NORD gratefully acknowledges Eric Kil, Jonathan Echeverri and Nancy Chukwumezie, NORD Editorial Interns from the Keck Graduate Institute and Christopher Pierson, MD, PhD, Associate Professor of Pathology and Anatomy, The Ohio State University, College of Medicine, Neuropathologist, Department of Pathology & Laboratory Medicine, Nationwide Children’s Hospital, for assistance in the preparation of this report.
Congenital myopathy (CM) is an extremely rare, inherited disease that affects the muscles (myopathy) and is characterized by the lack of muscle tone or floppiness at birth. There are several different subtypes of congenital myopathy and many are caused by changes (mutations) in specific genes. They differ in severity and onset of symptoms, cellular characteristics under a microscope, and prognosis. Symptoms can be present from birth or slowly progress throughout infancy and childhood, but this disorder does not typically get more severe in adulthood. Experimental treatments are still under development therefore CM disease management involves treatment of symptoms, prevention of possible life-threatening complications, and orthopedic, physical, occupational, speech or other forms of therapy.
The subtypes of CM have highly variable severity of muscle loss symptoms and differ in the age of onset.
General symptoms of congenital myopathy in a newborn are the slow, progressive loss of muscle tone characterized by floppiness (hypotonia) and general weakness. Early motor skills and other critical developmental milestones may be delayed. Toddlers with this disorder usually have mild muscle weakness and may be prone to falling or stumbling. The muscles of the pelvis, neck, and shoulder area are most commonly affected. Since the symptoms of this disease are not progressive during adulthood, most people with congenital myopathy walk normally as adults. However, some physical activities may be slightly impaired.
Typically, diagnosis of CM subtypes requires the use of muscle biopsy and looking at the structural make-up of the muscles under a microscope. Symptoms seen in one subtype are generally seen in other subtypes with slight exceptions and nuances.
Nemaline myopathy (NM) is also known as rod myopathy. NM is characterized by abnormal rod- or thread-like structures present in muscle fibers under a microscope. These abnormal rod structures are associated with problems in the contraction and tone of affected skeletal muscles, ultimately leading to muscle weakness.
There are six different types of NM which are based on age and severity: severe congenital, Amish, intermediate congenital, typical congenital, childhood-onset, and adult-onset. Severe cases of NM are typically seen in young children, while milder versions of NM are seen in adulthood. Muscle weakness is caused by decreased muscle tone in NM which generally occurs throughout the body and is most severe in the neck, face, and skin muscles. One symptom of NM includes bulbar muscle weakness indicated by difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and excess saliva production (sialorrhea). In infants, bulbar muscle weakness is mainly presented as difficulty feeding while older children and adults exhibit difficulty swallowing. Other symptoms include foot deformities, curvature of the spine (scoliosis), as well as joint deformities (contractures). (For more information, search for “nemaline myopathy” in the Rare Disease Database.)
Core myopathies are characterized by areas in the muscle fiber that lack oxidative enzymatic activity. There are two types of muscle fiber core myopathy: central core disease (CCD) and multiminicore disease (MmD). CCD is characterized by the presence of single, well-circumscribed circular regions in the middle of type 1 fibers of the muscle that do not contain mitochondria. CCD is more common in infants who have hypotonia or seen in children with delays in motor development. CCD mainly affects the proximal and axial muscles. Orthopedic and joint deformities seen in nemaline myopathy are not seen in these patients. Eye muscles are not affected in this type of congenital myopathy. Pathologically, CCD can be observed in the tissue fibers by staining sections of the muscle fiber for oxidative enzyme activity. Patients with MmD also exhibit similar severity of symptoms compared to CCD with the exception of axial muscle weakness, especially in the head and neck muscle, which is much more severe in MmD. (For more information, search for “central core disease” in the Rare Disease Database.)
Centronuclear myopathy (CNM) is characterized by the abundant amount of centralized nuclei in muscle fibers when viewed in the microscope. One type of CNM, XLMTM, affects newborn boys and is generally clinical severe. Symptoms of XLMTM include an excess of amniotic fluid (polyhydramnios) and reduced fetal movements during pregnancy, thin ribs, weak eye muscles (ophthalmoplegia), drooping upper eyelid (ptosis), pyloric stenosis, knee, and hip contractures, and muscle wasting. Other forms of CNM can affect either males or females and tend to show more mild clinical signs. (For more information, search for “centronuclear myopathy” in the Rare Disease Database.)
Congenital fiber-type disproportion (CFTD) occurs when an abundant amount of type I (slow twitch) muscle fibers are 35-40% smaller than type II (fast twitch) muscle fibers. Many symptoms from the previous three myopathy types can be seen in CFTD as well. Additional symptoms include respiratory failure and nocturnal hypoventilation. (For more information, search for “CFTD” in the Rare Disease Database.)
There is still emerging research on the causes of CM and mutations in more than twenty genes have been associated with CM. Genes responsible for calcium ion balance in muscle cells have been implicated in some inherited forms of the disease. Calcium ion balance is important in muscle cells because calcium is a signal for muscle cells to contract. Other mutations described in CM patients occur in genes that lead to malformed filaments in muscle cells. These filaments are normally responsible for the contraction of muscles.
Most types of CM follow an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working 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 working genes from both parents is 25%. The risk is the same for males and females.
Structural defects such as rods or protein accumulation are common in nemaline myopathies, core-rod myopathy, and other types of CM are associated with mutations in genes such as ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, RYR1, TNNT1, TPM2, and TPM3. The most common cause of nemaline myopathies is autosomal recessive mutations in the NEB gene which accounts for up to 50% of cases, followed by ACTA1 (~25%).
