NORD gratefully acknowledges Christopher Pierson, MD, PhD, Assistant Professor of Pathology, The Ohio State University, College of Medicine, Neuropathologist, Department of Pathology & Laboratory Medicine, Nationwide Children’s Hospital and Heinz Jungbluth, MD PhD, Senior Lecturer and Consultant in Paediatric Neurology, Children's Neuroscience Centre, St Thomas' Hospital, London, for assistance in the preparation of this report.
Centronuclear myopathy (CNM) is an umbrella term for a group of rare genetic muscle disorders. These disorders are characterized by muscle weakness that can range from mild to profound. Symptoms are often present at birth in the severe forms, but may first develop at any point during life, although onset in adulthood is unusual. There are several genetic forms of CNM including an X-linked form known as myotubular myopathy (XLMTM) and a few autosomal forms, usually referred to as centronuclear myopathy. Autosomal refers to genes that are found on autosomes, or chromosomes other than the X or Y chromosomes (sex chromosomes). Generally, the autosomal forms are less severe than XLMTM, however, in rare cases, individuals with an autosomal form can develop severe complications that are similar to those seen in XLMTM. CNMs derive their name from the abnormal location of the nucleus in the center of the muscle fiber (muscle cell) rather than the normal position on the edge. Centronuclear myopathies can be further classified into the larger, broader category of congenital myopathy, a group of genetic muscle disorders that are present at birth.
Common symptoms include mild to profound muscle weakness and diminished muscle tone (hypotonia or "floppiness"). In more severe cases, feeding difficulties and potentially severe breathing complications (respiratory distress) may occur. Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. Involvement of the muscles controlling eye movements is common in all different forms. The overall severity of the disorder can range from mildly affected individuals to individuals who develop severe, life-threatening complications during infancy and early childhood. Three different genes, DNM2, BIN1, and RYR1, have been identified that cause autosomal forms of CNM. XLMTM is caused by mutations to the myotubularin (MTM1) gene.
In the medical literature, centronuclear myopathy (CNM) is generally used for the autosomal forms of the disorder and myotubular myopathy is generally used for the X-linked form (XLMTM). Distinguishing between the X-linked myotubular form and the autosomal forms of CNM is essential as the symptoms are usually more severe in the X-linked form. NORD has a separate report on X-linked myotubular myopathy that describes that form in greater detail. This report specifically deals with the autosomal forms of centronuclear myopathy.
The specific symptoms and severity of CNMs can vary greatly among the different forms and from one person to another. Some individuals may only develop mild symptoms; others develop serious life-threatening complications. Unlike the X-linked form, the autosomal dominant form of CNM is rarely fatal during childhood. The autosomal recessive forms can be severe or mild. The course of an individual case is often unpredictable. Because of the variable nature of these disorders, parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.
This form of CNM is caused by mutations of the DNM2 gene and is highly variable in presentation and severity. The disorder can be present at birth or develop during childhood or even adulthood. Some individuals will have mild cases that go unnoticed for prolonged periods; others will have symptoms that are present in infancy or early childhood.
Many individuals with DNM2-related CNM have a mild form of the disorder and early development is normal. Symptoms may not develop until adolescence when abnormal fatigue, muscle pain (myalgia) and leg cramps may occur especially when exercising. Muscle weakness associated with DNM2-related CNM can be slowly progressive often during the teen-age years or even during adulthood. Often, weakness predominantly affects the upper legs or arms (proximally), but in some cases can start in the lower arms and legs (distally) and slowly progress to affect the upper arms and legs. Some individuals may experience delays in attaining certain developmental milestones such as walking, running or climbing stairs. Some individuals may have slowly progressive difficulty walking as they grow older. Ultimately, some affected individuals have lost the ability to walk, but this usually does not occur before the 6th decade of life.
Some affected individuals may develop drooping of the upper eyelid (ptosis) and complete or partial paralysis of the muscles that control the movements of the eyes (ophthalmoplegia).
When DNM2-related CNM occurs during infancy or early childhood common symptoms include hypotonia, generalized weakness, facial muscle weakness, ptosis, and ophthalmoplegia. Affected children may exhibit delays in attaining motor milestones, such as holding their head up. Facial weakness can cause infants to have a weak sucking ability and/or experience difficulties swallowing, potentially resulting in feeding difficulties. Eventually, affected individuals can develop breathing (respiratory) complications.
Additional symptoms have been reported in some individuals with DNM2-related CNM including cataracts, an increase in the size of skeletal muscle (muscle hypertrophy), a reduced jaw opening, a mildly high arch of the foot (pes cavus) and abnormal side-to-side curvature of the spine (scoliosis). Contractures of the Achilles tendon can also occur. A contracture is defined as shortening or hardening of muscle or tendon tissue that causes deformity and restricts the movements of affected areas, especially the joints.
