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| {{Infobox medical condition (new) | | {{Short description|A group of rare congenital myopathies}} |
| | name = Centronuclear myopathy | | {{Medical resources}} |
| | image = Centronuclear myotubular myopathy.JPEG
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| | caption = Muscle biopsy from the quadriceps taken at 3 months of age from a girl with X-linked centronuclear ("myotubular") myopathy due to a mutation in the myotubularin (MTM1) gene and extremely skewed X-inactivation ([[H&E stain]], transverse section). Note marked variability in fibre size, moderate increase in connective tissue and numerous central nuclei.
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| '''Centronuclear myopathies''' (CNM) are a group of [[congenital]] [[myopathies]] where cell nuclei are abnormally located in the center of skeletal muscle cells instead of their normal location at the periphery.
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| Symptoms of CNM include severe [[hypotonia]], [[Hypoxia (medical)|hypoxia]]-requiring breathing assistance, and [[scaphocephaly]]. Among centronuclear myopathies, the [[X-linked]] myotubular myopathy form typically presents at birth, and is thus considered a [[congenital]] myopathy. However, some centronuclear myopathies may present later in life.
| | '''Centronuclear myopathy''' (CNM) is a group of rare [[congenital myopathies]] characterized by muscle weakness and distinctive histological features, notably the presence of centrally located nuclei in muscle fibers. These myopathies are genetically heterogeneous and can be inherited in an [[autosomal dominant]], [[autosomal recessive]], or [[X-linked]] manner. |
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| == Presentation == | | ==Classification== |
| As with other [[myopathies]], the clinical manifestations of MTM/CNM are most notably muscle weakness and associated disabilities. Congenital forms often present with neonatal low [[muscle tone]], severe weakness, delayed developmental milestones (particularly gross [[Developmental milestones|motor milestones]] such as head control, crawling, and walking) and [[pulmonary]] complications (presumably due to weakness of the muscles responsible for respiration). While some patients with centronuclear myopathies remain [[ambulatory]] throughout their adult life, others may never crawl or walk and may require wheelchair use for mobility. There is substantial variability in the degree of functional impairment among the various centronuclear myopathies. Although this condition only affects the voluntary muscles, several children have suffered from cardiac arrest, possibly due to the additional stress placed on the heart.
| | Centronuclear myopathy is classified based on the mode of inheritance and the specific genetic mutations involved. The main types include: |
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| Other observed features have been high arched palate, long digits, bell shaped chest and long face.
| | * '''X-linked centronuclear myopathy''': Caused by mutations in the [[MTM1]] gene, this form is also known as [[myotubular myopathy]]. It primarily affects males and is the most severe form, often presenting in infancy. |
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| Myotubular myopathy only affects muscles and does not impact intelligence in any shape or form.
| | * '''Autosomal dominant centronuclear myopathy''': Often associated with mutations in the [[DNM2]] gene, this form can present at any age and varies in severity. |
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| [[X-linked]] myotubular myopathy was traditionally a fatal condition of infancy, with life expectancy of usually less than two years. There appears to be substantial variability in the clinical severity for different genetic abnormalities at that same MTM1 gene. Further, published cases show significant differences in clinical severity among relatives with the same genetic abnormality at the MTM1 gene. Most [[Genetic deletion|truncating mutation]]s of MTM1 cause a severe and early lethal [[phenotype]], while some [[missense mutation]]s are associated with milder forms and prolonged survival (up to 54 years).<ref>{{cite journal |vauthors=Laporte J, Biancalana V, Tanner S, Kress W, Schneider V, Wallgren-Pettersson C, Herger F, Buj-Bello A, Blondeau F, Liechti-Gallati S, Mandel J |title=MTM1 mutations in X-linked myotubular myopathy |journal=Hum Mutat |volume=15 |issue=5 |pages=393–409 |year=2000 |pmid=10790201 |doi=10.1002/(SICI)1098-1004(200005)15:5<393::AID-HUMU1>3.0.CO;2-R}}</ref>
