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-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. The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... // G00-G99 - Diseases of the nervous system (G00-G09) Inflammatory diseases of the central nervous system (G00) Bacterial meningitis, not elsewhere classified (G01) Meningitis in bacterial diseases classified elsewhere (G02) Meningitis in other infectious and parasitic diseases classified elsewhere (G03) Meningitis due to other and unspecified causes (G04) Encephalitis, myelitis... The International Statistical Classification of Diseases and Related Health Problems (commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... A congenital disorder is a medical condition or defect that is present at or before birth (for example, congenital heart disease). ... In medicine, a myopathy is a neuromuscular disease in which the muscle fibers dysfunction for any one of many reasons, resulting in muscular weakness. ... Hypotonia is a condition of abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. ... Hypoxia may refer to: Hypoxia (medical), the lack of oxygen in tissues Hypoxia or Oxygen depletion, a reduced concentration of dissolved oxygen in a water body leading to stress or even death in aquatic organisms This is a disambiguation page: a list of articles associated with the same title. ... Scaphocephaly is a type of cephalic disorder. ... Sex-linked genes are those carried on the mammalian X chromosome but not the Y chromosome. ... A congenital disorder is a medical condition or defect that is present at or before birth (for example, congenital heart disease). ...

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). It has been suggested that Refractory disease be merged into this article or section. ... A stroke, also known as cerebrovascular accident (CVA),[1] is an acute neurological injury in which the blood supply to a part of the brain is interrupted. ... Cerebral palsy (CP) is an umbrella term encompassing a group of non-progressive, non-contagious neurological disorders that cause physical disability in human development, specifically the human movement and posture. ... Poliomyelitis (polio), or infantile paralysis, is a viral paralytic disease. ... Spinal Muscular Atrophy (SMA) is a term applied to a number of different disorders, all having in common a genetic cause and the manifestation of weakness due to loss of the motor neurons of the spinal cord and brainstem. ...

History

In 1966, Dr. Gomez (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.^[1] The nuclear appearance reminded him of the nucleus-in-the-center appearance during the “myotubular” stage of embryonic 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. In medicine, a myopathy is a neuromuscular disease in which the muscle fibers dysfunction for any one of many reasons, resulting in muscular weakness. ... In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. ... It has been suggested that embryology be merged into this article or section. ...

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.^[2] While, other research suggests that the growth arrest mechanism may be responsible for all forms of MTM and CNM.^[3] 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.^[4] The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals (the other is the Y chromosome). ... An autosome is a non-sex chromosome. ...

As a reference to the term myotubular myopathy (MTM), when a 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". This article or section does not cite its references or sources. ... In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. ...

Incidence

The overall incidence of myotubular myopathy is 1 in 50,000 male live births.^[5] 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.^[5] Duchenne muscular dystrophy (DMD) (also known as muscular dystrophy - Duchenne type) is an inherited disorder characterized by rapidly progressive muscle weakness which starts in the legs and pelvis and later affects the whole body. ... In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. ...

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. A human infant The word Infant derives from the Latin in-fans, meaning unable to speak. ... In general, a diagnosis (plural diagnoses) covers a broad spectrum, or spectra, of testing in some form of analysis; such tests based on some collective reasoning is called the method of diagnostics, leading then to the results of those tests by ideal (ethics) would then be considered a diagnosis, but... Oral contraceptives. ... Genetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid or...

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.^[6] 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 deletion mutations.^[5] Sex-linked genes are those carried on the mammalian X chromosome but not the Y chromosome. ... The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals (the other is the Y chromosome). ... A phosphatase is an enzyme that hydrolyses phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group. ... A gene deletion, or deletion mutation is a genetic mutation in which a part of a chromosome or a sequence of DNA is missing. ...

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 (the MTM1 gene is located at site Xq28). 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. In biology, mutations are permanent, sometimes transmissible (if the change is to a germ cell) changes to the genetic material (usually DNA or RNA) of a cell. ...

X-linked forms

Genetically inherited traits and conditions are often referred to based upon whether they are located on the "sex chromosomes" (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). A sex-determination system is a biological system that determines the development of sexual characteristics in an organism. ... Sex-linked genes are those carried on the mammalian X chromosome but not the Y chromosome. ... An autosome is a non-sex 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.^[7] 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.^[7] In those species in which sex is determined by the presence of the Y or W chromosome rather than the diploidy of the X or Z, a Barr body is the inactive X chromosome in a female cell, or the inactive Z in a male. ...

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. A pedigree chart is a chart which tells you all of the known phenotypes for an organism and its ancestors, most commonly humans, show dogs, and race horses. ... Mother with her child (Sculpture) A mother is typically the biological or social female parent of a child or offspring while the male parent is the father. ... Generation (From the Greek γιγνμαι), also known as procreation, is the act of producing offspring. ...

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). It has been suggested that this article or section be merged into Dominance relationship. ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ... Chromosome 19 is one of the 23 pairs of chromosomes in humans. ...