Structural defects in cores seen in central core and multiminicore disease have been shown to be associated with mutations in the RYR1, MEGF10, MYH7, and SEPN1 genes. An overwhelming majority of patients with CCD (>90%) have a RYR1 mutation. Those with two RYR1 mutations have a more severe presentation than patients with a single RYR1 mutation or mutations in other genes. Most MmD is caused by recessive mutations in the SEPN1 gene.
Structural defects in central nuclei of centronuclear myopathy are associated with mutations in genes such as BIN1, CCDC78, DNM2, MTM1, RYR1, SPEG, and TTN.
X-linked myotubular myopathy is the most common and severe type with prenatal or neonatal onset. Autosomal recessive forms have a typical onset in infancy or childhood and autosomal dominant forms have the mildest symptoms and may present in adulthood. Most patients with centronuclear myopathy have mutations in the MTM1 gene which leads to X-linked myotubular myopathy, a type of CNM. DNM2 gene mutations are the second most common cause and result in milder symptoms. Mutations in the RYR1, TTN, and BIN1 genes have been identified in recessive forms and have highly variable symptom presentation.
Structural defects that lead to fiber size variation are commonly seen in congenital fiber-type disproportion CM and have been shown to involve genes including ACTA1, MYH7, RYR1, SEPN1, TPM2, and TPM3. Most CFTD CM are associated with mutations in the TPM3 gene and some patients have been identified with ACTA1, MYH1, SEPN1, and TPM2 mutations. Mutation in the LMNA gene have been found in several Japanese patients and could be related to a subset of CFTD CM patients at risk for cardiac disease.
Known genes have been found in 50-70% of families with CM, so other genetic causes remain to be identified.
Congenital myopathy is an extremely rare disorder that generally affects males and females in equal numbers. There are subsets of centronuclear myopathy, i.e. XLMTM that affect males more than females.
A diagnosis of congenital myopathy may be suspected upon a thorough clinical evaluation, detailed patient and family history, and identification of characteristic physical findings. A specific diagnosis can be made to confirm disease, track disease progression, and connect affected families with the relevant resources. The significant number of factors involved in CM makes a strict clinical, histopathological, or genetic diagnosis more complicated. Traditional clinical work-ups for myopathies use metabolic tests, electrocardiograms, and electromyography to identify which specific disease is suspected in the patient. In addition, clinical diagnosis based on symptom presentation can also assist in identifying the disease in patients. Metabolic tests can be used to look for abnormal elevations of creatine kinase levels. Electrocardiograms are done to observe the heart’s electrical activity and see if any disruptions are present that are common to specific subtypes such as congenital fiber-type disproportion CM. Electromyography are conducted to measure electrical activity within muscles. If these tests cannot identify the subtype of CM, a muscle biopsy can be done for a closer examination of the microscopic characteristics of the tissue to best characterize which exact subtype of CM an individual might have. Molecular testing of known genes implicated in CM can assist in narrowing down a diagnosis.
NM displays characteristic rod bodies in muscle that appear threadlike in longitudinal sections. In nemaline myopathy, creatine kinase levels are usually normal or slightly elevated. Electromyography may show changes in action potentials, indicative of a myopathy. If other tests are unsuccessful a muscle biopsy can confirm a diagnosis of nemaline myopathy.
Clinical features of core myopathy include presentation in the neonatal period but it may not be identified until later in infancy. It is characterized by hypotonia and muscle weakness, predominantly in the proximal extremities (i.e. biceps, thighs). Clinical progression of weakness can occur but those with core myopathy generally do not have progressive disease. Laboratory studies are not useful in diagnosis and the diagnosis must be confirmed by muscle biopsy.
Centronuclear myopathy subtypes are characterized by muscle fibers with central nuclei. One of two major clinical presentations can identify centronuclear myopathy. Certain symptoms can be indicative of centronuclear myopathy subtypes.
The more common form, also the most severe, is X-linked myotubular myopathy that occurs predominantly in males. The signs in infants include hypotonia, skeletal muscle weakness and respiratory muscle impairment leading to respiratory failure, which are components of the most severe clinical presentations. Impaired bulbar muscle function can lead to facial weakness, which can be associated with difficulty feeding, or to extraocular muscle weakness. Female carriers can present with limb girdle weakness as well as marked facial weakness.
A less common presentation of CNM occurs with autosomal dominant or recessive inheritance, presenting with mild weakness and hypotonia, which may be unrecognizable in infants. Unlike the more severe form (XLMTM), this type can be present in both males and females. Laboratory testing of creatine kinase often reveals normal levels although it is occasionally mildly elevated. The use of electromyography can be useful in detecting action potential changes however; diagnosis is confirmed by muscle biopsy or molecular genetic testing.
Congenital Fiber Type Disproportion
Clinical presentations of this myopathy include disproportions in the number and size of fast and slow twitch muscles, along with weakness of the limbs, neck, and trunk and facial muscles. Most infants are severely affected, but the degree of weakness can vary. Infants with congenital fiber type disproportion can have improvements in respiratory function as they age. The only definitive diagnosis for congenital fiber type disproportion is muscle biopsy.
Adults with congenital myopathy should be encouraged to get adequate exercise and to avoid unhealthy dietary and sedentary habits that may lead to obesity. Affected adults may experience episodes of mild muscle weakness, but generally there are no major physical disabilities.
Medications, nutritional and respiratory support, orthopedic support, physical, occupational, or speech therapy may also be necessary to recover quality of life in affected patients.
Genetic counseling is recommended for affected families.
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