| | * '''Autosomal recessive centronuclear myopathy''': This form can be caused by mutations in several genes, including [[BIN1]], [[RYR1]], and [[TTN]]. It typically presents in childhood or adolescence. |
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| Centronuclear myopathies typically have a milder presentation and a better prognosis. Recently, researchers discovered [[mutations]] at the gene [[dynamin]] 2 (DNM2 on [[chromosome 19]], at site 19p13.2), responsible for the [[autosomal dominant]] form of centronuclear myopathy.<ref>{{cite journal |vauthors=Bitoun M, Maugenre S, Jeannet P, Lacène E, Ferrer X, Laforêt P, Martin J, Laporte J, Lochmüller H, Beggs A, Fardeau M, Eymard B, Romero N, Guicheney P |title=Mutations in dynamin 2 cause dominant centronuclear myopathy |journal=Nat Genet |volume=37 |issue=11 |pages=1207–1209 |year=2005 |pmid=16227997 |doi=10.1038/ng1657}}</ref> This condition is now known as dynamin 2 centronuclear myopathy (abbreviated DNM2-CNM). Research has indicated that patients with DNM2-CNM have a slowly progressive muscular weakness usually beginning in [[adolescence]] or early adulthood, with an age range of 12 to 74 years.
| | ==Pathophysiology== |
| | The hallmark of centronuclear myopathy is the abnormal positioning of nuclei in the center of muscle fibers, rather than at the periphery. This is thought to result from defects in muscle cell development and maintenance. The specific pathophysiological mechanisms vary depending on the genetic mutation involved. For example, mutations in the MTM1 gene affect the protein myotubularin, which is involved in [[phosphoinositide metabolism]], while DNM2 mutations affect dynamin 2, a protein involved in [[endocytosis]] and membrane trafficking. |
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| == Genetic== | | ==Clinical Features== |
| The genetic abnormality associated with the [[X-linked]] form of myotubular myopathy (XLMTM) was first localized in 1990 to the [[X chromosome]] at site Xq28.<ref>{{cite journal |vauthors=Lehesjoki A, Sankila E, Miao J, Somer M, Salonen R, Rapola J, de la Chapelle A |title=X linked neonatal myotubular myopathy: one recombination detected with four polymorphic DNA markers from Xq28 |journal=J Med Genet |volume=27 |issue=5 |pages=288–91 |year=1990 |pmid=1972196 |doi=10.1136/jmg.27.5.288 |pmc=1017077}}</ref> MTM1 codes for the [[myotubularin]] protein, a highly conserved lipid [[phosphatase]] involved in cellular transport, trafficking and signalling. Approximately 80% of males with myotubular myopathy diagnosed by muscle biopsy have mutations in MTM1, and about 7% of these mutations are [[genetic deletion]]s.<ref name=Chicago/> | | The clinical presentation of centronuclear myopathy can vary widely depending on the type and severity of the condition. Common features include: |
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| Centronuclear myopathies where the genetic abnormality is NOT sex-linked (e.g., not located on the X chromosome) are considered autosomal. Autosomal abnormalities can either be dominant or recessive, and are often referred to as AD for "[[autosomal dominant]]" or AR for "[[autosomal recessive]]").
| | * Muscle weakness, particularly in the [[proximal muscles]] |
| | | * Hypotonia (reduced muscle tone) |
| Many researchers use the term "myotubular myopathy" (MTM) only for cases when the genetic test has come back positive for abnormalities ([[genetic mutations]]) at the MTM1 gene on the X chromosome. Cases with a centronuclear (nucleus in the center) appearance on muscle biopsy but a normal genetic test for MTM1 would be referred to as centronuclear myopathy until such time as a specific genetic site is identified to give a more detailed sub-classification.
| | * Delayed motor milestones |
| | | * Respiratory difficulties, especially in severe cases |
| The possible combinations of inheritance of myotubular myopathy are as follows:
| | * Facial muscle weakness, leading to a characteristic facial appearance |
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| {| class="wikitable"
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| ! Inheritance
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| ! [[OMIM]]
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| ! Gene(s)
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| ! Description
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| | X-linked recessive
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| | {{OMIM2|310400}}
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| | [[MTM1]] ([[X-linked myotubular myopathy]])
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| | The X-linked form of MTM/CNM is the most commonly diagnosed type. Almost all cases of X-linked MTM occurs in males.
