Myopathies are diseases that cause weakness and hypotonia (poor tone) in the muscles that control voluntary movements. Congenital myopathies are a group of myopathies, usually present from birth, that display structural changes in the skeletal muscles. The list of diseases defined as congenital myopathies varies. Three inherited conditions in particular are definitively known as congenital myopathies: central core disease, nemaline myopathy, and centronuclear (myotubular) myopathy. These myopathies lead to generalized muscle weakness, decreased muscle tone, weak muscle reflexes, poor muscle bulk, and often a characteristic facial and bodily appearance.
Central core disease
The muscle biopsy from a person with CCD typically displays a metabolically inactive "core" or central region that appears blank when stained (tested) for certain metabolic enzymes (proteins) that should be there. These central regions also lack mitochondria, the energy producing "factories" of the cells. Genetic testing for RYR1 mutations is available on a research basis. The same genetic test may be used to determine the presence of the gene change in family members who may have or be at-risk for the disease. For families in which a RYR1 mutation has been found, prenatal diagnosis may be possible using the DNA of fetal cells obtained from chorionic villus sampling (CVS) or amniocentesis.
Nemaline myopathy
The clinical diagnosis of NM is suspected in an infant under age one with muscle weakness and hypotonia (decreased muscle tone). Definitive diagnosis of nemaline myopathy is made by demonstration of nemaline bodies, rod-shaped structures characteristic of this disease, using a specific stain known as "Gomori trichrome" on a muscle biopsy sample. Muscle biopsy may also show predominance of structures known as type I fibers. As of 2004, genetic testing was available on a clinical basis for one gene, the ACTA1 gene located on the long arm of chromosome 1. About 15% of NM cases are due to mutations in this gene. Prenatal diagnosis is possible for families with known ACTA1 mutations. The DNA of a fetus can be tested using cells obtained from chorionic villus sampling (CVS) or amniocentesis.
Centronuclear (myotubular) myopathy
Diagnosis of X-linked MTM is usually made on muscle biopsy. Findings include: centrally located nuclei in muscle fibers that look like myotubules, absence of structures known as myofibrils, and possibly, persistence of certain proteins usually seen in fetal muscle cells. If timing is not an issue, genetic testing may be undertaken. Gene testing detects a mutation (disease-causing gene change) in up to 97-98% of people with the X-linked form. Though genetic testing is available, it tends to be time intensive and used to confirm a diagnosis, to screen potential carriers, or for prenatal testing.
Demographics
Although central core disease is thought to be rare, the incidence of this congenital myopathy remains unknown. Both males and females are affected. Due to the range of severity observed in CCD, it is possible that there are undiagnosed cases within CCD families and within the general population. The X-linked form of centronuclear myopathy affects approximately 1/50,000 newborn males. The autosomal recessive and autosomal dominant forms are apparently less common; however, the frequency of these forms remains unknown. Nemaline myopathy occurs in about 1/50,000 live births.
Causes
CENTRAL CORE DISEASE Central core disease is inherited in an dominant manner, due to a mutation in one copy of the RYR1 (ryanodine receptor) gene on the long arm of chromosome 19. Researchers think that mutations in this receptor affect the way calcium flows out of the sarcoplasmic reticulum, a functional unit in the muscle. Mutations in the RYR1 gene are also known to cause malignant hyperthermia (MH), a genetic predisposition that makes an individual prone to serious reactions to certain general anesthetics. In fact, MH is a feature of CCD. An individual with CCD has a 50% chance of passing the disorder on to each child. There are also occurrences of sporadic inheritance, which means that a gene alters spontaneously to cause the disorder in a person with no family history of the disease.
