was assigned in 1987 to the proximal Xq28 region (203; 56; 138; 192; 204; 139; 106). The determination of the breakpoints of a deletion in a female patient with X-linked myotubular myopathy (53) 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 (104). These two male patients were later found to have unusually large deletions, including an alternatively spliced gene in proximal Xq28 (130). Bartsch and colleagues published a description of a familial deletion associated with male hypogenitalism (13). A further patient with a well-characterized deletion in this region had hypospadias and scrotal hypoplasia (179). In contrast, another patient described with a big deletion had normal genitalia (209).
This led to the characterization of a gene in this region (MTM1) showing mutations in affected males (129; 58; 128; 62; 154; 196; 37; 59; 198; 125; 25; 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 (198; 125; 100; 144; 209). The complete genomic structure of the human myotubularin gene has been determined (127), 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 (128; 125; 100; 22; 25; 114; 142; 179). It has also become evident that many female carriers manifest symptoms (165) and may present as index patients (122; 28; 229).
Grandpaternal inheritance of X-linked myotubular myopathy from a mosaic maternal grandfather has been described (98).
Genotype-phenotype correlations. The majority of the mutations are clustered in 5 of the 15 exons (100; 26; 22; 25; 114). Eight mutations are found in approximately one fourth of the families, but private mutations account for a major part of the more than 500 known mutations hitherto (http://databases.lovd.nl/shared/genes/MTM1). In addition to small mutations, further reports present large deletions and duplications (25; 208; 05; 157; 179; 120; 84). Most point mutations are truncating, but approximately 30% are missense mutations that affect conserved residues (125; 22). 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 (125; 100; 147; 51; 193). 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 (71). In a few families, manifestations have been mild from the outset, and a 67-year-old grandfather was still mildly affected (14; 26; 227). An exceptional patient with progressive dementia had a mutation removing the start signal of exon 2 (146). In two studies, eighty-five percent of mothers were carriers, and approximately 5% of index cases were female (25; 114). The latter figure is, however, likely to be an underestimate because females with this X-linked disorder presenting as index cases may go undiagnosed (28; 229).
Pathogenesis. There are homologous genes in many species, including dogs, mice, Drosophila, zebrafish, and yeast, as well as many human homologs (129; 117; 125; 10). Mutations in two of these have been found to cause separate neuromuscular disorders, ie, Charcot-Marie-Tooth disease type 4B1 (32; 19) and type 4B2 (11; 182). Gomez-Oca and colleagues provide a review on the subject (85). 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 (228). 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 (20; 116; 151; 47; 18).
Myotubularin is thought to be involved in intracellular pathways necessary for myogenesis. Disease-causing mutations have been identified in all four active sites: GRAM, RID, PTP/DSP, and SID (100; 26; 22). 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 (128; 52; 127; 31; 201; 126; 131; 210; Robinson and Dixon 2006; 41; 85). Gene expression analysis suggests that remodeling of the cytoskeletal and extracellular architecture may contribute to atrophy and disorganization of organelles in affected myofibers (155; 08).
A defect in muscle fiber maturation has been suggested as a pathogenetic mechanism in X-linked myotubular myopathy (186). However, studies have demonstrated the presence in muscle fibers of mature isoforms of myofibrillar proteins (183). A transgenic knockout mouse model confirmed these findings (39). 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 (94).
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 (64). 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 (207; 172), 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 (64; 85; 134). 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 (124). Studies in human muscle suggest epigenetic modifications (12).
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 (102). 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 (164). Apoptosis is also impaired (132).
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 (109).
Currently, Drosophila and zebrafish models provide further prospects for pathogenetic studies aiming toward identifying future therapeutic possibilities (113; 64; 91).
Myostatin has been proposed as a circulating biomarker in an Mtm1 mouse model (118). 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 (135). The mice showed selective hypertrophy of type 2B fibers. A method for studying sarcomere structure and function in vivo in mice has been developed (148), and the proteomics of different mouse models have been studied (61).
Buj-Bello and coworkers reported successful viral transfer of myotubularin to selected murine muscles (38). 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 (161; 136; 141). Childers and colleagues described successful systemic AAV myotubularin gene delivery in both mice and dogs (46; 70). Further articles report improvement in MTM1-deficient mice by downregulation of dynamin 2 expression (50; 200; 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 (81; 143). AAV delivery of the mtm1 homolog mtmr2 also appears to have an ameliorating effect in mice (162; 55).
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 (205; 159; 113; 16; 88; 46; 82; 178; 83; 185; 190; 156). 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 (70; 68). AAV gene transfer appeared to correct fiber properties in these dogs (171).
In preparation for clinical trials, now ongoing, natural history studies have been reported (06; 17; 09; 87; 79). 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). A paper suggested using a Bayesian statistical model for comparing each patient’s possible treatment response with the progression expected from their own natural history data (77). Outcome measures have been defined (67).
