Congenital Myopathy

Congenital myopathy is a rare genetic condition that causes muscle weakness and lack of muscle tone, typically present at birth or appearing in early childhood. These inherited disorders affect skeletal muscles throughout the body, with symptoms ranging from mild weakness to severe breathing and feeding difficulties.

Table of contents

• What is congenital myopathy?
• Types of congenital myopathy
• Signs and symptoms
• Causes and inheritance
• Diagnosis
• Treatment and management
• Outlook and prognosis

What is congenital myopathy?

Congenital myopathy is a term for any genetic muscle disorder that causes muscle weakness and is typically noticed at birth. The word congenital means “present at birth” and myopathy means “disease of muscle.”^[1] These conditions affect the skeletal muscles, which are the muscles that control voluntary movements throughout the body.^[3]

Babies with congenital myopathies lack muscle tone at birth, a condition called hypotonia or “floppiness.” While symptoms can appear at birth, they may also develop during infancy or throughout childhood. In some cases, milder forms may not show symptoms until later in childhood.^[1][2]

Unlike some other muscle disorders, congenital myopathies are usually non-progressive or slow-progressive. This means the weakness typically does not worsen rapidly over a person’s lifetime. In fact, some children with myopathies may actually gain strength as they grow older.^[3]

Congenital myopathies account for approximately 6 in 100,000 live births every year, making them one of the top neuromuscular disorders worldwide.^[8]

• Skeletal muscles
• Respiratory muscles
• Facial muscles
• Neck muscles

Types of congenital myopathy

There are six main types of congenital myopathy, though more than 40 types have been identified involving over 30 causative genes. The different types vary in symptoms, severity, treatment options and outlook.^[1][6]

Central core disease is a type of core myopathy and the most common form of congenital myopathy. Typically, floppiness is seen in infants, and children have delayed milestones and moderate arm and leg weakness. However, weakness doesn’t seem to worsen over time. This condition is characterized by regions in muscle fibers where oxidative enzyme staining is absent. A change in the RYR1 gene causes central core disease.^[1][5]

Minicore (multicore) disease is another type of core myopathy with many subtypes. Most subtypes include severe weakness in the arms and legs. Scoliosis, a curve in the spine, is frequently seen. Breathing difficulties are common, and weakened eye movements can occur. A mutation in the RYR1 gene or another gene causes multicore disease.^[1]

Nemaline myopathy is one of the more common congenital myopathies. This condition is characterized by electron-dense rods within muscle fibers. Babies with nemaline myopathy typically have breathing problems and feeding issues. They also frequently have weakness in their face, neck, arms and legs. Skeletal complications such as scoliosis can occur. A mutation in one of several genes, including NEM2, ACTA1 and TPM2, causes nemaline myopathy.^[1][5]

Centronuclear myopathy is a very rare congenital myopathy characterized by an abundance of central nuclei on muscle biopsy. Symptoms include weakness in the baby’s arms, legs and face, droopy eyelids and problems with eye movement. Weakness tends to worsen over time. A mutation in the DNM2, BIN1 or RYR1 gene causes centronuclear myopathy.^[1][5]

Myotubular myopathy is a rare kind of congenital myopathy that usually only affects male babies. Floppiness and weakness are very severe. Breathing and swallowing difficulties are common. A condition called osteopenia, meaning weak bones, is common as well. Many children don’t survive their first year of life. A mutation in the MTM1 gene causes myotubular myopathy.^[1]

Congenital fiber-type disproportion myopathy is a rare condition that starts with floppiness. Symptoms include face, arm and leg weakness along with breathing difficulties. This condition occurs when type 1 muscle fibers, the slow-twitch fibers involved in sustaining activity, are smaller than type 2 fibers, the fast-twitch fibers involved in quick activity. Most infants are severely affected, but their respiratory function can improve with age. Mutations in the TPM3, ACTA1, TPM2, MYH7 and RYR1 genes have been found in children with this condition.^[1][8]

Signs and symptoms

Symptoms of congenital myopathy can vary depending on the type and severity. They can be present at birth or develop throughout infancy and childhood. Some symptoms may remain stable or progress slowly.^[2]

The most common symptoms of congenital myopathy include muscle weakness and floppiness. Hypotonia refers to loss of muscle tone that may progress over time. The muscles most affected are typically in the neck, shoulders and pelvis. These are called proximal muscles, meaning they are close to the center of the body. The hands and feet are usually less affected, though there are exceptions.^[1][17]