NEMALINE ROD MYOPATHY Nemaline myopathy is caused by alterations in genes that affect filament proteins. When the filament proteins aren't working, muscles can't contract and there is a subsequent loss of tone and strength. Nemaline myopathy can be inherited as an autosomal dominant or an autosomal recessive condition. Autosomal dominant inheritance implies that the affected person has one altered or non-functioning copy and one normal copy of a particular NM gene. The changed gene may occur for the first time in that individual (de novo) or may be inherited from a parent (familial). When NM occurs as an autosomal recessive condition, the affected individual has two altered or non-functioning NM genes, one from each parent. As of March 2004, there were five genes known to cause NM abbreviated as ACT1, NEB, TNNT1, TMP2, and TMP3; each gene codes for protein components of thin filament, a type of muscle fiber.
MYOTUBULAR MYOPATHY The MTM1 gene on the long arm of the X chromosome encodes myotubularin, a protein thought to promote normal muscle development. As of 2004, the precise mechanisms by which MTM1 mutations cause XLMTM were unresolved. X-linked MTM primarily affects males because they have only one X chromosome and therefore lack a second, normal copy of the gene responsible for the condition. Female carriers of the X-linked MTM have one X chromosome with a normal MTM1 gene and one X chromosome with a nonworking MTM1 gene. As of March 2004, researchers were working to identify the gene or genes responsible for the autosomal recessive form of centronuclear myopathy. One gene, the myogenic factor-6 gene (MYF6) has been shown to cause some cases of the autosomal dominant form. It is possible that other genes will be discovered in the future.
Symptoms
CENTRAL CORE DISEASE Central core disease is characterized by a mild, non-progressive muscle weakness. Signs of central core disease usually appear in infancy or early childhood and may present even earlier. There may be decreased fetal movements and breech (feet first) presentation in utero. The main features of CCD are poor muscle tone (hypotonia), muscle weakness, and skeletal problems including congenital hip dislocation, scoliosis (curvature of the spine), pes cavus (high-arched feet), and clubbed feet. Children with CCD experience delays in reaching motor milestones and tend to sit and walk much later than those without the disorder. A child with the disease usually cannot run easily, and may find that jumping and other physical activities are often impossible. Although central core disease may be disabling, it usually does not affect intelligence or life expectancy.
People who have central core disease are sometimes vulnerable to malignant hyperthermia (MH), a condition triggered by anesthesia during surgery. MH causes a rapid, and sometimes fatal, rise in body temperature, producing muscle stiffness.
NEMALINE MYOPATHY There is variability in age of onset, presence of symptoms, and severity of symptoms in nemaline myopathy. Most commonly, NM presents in infancy or early childhood with weakness and poor muscle tone. In some cases there may have been pregnancy complications such as polyhydramnios (excess amniotic fluid) and decreased fetal movements. Affected children with NM tend to have delays in motor milestones such as rolling over, sitting and walking. Muscle weakness commonly occurs in the face, neck and upper limbs. Over time, a characteristic myopathic face (a long face that lacks expression) develops. Skeletal problems including chest deformities, scoliosis, and foot deformities may develop. In the most severe cases of NM, feeding difficulties and potentially fatal respiratory problems may also occur. In those who survive the first two years of life, muscle weakness tends to progress slowly or not at all.
CENTRONUCLEAR MYOPATHY Typically the X-linked form of MTM (XLMTM) is the most severe of the three forms (X-linked, autosomal recessive, and autosomal dominant). XLMTM usually presents as a newborn male with poor muscle tone and respiratory distress. The pregnancy may have been complicated by polyhydramnios and decreased fetal movements. Of those who survive the newborn period, many will at least partially depend on a ventilator for breathing. Because of the risk of aspiration, many will also have a gastrostomy tube (G-tube). Boys with XLMTM can experience significant delays in achieving motor milestones and may not ever walk independently. They tend to be tall with a characteristic facial appearance (long, narrow face with a highly arched roof of the mouth and crowded teeth). Intelligence is generally not affected. Medical complications that may develop include: scoliosis, eye problems (eye muscle paralysis and droopy eyelids), and dental malocclusion (severe crowding). In X-linked MTM, other problems including undescended testicles, spherocytosis, peliosis, elevated liver enzymes, and gallstones may occur.