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| | Autosomal recessive
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| | {{OMIM2|255200}}
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| | [[BIN1]], [[RYR1]], [[TTN (gene)|TTN]]
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| | A "recessive" abnormality will only cause disease if both copies of the gene are abnormal.
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| | Autosomal dominant
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| | {{OMIM2|160150}}
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| | [[DNM2]] ([[MYF6]] and [[MTMR14]] less common)
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| | A "dominant" abnormality will exert its abnormal influence (e.g., causing a disease or medical condition) regardless of whether the other copy of the gene is normal or not. Within centronuclear myopathies, researchers have identified an autosomal dominant form at a gene called [[dynamin]] 2 (DNM2) on [[chromosome 19]], and this particular condition is now referred to as [[dynamin 2 centronuclear myopathy]] (DNM2-CNM).
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| Sporadic cases have also been reported where there is no previous family history (these cases are presumably due to a new mutation that was not present in either parent).
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| == Pathology ==
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| On examination of muscle [[biopsy]] material, the nuclear material is located predominantly in the center of the muscle cells, and is described as having any "myotubular" or "centronuclear" appearance. In terms of describing the muscle biopsy itself, "myotubular" or "centronuclear” are almost synonymous, and both terms point to the similar cellular-appearance among MTM and CNM. Thus, [[pathologist]]s and treating [[physician]]s use those terms almost interchangeably, although [[researcher]]s and [[clinician]]s are increasingly distinguishing between those phrases.
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| In general, a clinical myopathy and a muscle biopsy showing a centronuclear (nucleus in the center of the muscle cell) appearance would indicate a centronuclear myopathy (CNM). The most commonly diagnosed CNM is myotubular myopathy (MTM). However, muscle biopsy analysis alone cannot reliably distinguish myotubular myopathy from other forms of centronuclear myopathies, and thus [[genetic testing]] is required.
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| Diagnostic workup is often coordinated by a treating [[neurologist]]. In the United States, care is often coordinated through clinics affiliated with the [[Muscular Dystrophy Association]].
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| ==Diagnosis== | | ==Diagnosis== |
| === Electrodiagnostic testing ===
| | Diagnosis of centronuclear myopathy typically involves a combination of clinical evaluation, [[muscle biopsy]], and genetic testing. Muscle biopsy reveals the characteristic central nuclei in muscle fibers. Genetic testing can identify specific mutations responsible for the condition. |
| [[Electrodiagnostic]] testing (also called electrophysiologic) includes [[nerve conduction studies]] which involves stimulating a peripheral [[motor nerve|motor]] or [[sensory nerve]] and recording the response, and needle [[electromyography]], where a thin needle or pin-like [[electrode]] is inserted into the muscle tissue to look for abnormal electrical activity.
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| Electrodiagnostic testing can help distinguish myopathies from neuropathies, which can help determine the course of further work-up. Most of the electrodiagnostic abnormalities seen in myopathies are also seen in [[neuropathies]] (nerve disorders). Electrodiagnostic abnormalities common to myopathies and neuropathies include; abnormal spontaneous activity (e.g., fibrillations, positive sharp waves, etc.) on needle EMG and, small amplitudes of the motor responses compound muscle action potential, or CMAP during nerve conduction studies. Many neuropathies, however, cause abnormalities of sensory nerve studies, whereas myopathies involve only the muscle, with normal sensory nerves. The most important factor distinguishing a myopathy from a neuropathy on needle EMG is the careful analysis of the motor unit [[action potential]] (MUAP) size, shape, and recruitment pattern.