Breathing difficulties are common in congenital myopathies due to weakness in the respiratory muscles. Infants may have trouble breathing at birth or develop respiratory problems later. Some children may require breathing support devices to increase breath volumes or assist with coughing.^[2][15]

Feeding and swallowing problems frequently occur in babies with congenital myopathies. These difficulties can result in poor nutritional status and other health problems. Some children are not able to eat safely by mouth due to swallowing problems, either early in life or later.^[1][15]

Children with congenital myopathies often experience delayed developmental milestones and delayed motor skills. They may be slow to reach goals like turning over, sitting up, or walking. In milder forms, weakness may not be obvious until a child is slow to walk.^[2][7]

Skeletal problems are common complications. These include scoliosis, which is a curve in the spine, and other bone alignment issues. Weakened muscles can lead to problems with bone positioning and movement.^[1][5]

The muscles of the face and head may be affected, leading to an elongated facial structure sometimes called a “myopathic facies.” There may be decreased movement of facial muscles. The muscles that hold up the eyelids and control eye movement may also be weak, causing droopy eyelids and double vision.^[17]

In severe forms, an infant may be described as “floppy,” have difficulty breathing or feeding, and lag behind other babies in meeting normal developmental milestones. In the most severe cases, the breathing problems may be so severe that a breathing machine is needed to keep the child alive.^[7][17]

Causes and inheritance

Congenital myopathies are caused by genetic mutations that affect various proteins necessary for muscle tone and contraction. These genetic changes can be passed from parent to child, making them inherited disorders.^[3]

The pathogenic mechanisms vary based on the specific genes involved. Some mutations affect excitation-contraction coupling and the assembly of structures within muscle cells. For example, mutations in the RYR1, MTM1, DNM2, and BIN1 genes fall into this category. Other mutations affect the interaction between actin and myosin proteins and the production of forces in muscle fibers. These include mutations in NEB, ACTA1, TNNT1, TPM2, and TPM3 genes.^[6]

Congenital myopathies exhibit both pleiotropy, where one gene mutation can cause multiple symptoms, and genetic heterogeneity, where mutations in different genes can cause similar symptoms. This makes diagnosis challenging, as various congenital myopathies can present with similar clinical manifestations.^[6]

The inheritance patterns vary depending on the specific type. Some forms are inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene from one parent is needed to cause the disorder. Others follow an autosomal recessive pattern, requiring two copies of the mutated gene, one from each parent. Some forms, like myotubular myopathy, are X-linked, primarily affecting males.^[5]

Diagnosis

Diagnosing congenital myopathies requires a comprehensive approach involving clinical evaluation, laboratory tests, imaging studies, and often genetic testing and muscle biopsy.^[1]

The diagnostic process typically begins with a detailed physical examination and medical history. Doctors look for characteristic patterns of muscle weakness, particularly in the face, shoulders, upper arms, and hips. The presence of hypotonia, skeletal problems, and breathing or feeding difficulties also provide important diagnostic clues.^[17]

Blood tests may be performed to check levels of creatine kinase, a marker of muscle breakdown. In congenital myopathies, creatine kinase levels are often normal or only slightly elevated, which helps distinguish these conditions from other muscle disorders.^[8][17]

Electromyography can be performed to evaluate the electrical activity of muscles. However, this test can be unreliable and non-specific for congenital myopathies.^[8]

A muscle biopsy is valuable in the diagnosis of congenital myopathies. During this procedure, a small piece of muscle is surgically removed and examined under a microscope. Histopathologic or ultrastructural features within the muscle provide important basis for differential diagnosis. For example, central core disease shows a lack of oxidase in the core of muscle fibers, centronuclear myopathy shows central nuclei in muscle fibers, and nemaline myopathy shows electron-dense rods within muscle fibers.^[6][8]

However, muscle biopsy has limitations. Due to the limitations of sampling, only focal pathological changes may be observed, and typical changes might not be detected in a single biopsy. Minor or nonspecific pathological changes may not assist in making a definitive diagnosis. Structural changes may also change over time, potentially requiring repeated muscle biopsies.^[6]