The autosomal recessive and autosomal dominant forms of MTM tend to have a milder course than the X-linked form. The autosomal recessive form can present in infancy, childhood, or early adulthood. Common features include generalized muscle weakness with or without facial weakness and ophthalmoplegia (paralysis of the eye muscles). Although feeding and breathing problems can occur, affected individuals usually survive infancy. Onset of the autosomal dominant form ranges from late childhood through early adulthood. It tends to be the mildest of the three forms of MTM. Unlike the X-linked form of the condition, problems with other organs (such as the liver, kidneys, and gall bladder) haven't been reported with the autosomal recessive and autosomal dominant forms of MTM.
Diagnosis
Diagnosis of a congenital myopathy generally includes evaluation of the patient's personal and family history, physical and neurological examinations that test reflexes and strength, and specialized tests. Since there is overlap between the symptoms of a congenital myopathy and other neuromuscular disorders, a number of tests may be performed to help narrow down the diagnosis. Serum CK (creatinine kinase) analysis, EMG (electromyelogram), nerve conduction studies, and muscle ultrasound tend to be of limited value in making this diagnosis. The definitive diagnosis of a congenital myopathy usually relies upon genetic testing and/or muscle biopsy. Also, muscle biopsy can be used to determine a patient's susceptibility to malignant hyperthermia.
Treatment team
Management of a congenital myopathy requires a multidisciplinary approach. In addition to the patient's primary health care professionals, medical professionals involved in the care of patients with may include specialists in neurology, neonatology, pulmonology, gastroenterology, orthopedics, ophthalmology, and orthodontistry. Additional specialists in physical therapy, speech therapy and occupational therapy may be needed. Patients with one of the congenital myopathies may receive comprehensive services through a muscular dystrophy association (MDA) clinic and/or a Shriner's Hospital for Children. Genetic evaluation and counseling may be helpful to the patient and family, especially at the time of diagnosis. Psychological counseling and support groups may also assist families in coping with this condition.
Treatment
As of 2004, there is no cure for the congenital myopathies. The purpose of treatment, which is largely supportive, is to help patients optimize function and to manage any medical complications associated with the disorder. Treatment measures for the congenital myopathies greatly depend on the severity of the individual's symptoms, and especially upon the degree of muscle weakness and presence of skeletal deformities. Treatment mainly consists of respiratory and feeding support, and orthopedic intervention. Ophthalmologic and dental care is also important to help manage problems that may arise such as dry eyes and dental crowding. In the case of X-linked MTM, management of associated complications including undescended testicles, spherocytosis, peliosis, elevated liver enzymes, and gallstones is also recommended.
Affected infants, especially those with X-linked myotubular myopathy or nemaline myopathy, usually require a feeding tube (a gastrostomy or G-tube) for nutrition and mechanical ventilation through a tracheostomy to help with breathing. Other means of ventilation such as BiPAP (bilevel positive airway pressure) may be used. Even children and adults who don't require help with daytime breathing may require respiratory support at night, since respiratory failure during sleep can occur.
Braces or surgery may be necessary to treat scoliosis, dislocated hips, and foot deformities. Since individuals with central core disease can develop malignant hyperthermia during surgery, they should consult a neurologist or anesthesiologist prior to these or other surgeries.
Recovery and rehabilitation
Given the rarity of the congenital myopathies, the potential for rehabilitation in these disorders is largely unknown. Speech, physical, and occupational therapies may be recommended. Though intellect is typically normal, educational support through early intervention services and/or through an individualized education plan (IEP) may also be appropriate for some children. In severe cases, consideration may be given to placement in a residential care facility that can provide 24-hour care and support services.