This form of CNM is caused by mutations of the BIN1 gene and is inherited as an autosomal recessive condition. The symptoms of this disorder can vary greatly from one person to another and the severity can range from mildly affected individuals to those with severe, life-threatening complications early in life. However, relatively few families with BIN1-related CNM have been reported to date and the full spectrum of manifestations may not be known yet.
BIN1-related CNM may be present at birth or during early childhood. Overall, the severity of muscle weakness can vary. Affected individuals have mildly progressive muscle weakness. Facial muscle weakness is usually present and affected infants or children may exhibit ptosis or ophthalmoplegia. The muscles used for chewing (mastication) may be particularly involved in some cases. Muscles weakness predominantly affects the muscles of the upper arms and legs (proximally), but can potentially affect the muscles of the lower arms and legs as well (distally). Loss of muscle tissue mass (atrophy) may also occur. Some individuals will not experience respiratory involvement; others will experience potentially severe respiratory difficulties requiring ventilation. Feeding difficulties can also occur. Some individuals will experience delays in attaining developmental milestones such as sitting up, walking, or climbing stairs. In the severe form of BIN1-related CNM, progressive muscle weakness can result in difficulty walking and some individuals may lose the ability to walk unassisted by their 20s.
Individuals with early onset BIN1-related CNM may develop distinctive facial features including a long face and a highly arched palate.
Affected individuals may also exhibit skeletal abnormalities including a high arch of the foot (pes cavus), clubfoot, joint contractures, and side-to-side curvature of the spine (scoliosis) or abnormal front-to-back curvature of the spine (kyphosis).
Individuals with later onset of BIN1-related CNM typically do not exhibit ophthalmoplegia and may not have distinctive facial features. These individuals usually develop mild, slowly progressive muscle weakness that particularly affects the proximal muscles of the arms and legs. Some individuals may go undiagnosed until adulthood because the symptoms are subtle and cause little difficulty.
Most cases of this form of CNM tend to fall somewhere in between the severe or mild ends of the CNM spectrum. Many affected infants are profoundly hypotonic and weak at birth. However, some of these infants may improve significantly over time. Muscle weakness predominantly affects the proximal and axial muscles. Feeding difficulties and frequent respiratory infections may affect infants with RYR1-related CNM. Delays in attaining developmental milestones such as walking and climbing stairs may also occur.
Most affected individuals have distinctive facial features such as a V-shaped mouth. Addition symptoms that have been reported include scoliosis, absent reflexes, ophthalmoplegia, and bilateral ptosis. Some individuals may develop contractures. In some cases, individuals who experience profound difficulties at birth improve and only have mild issues during their teen-aged years.
At least one male child with RYR1-related CNM developed a severe form of the disorder and was initially diagnosed with X-linked myotubular myopathy before being identified as having a mutation in the RYR1 gene.
Centronuclear myopathies are caused by a mutation in a specific gene. The autosomal forms are denoted by their associated gene. DNM2-related myopathy is caused by a mutation in the dynamin 2 (DNM2) gene and is inherited as an autosomal dominant condition. Some cases of DNM2-related CNM may occur spontaneously (sporadically) with no previous family history of the disorder (i.e. new mutations). BIN1-related CNM is caused by mutations to the amphiphysin 2 (BIN1) gene and is inherited as an autosomal recessive condition. RYR1-related CNM is caused by mutations to the skeletal muscle ryanodine receptor (RYR1) gene and is thought to be inherited as an autosomal recessive condition.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The protein products produced by the genes associated with the various forms of centronuclear myopathy are believed to be critical for the proper development, maintenance, and function of muscle tissue. The exact, specific functions of these proteins are not fully understood.
Each individual receives a separate set of genes from each of their parents. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single faulty copy of a gene is sufficient for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the DNM2 gene is located on the short arm (p) of chromosome 19 (19p13.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 19p13.2” refers to band 13.2 on the short arm of chromosome 19. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The BIN1 gene is located on the long arm (q) of chromosome 2 (2q14.3). The RYR1 gene is located on the long arm (q) of chromosome 19 (19q13.2).
Mutations in the genes that cause CNM have also been associated with other disorders (allelic disorders). Mutations in the DNM2 gene are also associated with specific forms of Charcot Marie Tooth disease. Mutations in the RYR1 gene are also associated with other forms of congenital myopathies, namely central core disease, multi-minicore disease, and congenital fiber-type disproportion, and a susceptibility to malignant hyperthermia, a genetically determined adverse reaction to certain anesthetics and muscle relaxants. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A gene known as the myotubularin-related protein 14 (hJumpy) gene on the short arm of chromosome 3 (3p25.3) has been linked to CNM. Researchers are unsure whether this gene can directly cause CNM or is a modifier gene that influences the expression of the disorder in individuals with a different mutation.