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| There is substantial overlap between the electrodiagnostic findings the various types of myopathy. Thus, electrodiagnostic testing can help distinguish neuropathy from myopathy, but is not effective at distinguishing which specific myopathy is present, here [[muscle biopsy]] and perhaps subsequent [[genetic testing]] are required.
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| == Treatment ==
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| Currently there is no cure for myotubular or centronuclear myopathies. Treatment often focuses on trying to maximize functional abilities and minimize medical complications, and involvement by physicians specializing in Physical Medicine and Rehabilitation, and by [[physical therapist]]s and occupational therapists.
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| Medical management generally involves efforts to prevent [[pulmonary]] complications, since lung [[infection]]s can be fatal in patients lacking the muscle strength necessary to clear secretions via coughing. Medical devices to assist with coughing help patients maintain clear airways, avoiding [[mucus|mucous]] plugs and avoiding the need for [[tracheostomy]] tubes.
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| Monitoring for [[scoliosis]] is also important, since weakness of the trunk muscles can lead to deviations in spinal alignment, with resultant compromise of respiratory function. Many patients with congenital myopathies may eventually require surgical treatment of scoliosis.
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| == Epidemiology ==
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| The overall incidence of myotubular myopathy is 1 in 50,000 male live births.<ref name=Chicago>[http://genes.uchicago.edu/LabPDF/01MTM1.pdf MTM1 analysis for Myotubular Myopathy] {{webarchive |url=https://web.archive.org/web/20060904215538/http://genes.uchicago.edu/LabPDF/01MTM1.pdf |date=September 4, 2006 }} The University of Chicago Genetic Services.</ref> The incidence of other centronuclear myopathies is extremely rare, with there only being nineteen families identified with CNM throughout the world. The symptoms currently range from the majority who only need to walk with aids, from a stick to a walking frame, to total dependence on physical mobility aids such as wheelchairs and stand aids, but this latter variety is so rare that only two cases are known to the CNM "community".
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| Approximately 80% of males with a diagnosis of myotubular myopathy by [[muscle biopsy]] will have a mutation in MTM1 identifiable by genetic sequence analysis.<ref name= Chicago/>
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| Many patients with myotubular myopathy die in [[infancy]] prior to receiving a formal [[diagnosis]]. When possible, muscle biopsy and genetic testing may still be helpful even after a neonatal death, since the diagnostic information can assist with [[family planning]] and [[genetic counseling]] as well as aiding in the accurate diagnosis of any relatives who might also have the same genetic abnormality.
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| == History ==
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| In 1966, Dr. Spiro (a New York City neurologist) published a medical report of a boy with [[myopathy]], which upon [[muscle biopsy]], showed that the nuclei of the muscle cells were located in the center of the muscle cells, instead of their normal location of the periphery.<ref>{{cite journal |vauthors=Spiro A, Shy G, Gonatas N |title=Myotubular myopathy. Persistence of fetal muscle in an adolescent boy |journal=Arch Neurol |volume=14 |issue=1 |pages=1–14 |year=1966 |pmid=4954227 |doi=10.1001/archneur.1966.00470070005001}}</ref>
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| The nuclear appearance reminded him of the nucleus-in-the-center appearance during the “myotubular” stage of [[embryo]]nic development. Thus, he coined the term "myotubular myopathy". Spiro speculated that the embryonic muscle development he had seen in the boy was due to growth arrest during the myotubular phase, causing the myopathy.