The goal of rehabilitation for the congenital myopathies is to maintain or improve the patient's existing functions. Physical therapy may be recommended to improve mobility and muscle strength. For example, people with central core disease can benefit from exercise, under the direction of a physician. Speech therapy can help a person with a congenital myopathy to learn speech and/or ways to communicate. For example, a boy with X-linked myotubular myopathy who has a tracheostomy may need help learning how to communicate with sign language and, later, with writing boards. Occupational therapy can teach patients to use adaptive techniques and devices that may help compensate for muscle weakness. For example, someone with a severe form of nemaline myopathy may benefit from a walker, wheelchair or other device in order to get around.
Clinical trials
As of March 2004, one clinical trial was recruiting patients with congenital myopathy. A study designed to learn more about the natural history of inherited neurological disorders and the role of heredity in their development will be conducted in the United States. Updated information on this trial can be found at <http://www.clinicaltrials.gov> or by contacting the patient recruitment and public liaison office of the National Institute of Neurological Disorders and Stroke (NINDS) at 1-800-411-1222 or <prpl@mail.cc.nih.gov>.
Prognosis
The outlook for children with central core disease is generally positive. Although they begin life with some developmental delays, many improve as they get older and stay active throughout their lives. The outcome for patients with nemaline rod myopathy is quite variable. Depending upon disease severity, affected individuals can have normal life span, despite progressive muscle weakness, or they can die in infancy due to respiratory problems. Severe neonatal respiratory disease and the presence of arthrogryposis (limited joint movement due to contracted muscles and tendons) generally predict a poor outcome with death by age one. The prognosis for myotubular myopathy varies according to the presence and severity of respiratory disease and scoliosis. X-linked myotubular myopathy was once described as fatal in the first few months of life. Yet, it is now known that support of feeding (G-tube) and ventilation (tracheostomy) can significantly improve life expectancy and quality of life.
Special concerns
Malignant hyperthermia, a problem seen in some individuals with central core disease is a severe and potentially life-threatening complication of anesthesia. People with central core disease or a family history of the disease should consult their doctors about anesthesia risks. Also, wearing a medical alert bracelet may be advised.
Individuals with even mild cases of myotubular myopathy can experience potentially serious breathing problems such as hypoxia (lack of oxygen) during sleep. It is crucial that even patients with minimal disease severity be monitored for respiratory problems as they may require help with breathing at night.
BOOKS
Wallgren-Pettersson, Carina A., and Angus Clarke. "Congenital Myopathies." In Principles and Practice of Medical Genetics. 4th ed., edited by David Rimoin, MD, PhD, Michael Connor, Reed E. Pyeritz, MD, PhD, and Bruce Korf, MD, PhD, 4th ed. New York: Churchill Livingstone, 2002.
"Muscle Diseases." In Textbook of Primary Care Medicine. 3rd ed. edited by John Noble, MD, Harry Greene, II, MD, Wendy Levinson, MD, Geoffrey A. Modest, MD, Cynthia D. Mulrow, MD, Joseph Scherger, MD; and Mark J. Young, MD. St. Louis, MO: Mosby, 2000.
PERIODICALS
Bruno, C., and C. Minetti. "Congenital myopathies." Current Neurol Neurosci Rep 4 (January 2004): 68–73.
Jungbluth, H., C. A. Sewry, and F. Muntoni. "What's new in neuromuscular disorders? The congenital myopathies." European Journal of Paediatric Neurology 7 (2003): 23–30.
Prasad, A. N., and C. Prasad. "The floppy infant: contribution of genetic and metabolic disorders." Brain Dev 25 (October 2003): 457–76.
Quinllivan, R. M., C. R. Muller, M. Davis, N. G. Laing, G. A. Evans, J. Dwyer, J. Dove, A. P. Roberts, and C. A. Sewry. "Central core disease: clinical, pathological, and genetic features." Archives of Disease in Childhood 88 (December 2003): 68–1051–1055.
Sanoudou, D., and A. Beggs. "Clinical and genetic heterogeneity in nemaline myopathy—a disease of skeletal muscle thin filaments." Trends in Molecular Medicine 7 (August 2001): 362–368.