One person has been identified with a mutation in the myogenic factor 6 (MYF6) gene located on chromosome 12. Mutations in the CCDC78 gene have recently (August 2012) been reported in one family with a unique form of congenital myopathy with central nuclei. It is important to note that mutations in these genes have been reported in a limited number of patients. Some individuals with a diagnosis of CNM (based upon muscle biopsy results) do not have an identifiable mutation in any of the genes known to be associated with CNM. This may be due to specific mutations that are undetectable by current testing methods, but also suggests that additional, as-yet-unidentified genes may also cause CNM. More research is necessary to fully understand the complex genetics factors associated with CNM.
Autosomal forms of CNM affect males and females in equal numbers. The disorders are often present at birth, but in mild cases may go undiagnosed into adulthood. The exact incidence of these disorders is unknown. More than 100 families have been reported in the medical literature with DNM2-related CNM. Both BIN1-related CNM and RYR1-related CNM have been reported in fewer than 50 individuals respectively. Because these disorders may go undiagnosed or misdiagnosed, it is difficult to determine the true frequency of CNMs in the general population.
CNM should be suspected in newborns with hypotonia and muscle weakness and older children or adults with weakness in the arms and legs. A diagnosis is based upon identification of additional characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests.
Clinical Testing and Workup
A muscle biopsy may be performed to aid in obtaining a diagnosis. A biopsy involves surgical removal a small sample of affected muscle tissue and examining the sample under a microscope. This allows physicians to note the characteristic, microscopic changes to muscle tissue, specifically the presence of the nucleus in the center of the muscle fiber (muscle cell) rather than toward the edge.
Specialized imaging techniques such as a muscle MRI (magnetic resonance imaging) may be used to inform the choice of genetic testing in different forms of CNM, particularly in DNM2- and RYR1-related CNM. An MRI uses a magnetic field to produce cross-sectional images of particular organs and bodily tissues such as skeletal muscle tissue.
A diagnosis of some cases of CNM can be confirmed through molecular genetic testing, which can detect the characteristic gene mutation that causes specific forms the disorder. Molecular genetic testing is available as a diagnostic service at specialized laboratories.
The treatment of CNM is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians, pulmonologists, neurologists, orthopedists, eye specialists, dental specialists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.
Some individuals may not require ventilation assistance. Other individuals may only need ventilation-assistance for a specific period of time (e.g. infancy) or at night when asleep. Individuals with severe forms of CNM will require prolonged, constant ventilation support. There are different methods for ventilation including noninvasive and invasive techniques. The decision about the type of ventilation and the duration of respiratory support is best made by the family in careful consultation with the patient’s physicians and other members of the healthcare team based upon the specifics of their case.
In some individuals feeding difficulties will require the insertion of a feeding tube (gastrostomy). This procedure involves inserted a tube directly into the stomach through a smalls surgical opening in the abdominal wall.
Physical and occupational therapy is recommended to improve muscle strength and prevent contractures. Special measures may be necessary to allow ventilator-dependent individuals to communicate. Additional therapies are symptomatic and supportive. For example, scoliosis may require surgical intervention.
Mutations in the RYR1 gene may be associated with a susceptibility to malignant hyperthermia, a potential life-threatening condition in which individuals experience a fast raise in body temperature and severe muscle contractions when under general anesthesia. Although no individuals with RYR1-related CNM are known to have developed malignant hyperthermia, physicians need to be aware of the potential risk and plan treatment accordingly. Consultation with a specialist center experienced in the diagnosis and management of malignant hyperthermia may also be advisable.
Treatment of the different forms of CNM is largely supportive and there is currently no cure. Researchers are studying the use of a class of drugs known as acetylcholinesterase (ACE) inhibitors, a well-established pharmacological therapy for individuals affected by congenital myasthenic syndromes (CMS), also for the treatment of individuals with CNM. Initial results have shown an improvement in strength in affected individuals. More research is necessary to determine the long-term safety and effectiveness of ACE inhibitors for the treatment of individuals with CNM.
Salbutamol, a drug commonly used in the treatment of bronchial asthma, has been used with some benefit in individuals with RYR1-related myopathies such as some forms of CNM.
Gene therapy is also been studied as another potential approach to therapy for neuromuscular disorders like CNM. The discovery of specific genes that cause CNM has enabled researchers to explore this potential therapy. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active protein and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active protein at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure”. However, at this time, there remain significant technical difficulties to resolve before gene therapy can be advocated as a viable alternative therapeutic approach.
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