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| More than three decades later, it is not fully understood whether this theory regarding halted (or delayed) embryonic muscle development is correct. Some research suggests that this theory may be acceptable for infant-onset myotubular myopathy (mutations at the MTM1 gene on the [[X chromosome]]) but may not be acceptable for the [[autosomal]] forms of centronuclear myopathy,<ref>[https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=160150 Myotubular Myopathy, Autosomal Dominant] Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD.</ref> while other research suggests that the growth arrest mechanism may be responsible for all forms of MTM and CNM.<ref>{{cite journal |vauthors=Manta P, Mamali I, Zambelis T, Aquaviva T, Kararizou E, Kalfakis N |title=Immunocytochemical study of cytoskeletal proteins in centronuclear myopathies |journal=Acta Histochem |volume=108 |issue=4 |pages=271–6 |year=2006 |pmid=16893562 |doi=10.1016/j.acthis.2006.05.004}}</ref>
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| Regardless of whether the myopathy is caused by arrest at the "myotubular" stage, for historical reasons the name myotubular myopathy persists and is widely accepted.<ref>{{cite journal |vauthors=Pierson C, Tomczak K, Agrawal P, Moghadaszadeh B, Beggs A |title=X-linked myotubular and centronuclear myopathies |journal=J Neuropathol Exp Neurol |volume=64 |issue=7 |pages=555–64 |year=2005 |pmid=16042307 |doi=10.1097/01.jnen.0000171653.17213.2e|doi-access=free }}</ref>
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| As a reference to the term myotubular myopathy (MTM), when a [[Genetics|genetic]] abnormality on the X chromosome was determined to be involved in a substantial percentage of individuals with the myotubular/centronuclear appearance on [[muscle biopsy]], researchers named the gene segment MTM1. Similarly, the protein typically produced by that gene is called "[[myotubularin]]".
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| === Advocacy ===
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| There are several global advocacy groups working closely to educate newly affected families on care guidelines. The [http://joshuafrase.org/ Joshua Frase Foundation] is a comprehensive resource for care guidelines for Centronuclear myopathies. In the [[United States]], children with congenital myopathies often receive therapy services through Early Intervention Programs (EIP, providing services from birth to 3 years old) administered by the state of residence. After the child is 3 years old, [[Special Education]] services are provided under the federal [[Individuals with Disabilities Education Act]] (IDEA, with myopathies being eligible when classified under conditions causing muscular weakness). IDEA is meant to protect the rights of every disabled student to receive a [[free and appropriate public education]] (FAPE) in the [[least restrictive environment]] (ideally meaning integrated with able-bodied classmates).
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| Centronuclear myopathies involve pathology at the skeletal muscles, generally without brain involvement or cognitive deficits. Even so, the motor deficits (weakness and associated impairments) may impede in individual’s ability to access the [[education]]al [[curriculum]] (e.g., difficulties lifting or carrying books, difficulties grasping a writing instrument, endurance difficulties throughout the school day, etc.). Further, recurrent respiratory infections may result in missed school days.
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| ==Terminology==
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| Although all forms of centronuclear myopathy are considered rare, the most commonly known form of CNM is Myotubular Myopathy (MTM). (The terms "centronuclear myopathy" and "myotubular myopathy" are sometimes equated.)<ref>{{DorlandsDict|five/000069759|centronuclear myopathy}}</ref>
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| Literally, a myopathy is a [[disease]] of the muscle tissue itself. ''Myo'' derives from the word muscle and ''pathos'' means disease. There are dozens of different myopathies, and myopathies are not the only conditions that can cause muscle weakness. Other diseases can cause weakness such as medical conditions affecting sites outside of the muscle itself, including problems in the brain (such as [[stroke]], [[cerebral palsy]], [[multiple sclerosis]]), or problems in the spinal cord and/or nerve (such as [[polio]] and [[spinal muscular atrophy]]).