Genetic testing is the best way to learn whether someone definitely has a form of congenital myopathy. DNA testing can identify the specific genetic variants responsible for many different forms. The two most common genetic tests are sequencing, which reads through all the letters in the gene looking for errors, and deletion/duplication testing, which looks for large chunks of genetic code that are missing or extra.^[15][17]

Imaging studies such as MRI of muscles may also be performed as part of the diagnostic workup.^[5]

Treatment and management

Currently, there is no cure for congenital myopathy, and no genetic cure exists for any type. Treatment remains focused on managing symptoms and maintaining quality of life through therapy, medical care, surgical interventions, and psychosocial support.^[2][9]

Physical therapy, occupational therapy, and speech therapy are important treatments that support people with symptoms. Physical therapy helps with stretching, maintaining range of motion, and preventing contractures, which are permanent tightening of muscles and joints. Depending on the specific condition, appropriate bracing may be recommended, though in some cases where immobility can worsen weakness, bracing may be contraindicated.^[2][9]

Respiratory management is crucial for many patients. Breathing support devices can take over the effort of breathing to increase breath volumes or assist with coughing. Evaluation for signs of nighttime hypoventilation, including morning headaches, snoring, or daytime sleepiness, is important. In severe cases, a breathing machine may be needed. Some patients may require continuous respiratory support.^[9][15]

For children with feeding and swallowing difficulties, a feeding tube may be needed to ensure adequate nutrition. Maintaining good nutrition along with gut and dental health is important because it improves growth, energy levels, activity levels, and breathing ability. A team including speech/swallow/feeding therapists, gastroenterologists, and nutritionists or dieticians typically manages this aspect of care.^[15]

Orthopedic interventions may be necessary to address skeletal problems. Scoliosis and other skeletal complications can usually be corrected by use of orthopedic devices or by surgery. Before having surgery, people who have a personal or family history of congenital myopathy should consult their doctors about the risks of anesthesia. Individuals with central core disease are at increased risk for malignant hyperthermia, a life-threatening reaction to certain anesthetic drugs, and should receive “non-triggering” anesthetics.^[1][12]

For severe weakness, assistive devices including wheelchairs or similar mobility devices may be needed to maintain independence and participation in activities.^[9]

Gene therapy can provide some treatment for some congenital myopathies. Some adeno-associated viruses show promising prospects in the treatment of MTM1 and BIN1-associated myopathies. New targeted gene therapies and medications aimed at calcium and myosin regulation are under investigation.^[2][6][9]

For central core disease specifically, treatment with the drug salbutamol has been shown to reduce weakness significantly, although it does not cure the disorder.^[7]

A multidisciplinary approach involving various subspecialists is recommended for comprehensive care. Follow-up visits should assess muscle function, contractures, ability to perform activities of daily living, and cardiopulmonary function. For newly diagnosed patients or children, more frequent visits every 3-6 months may be appropriate. For older patients or those with milder disease, at least yearly visits are warranted.^[9]

Outlook and prognosis

The outlook for congenital myopathy depends on the type and severity of the condition. Myopathies are usually non-progressive, meaning they usually don’t grow worse over a person’s lifetime. Some children with myopathies may actually gain strength as they grow older.^[3][5]

In central core disease, weakness is typically non-progressive, and life expectancy is normal for most patients. However, some patients are severely affected and may require a wheelchair.^[5]

For nemaline myopathy, the severity varies. Severe disease may cause weakness of respiratory muscles and respiratory failure. Moderate disease causes progressive weakness but life expectancy may be nearly normal. Mild disease is non-progressive with normal life expectancy.^[5]

Myotubular myopathy has the most severe prognosis. Most affected children historically did not survive beyond the first year of life. However, it is now clear that intensive, continuous support of feeding and ventilation can significantly improve life expectancy and allow a high quality of life.^[1][12]

Centronuclear myopathy typically manifests with progressive weakness. X-linked forms are the most severe, with most affected children not surviving beyond the first year of life. Autosomal dominant forms typically manifest in adolescence or adulthood with milder symptoms.^[5]

For congenital fiber-type disproportion myopathy, most infants are severely affected, but respiratory function can improve with age.^[1]

A happy, joyful family life is possible for people with congenital myopathies. Support from healthcare teams, family, and connections with others who have similar experiences can be invaluable. Online groups and local support groups for people with disabilities and families can provide important emotional support.^[15]