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 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. In medicine, a myopathy is a neuromuscular disease in which the muscle fibers dysfunction for any one of many reasons, resulting in muscular weakness. ... Muscle tone is the continuous and passive partial contraction of the muscles. ... Developmental milestones are tasks most children can perform at certain ages. ... The heart and lungs (from an older edition of Grays Anatomy) The lung is an organ belonging to the respiratory system and interfacing to the circulatory system of air-breathing vertebrates. ... The ambulatory (Med. ...

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 truncating mutations of MTM1 cause a severe and early lethal phenotype, while some missense mutations are associated with milder forms and prolonged survival (up to 54 years).^[8] Sex-linked genes are those carried on the mammalian X chromosome but not the Y chromosome. ... A genetic deletion is a genetic aberration in which part of a chromosome is missing. ... Individuals in the mollusk species Donax variabilis show diverse coloration and patterning in their phenotypes. ... Missense mutations or nonsynonymous mutations are types of point mutations where a nucleotide is changed which results in a different amino acid. ...

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.^[9] 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. This article is about mutation in biology, for other meanings see: mutation (disambiguation). ... Dynamin is a GTPase thought to be responsible for endocytosis in the eukaryotic cell, and is involved in vesicle (biology) trafficking both at the cell surface (particularly caveolae internalization) as well as at the Golgi (1)(2)(4). ... Chromosome 19 is one of the 23 pairs of chromosomes in humans. ... It has been suggested that this article or section be merged into Dominance relationship. ... American high school students Adolescence (Latin adolescentia, from adolescere, to grow up) is the period of psychological, social, and physical transition between childhood and adulthood (gender-specific, manhood or womanhood). ...

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, pathologists and treating physicians use those terms almost interchangeably, although researchers and clinicians are increasingly distinguishing between those phrases. A biopsy (in Greek: bios = life and opsy = look/appearance) is a medical test involving the removal of cells or tissues for examination. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... The Doctor by Samuel Luke Fildes This article is about the term physician, one type of doctor; for other uses of the word doctor see Doctor. ... For the suburb of Melbourne, Australia, see Research, Victoria. ... Clinician is a term used generically to describe a wide range of medical professionals See Doctor, Medicine Category: ...

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. Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ...

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. Neurology is the branch of medicine that deals with the nervous system and disorders affecting it. ... Muscular Dystrophy Association (MDA) is a U.S. organization founded in 1950 which combats muscular dystrophy and diseases of the nervous system and muscular system in general by funding research, providing medical and community services, and educating health professionals and the general public. ...

Electrodiagnostic Testing

Electrodiagnostic testing (also called electrophysiologic) includes nerve conduction studies which involves stimulating a peripheral 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. A nerve conduction study (NCS) is a test commonly used to evaluate the function, especially the ability of electrical conduction, of the motor and sensory nerves of the human body. ... Motor nerves enable the brain to stimulate muscle contraction. ... The mechanism of the reflex arc Sensory neurons (or neurones) are nerve cells within the nervous system responsible for converting external stimuli from the organisms environment into internal electrical impulses. ... Electromyography (EMG) is a medical technique for evaluating and recording physiologic properties of muscles at rest and while contracting. ... An electrode is a conductor used to make contact with a nonmetallic part of a circuit (e. ...

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. Neuropathy strictly speaking is any disease that affects the neurons of the nervous system. ... A. A schematic view of an idealized action potential illustrates its various phases as the action potential passes a point on a cell membrane. ...

There is substantial overlap between the electrodiagnostic findings the various types of 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. In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. ... Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ...

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 therapists and occupational therapists. Physical medicine and rehabilitation is a particular field of medicine. ... Physical therapy can help restore lost functionality in many people. ...

Medical management generally involves efforts to prevent pulmonary complications, since lung infections 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. The heart and lungs (from an older edition of Grays Anatomy) The lung is an organ belonging to the respiratory system and interfacing to the circulatory system of air-breathing vertebrates. ... An infection is the detrimental colonization of a host organism by a foreign species. ... The word mucous is an adjective which means pertaining to mucus or having the qualities of mucus. ... Tracheotomy is a surgical procedure used to cut a hole in the trachea through which a small tube is inserted. ...

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). Special education consists of educational programs designed to support students whose singular needs or disabilities require special teaching approaches, equipment, or care within or outside a regular classroom. ... The Individuals with Disabilities Education Act (IDEA) is a United States federal law, , most recently amended in 2004, meant to ensure a free appropriate public education for students with disabilities, designed to their individualized needs in the Least Restrictive Environment. ... As part of the U.S. Individuals with Disabilities Education Act, the least restrictive environment is identified as one of the six principles that govern the education of students with disabilities. ...

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 educational 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. In education, a curriculum (plural curricula) is the set of courses and their contents offered by an institution such as a school or university. ...

References

External links

• PubMed Article search
• Centronuclear myopathy: Images - Geneva Foundation for Medical Education and Research
• Myotubular Myopathy from the Muscular Dystrophy Association
• Muscular Dystrophy Association's website in Greece

Support and fundraising groups

• Myotubular Myopathy Resource Group
• Yahoo online group
• The Information Point for Centronuclear / Myotubular Myopathy. Based in the United Kingdom
• The Joshua Frase Foundation
• The Myotubular Trust