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| == References ==
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| {{Reflist}}
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| == External links ==
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| {{Medical resources
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| | DiseasesDB = 31983
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| | ICD10 = {{ICD10|G|71|2|g|70}}
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| | ICD9 = {{ICD9|359.0}}
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| | ICDO =
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| | OMIM = 160150
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| | OMIM_mult = {{OMIM2|310400}} {{OMIM2|255200}}
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| | MedlinePlus =
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| | eMedicineSubj = neuro
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| | eMedicineTopic = 76
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| | MeshID = D020914
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| | GeneReviewsNBK = NBK1432
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| | GeneReviewsName = X-Linked Centronuclear Myopathy
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| | SNOMED CT = 82077006
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| | Orphanet = 595
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| }}
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| * [https://www.ncbi.nlm.nih.gov/books/NBK1432/ GeneReviews/NCBI/NIH/UW entry on X-Linked Myotubular Myopathy or Centronuclear Myopathy]
| | ==Management== |
| | There is currently no cure for centronuclear myopathy, and management focuses on supportive care to improve quality of life. This may include: |
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| | * Physical therapy to maintain muscle strength and flexibility |
| | * Respiratory support, such as [[non-invasive ventilation]] |
| | * Orthopedic interventions to address skeletal deformities |
| | * Nutritional support to ensure adequate caloric intake |
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| | ==Prognosis== |
| | The prognosis for individuals with centronuclear myopathy varies widely depending on the type and severity of the condition. X-linked myotubular myopathy often has a poor prognosis due to severe respiratory involvement, while other forms may have a more favorable outcome with appropriate management. |
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| {{Diseases of myoneural junction and muscle}}
| | ==Related pages== |
| {{X-linked disorders}}
| | * [[Congenital myopathy]] |
| | * [[Muscle biopsy]] |
| | * [[Genetic testing]] |
| | * [[Respiratory support]] |
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| {{DEFAULTSORT:Centronuclear Myopathy}}
| | [[Category:Congenital myopathies]] |
| [[Category:Myoneural junction and neuromuscular diseases]] | | [[Category:Genetic disorders]] |
| {{dictionary-stub1}}
| | [[Category:Neuromuscular disorders]] |
| <gallery>
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| File:Centronuclear_myotubular_myopathy.JPEG
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| </gallery>
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A group of rare congenital myopathies
Centronuclear myopathy (CNM) is a group of rare congenital myopathies characterized by muscle weakness and distinctive histological features, notably the presence of centrally located nuclei in muscle fibers. These myopathies are genetically heterogeneous and can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
Classification
Centronuclear myopathy is classified based on the mode of inheritance and the specific genetic mutations involved. The main types include:
- X-linked centronuclear myopathy: Caused by mutations in the MTM1 gene, this form is also known as myotubular myopathy. It primarily affects males and is the most severe form, often presenting in infancy.
- Autosomal dominant centronuclear myopathy: Often associated with mutations in the DNM2 gene, this form can present at any age and varies in severity.
- Autosomal recessive centronuclear myopathy: This form can be caused by mutations in several genes, including BIN1, RYR1, and TTN. It typically presents in childhood or adolescence.
Pathophysiology
The hallmark of centronuclear myopathy is the abnormal positioning of nuclei in the center of muscle fibers, rather than at the periphery. This is thought to result from defects in muscle cell development and maintenance. The specific pathophysiological mechanisms vary depending on the genetic mutation involved. For example, mutations in the MTM1 gene affect the protein myotubularin, which is involved in phosphoinositide metabolism, while DNM2 mutations affect dynamin 2, a protein involved in endocytosis and membrane trafficking.
Clinical Features
The clinical presentation of centronuclear myopathy can vary widely depending on the type and severity of the condition. Common features include:
- Muscle weakness, particularly in the proximal muscles
- Hypotonia (reduced muscle tone)
- Delayed motor milestones
- Respiratory difficulties, especially in severe cases
- Facial muscle weakness, leading to a characteristic facial appearance
Diagnosis
Diagnosis of centronuclear myopathy typically involves a combination of clinical evaluation, muscle biopsy, and genetic testing. Muscle biopsy reveals the characteristic central nuclei in muscle fibers. Genetic testing can identify specific mutations responsible for the condition.
Management
There is currently no cure for centronuclear myopathy, and management focuses on supportive care to improve quality of life. This may include:
- Physical therapy to maintain muscle strength and flexibility
- Respiratory support, such as non-invasive ventilation
- Orthopedic interventions to address skeletal deformities
- Nutritional support to ensure adequate caloric intake
Prognosis
The prognosis for individuals with centronuclear myopathy varies widely depending on the type and severity of the condition. X-linked myotubular myopathy often has a poor prognosis due to severe respiratory involvement, while other forms may have a more favorable outcome with appropriate management.
Related pages
