Centronuclear myopathy
4960443
215576025
2008-05-28T20:26:05Z
DOI bot
6652755
Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]].
{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 31983 |
ICD10 = {{ICD10|G|71|2|g|70}} |
ICD9 = {{ICD9|359.0}} |
ICDO = |
OMIM = 160150 |
MedlinePlus = |
eMedicineSubj = neuro |
eMedicineTopic = 76 |
MeshID = D020914 |
}}
'''Centronuclear myopathies''' (CNM) are a group of [[congenital]] [[myopathies]] where cell nuclei are abnormally located in skeletal muscle cells. In CNM the nuclei are located at a position in the center of the cell, instead of their normal location at the periphery. Although all forms of centronuclear myopathy are considered rare, the most commonly known form of CNM is Myotubular Myopathy (MTM). 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.
Literally, a myopathy is a [[disease]] of the muscle tissue itself. ''Myo'' derives from the word muscle and ''pathos'' means disease. There are literally 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]]).
== History ==
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 |author=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}}</ref>
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.
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>[http://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 |author=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>
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 |author=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}}</ref>
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]]".
== Incidence ==
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] The University of Chicago Genetic Services.</ref> The incidence of other centronuclear myopathies is unknown, but they are far less common than more well-known muscle disorders like [[Duchenne's muscular dystrophy]]. 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/>
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.
== Genetic causes==
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 |author=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}}</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 possible combinations of inheritance of myotubular myopathy are as follows:
* X-linked recessive, such as mutations in MTM1; myotubular myopathy.
* Autosomal recessive, specific genetic site has not yet been identified for centronuclear myopathy, but there is ongoing research in this area.
* Autosomal dominant, such as DNM2 centronuclear myopathy.
* 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).
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.
=== X-linked forms===
Genetically inherited traits and conditions are often referred to based upon whether they are located on the "[[sex chromosome]]s" (the X or Y chromosomes) versus whether they are located on "autosomal" chromosomes (chromosomes other than the X or Y). Thus, genetically inherited conditions are categorized as being [[sex-linked]] (e.g., X-linked) or [[autosomal]]. Females have two X-chromosomes while males only have a single X chromosome, and a genetic abnormality located on the X chromosome is much more likely to cause clinical disease in a male (who lacks the possibility of having the normal gene present on any other chromosome) than in a female (who is able to compensate for the one abnormal X chromosome).
The X-linked form of MTM/CNM is the most commonly diagnosed type. Almost all cases of X-linked MTM occurs in males. Females can be "carriers" for an X-linked genetic abnormality, but usually they will not be clinically affected themselves. Two exceptions for a female with a X-linked recessive abnormality to have clinical symptoms: one is a manifesting carrier and the other is [[X-inactivation]]. A manifesting carrier usually has no noticeable problems at birth; symptoms show up later in life. In X-inactivation, the female (who would otherwise be a carrier, without any symptoms), actually presents with full-blown X-linked MTM. Thus, she congenitally presents (is born with) MTM.<ref name= Jungbluth>{{cite journal |author=Jungbluth H, Sewry C, Buj-Bello A, Kristiansen M, Ørstavik K, Kelsey A, Manzur A, Mercuri E, Wallgren-Pettersson C, Muntoni F |title=Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation |journal=Neuromuscul Disord |volume=13 |issue=1 |pages=55–9 |year=2003 |pmid=12467733 |doi=10.1016/S0960-8966(02)00194-3}}</ref>
Thus, researchers point out that although MTM1 mutations most commonly cause problems in boys, these mutations can also can clinical myopathy in girls, for the reasons noted above. Thus, experts recommend that girls with myopathy and a muscle biopsy showing a centronuclear pattern be tested for MTM1 mutations.<ref name= Jungbluth/>
Many clinicians and researchers use the abbreviations XL-MTM, XLMTM or X-MTM to emphasize that the genetic abnormality for myotubular myopathy (MTM) is X-linked (XL), having been identified as occurring on the X chromosome. The specific gene on the X chromosome is referred to as MTM-1. It is theoretically possible that some cases of CNM may be caused by an abnormality on the X chromosome, but located at a different site than the gene MTM1, but currently MTM1 is the only X-linked genetic mutation site identified for myotubular or centronuclear myopathy. Clinical suspicion for X-linked inheritance would be a disease affecting multiple boys (but no girls) and a [[pedigree chart]] showing inheritance only through the [[maternal]] (mother’s) side of each [[generation]]. To date, the only X-linked mutation site causing centronuclear myopathy is the MTM1 gene.
=== Dominant and recessive forms===
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]]"). 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. Conversely, a "recessive" abnormality will only cause disease if both copies of the gene are abnormal. 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).
== Clinical presentation ==
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.
Other observed features have been high arched palate, long digits, bell shaped chest and long face, it has to be added that myotubular myopathy only affects muscles and does not impact intelligence in any shape or form.
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.
[[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 |author=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 |doilabel=10.1002/(SICI)1098-1004(200005)15:5<393::AID-HUMU1>3.0.CO;2-R}}</ref>
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 |author=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=1207–9 |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.
== Pathology ==
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.
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.
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]].
== Electrodiagnostic Testing ==
[[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.
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.
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.
== Treatment ==
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 ([[Physiatry]]), and by [[physical therapist]]s and occupational therapists.
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 [[mucous]] plugs and avoiding the need for [[tracheostomy]] tubes.
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.
==Advocacy==
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).
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.
==References==
{{reflist}}
== External links ==
*[http://www.mda.org/disease/mm.html Myotubular Myopathy] from the Muscular Dystrophy Association
* [http://www.mdahellas.gr/ Muscular Dystrophy Association's website in Greece]
*[http://www.mtmrg.org/info.htm Myotubular Myopathy Resource Group]
{{PNS diseases of the nervous system}}
[[Category:Muscular disorders]]