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 (176; 177; 186), but this is not a consistent feature. These intermediate filament cytoskeletal proteins attach to the membranes of the sarcolemma, nuclei, and mitochondria.
No reliable incidence figures are available. The disorder is rare; mutations have been reported in hundreds of patients from different parts of the world (215; 125; 100; 26; 22; 209; 25; 114). Many infants with this disorder may, however, have died undiagnosed whereas unusually mild cases may remain unidentified. A theoretical model has been described for estimating the prevalence (211).
Primary prevention is not currently feasible. Determination of carrier status and prenatal diagnosis is possible through mutation analysis (129; 128; 196; 197; 216; 22; 142). The frequency of new mutations appears to be rather low, and most mothers of affected boys are carriers of a mutated gene (128; 100; 22). A previous suggestion of genetic linkage heterogeneity for the X-chromosomal form of myotubular myopathy (175) was later invalidated (90). Mosaicism has been documented (214; 96) and needs to be taken into account in genetic counseling and prenatal diagnosis, but it remains to be determined how commonly it occurs (125).
Clinical manifestations are seen in a proportion of female carriers (218; 197; 95; 216; 194; 110; 122; 180; 89; 97; 71; 179; 28; 48; 165) and may be late (160). Muscle biopsy studies were previously used in carrier diagnosis (176; 33) but the carrier status of female relatives is best determined using direct mutation detection (129; 128; 196; 197; 142).
For surviving patients, a risk factor to keep in mind is any insidious respiratory difficulty (217; 188; 195). In some cases, this necessitates the use of a mechanical ventilator for intermittent or prolonged use (147). Other organs may become involved (99), and hepatic peliosis may ensue (93; 150). Treatment of peliosis has been done through arterial embolization (202) or liver transplantation (158). A follow-up study confirms that hepatobiliary involvement is common and unrelated to the severity of the muscle disorder (54).
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 (197; 95; 216; 194; 110; 122; 180; 89; 160; 114; 179; 165). In a family, female carriers manifested spastic paraplegia (121). 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 (184) than molecular genetic studies (35).
Profoundly affected boys with clinical features indistinguishable from those of X-linked myotubular myopathy have been diagnosed with RYR1-caused centronuclear myopathy (114).
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 (218; 107). Four genes for autosomal forms have been characterized (30; 115; 153; 42), and muscle biopsy findings may provide clues for directing mutation detection (23; 113; 170). One workshop report provides a diagnostic algorithm for distinguishing between the various forms of centronuclear myopathy (113).
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 (23; 92).
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 (129; 128; 196; 198; 216; 76; 100; 22; 71; 108), some cases requiring analyses of copy number variation (208; 25; 05; 157; 179; 120; 84). In a further subset of patients, RNA- or protein-based methods may be needed (169; 206; 213; 145; 02; 74; 36). In the absence of such confirmation, the autosomal forms should be considered (23; 113; 170; 114).
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 (129; 128; 196; 216; 22). It is to be noted that female carriers may show clinical symptoms, easily mistaken for manifestations of autosomal forms of the disorder (197; 95; 216; 194; 110; 122; 180; 97; 71; 179; 165). Carrier females with unilateral weakness have been described (65), and in one family, female patients had a clinical picture of hereditary spastic paraplegia (121). 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 (57).
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 (111; 195). No reliable prognostic indicators have been established (147), 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 (195).
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 (217; 220; 188; 195). 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).
The families should be provided 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. Gomez-Oca and colleagues and Lawlor and Dowling provide reviews on the subject (85; 134). This brightens the outlook for future therapeutic trials, and preparations are in progress, covering many aspects of the disorder (38; 167; 03; 72; 133; 46; 50; 60; 82; 123; 173; 70; 163; 81; 143; 55; 199; 171; 61; 67; 166). The first-in-human AAV therapy of the myotubularin gene, however, was seriously set back by the deaths of two participating patients (187; 225). The economic disease burden of X-linked myotubular myopathy has been studied in the United States (174), but the results may not be applicable to other countries as both health economy and treatment policies vary between countries (147).
Pregnancies in which the fetus has X-linked myotubular myopathy are often complicated by polyhydramnios, and premature births are common. Continued pregnancies require careful follow-up. Planning for the delivery should be a collaborative effort between the pregnant woman, her obstetrician, and the anesthetist, and a pediatrician should be on call at delivery.
Although malignant hyperthermia is not recognized as a specific risk factor in the anesthesia of patients with X-linked myotubular myopathy, the anesthesiologist needs to be informed of the patient's diagnosis (86; 34; 49). Muscle relaxants are probably best avoided, and benzodiazepines should be used with caution because of their potentially adverse effects on breathing and muscle power. Careful evaluation of respiratory capacity should be performed before administering anesthesia (217; 220; 188). In especially severe cases, positioning during anesthesia may require special attention (75).
Carina Wallgren-Pettersson MD
Dr. Wallgren-Pettersson of the University of Helsinki and Folkhalsan has no relevant financial relationships to disclose.See Profile
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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