Nemaline myopathy is a congenital muscle disorder affecting the skeletal muscles used for voluntary movement. The name comes from the Greek word “nema,” meaning thread, referring to the tiny, rod-like structures called nemaline bodies found within muscle fibers. While these rods are a primary identifier of the disorder, they are considered a byproduct of underlying cellular issues rather than the direct cause of muscle dysfunction.
The disorder is characterized by muscle weakness that can impact the face, neck, arms, and legs. It is often noted at birth or in early infancy due to symptoms like low muscle tone, sometimes described as being “floppy.” Nemaline myopathy is the most common non-dystrophic congenital myopathy, with an estimated prevalence of 1 in 50,000 live births.
The Underlying Genetic Causes
Nemaline myopathy stems from mutations in genes that create proteins for muscle function. These proteins are components of the sarcomere, the contractile unit of a muscle cell. When mutations occur, the resulting proteins can be disorganized, impairing the muscle’s ability to contract and leading to weakness. At least a dozen different genes have been identified as causes of this disorder.
The two most frequently implicated genes are NEB (nebulin) and ACTA1 (alpha-actin). Mutations in the NEB gene are the most common, accounting for about half of all cases, and result in symptoms that appear at birth or in early childhood. Changes in the ACTA1 gene are responsible for 15 to 25 percent of cases and are associated with a wide range of severity. Other genes, such as TPM2, TPM3, and TNNT1, account for a smaller percentage of cases.
The condition is passed down through families in different inheritance patterns. The most common is autosomal recessive, where an individual inherits two copies of the mutated gene, one from each parent, who are often asymptomatic carriers. Less frequently, the disorder is inherited in an autosomal dominant pattern, where one copy of the mutated gene is enough to cause the condition. Sometimes, the genetic change occurs spontaneously and is not inherited.
Clinical Presentation and Symptoms
The disorder presents with hypotonia (diminished muscle tone) and weakness that is often most pronounced in the proximal muscles of the shoulders, upper arms, pelvis, and thighs. The muscles of the face, neck, and torso are also frequently affected, which can lead to a range of secondary complications.
Consequences of muscle weakness include difficulties with feeding and swallowing (dysphagia), which can be challenging in infants and lead to poor nutrition. Weakness of the respiratory muscles is a common issue, potentially causing hypoventilation, frequent respiratory infections, and respiratory failure. Other physical signs can include an elongated face, a high-arched palate, and skeletal deformities like scoliosis or joint contractures.
To account for the wide variability in presentation, nemaline myopathy is classified into several overlapping clinical forms based on the age of onset and severity:
- Typical congenital: The most common form, where infants show weakness but are often able to walk.
- Severe congenital (neonatal): The most serious form, with profound weakness and respiratory distress from birth.
- Intermediate congenital: More severe than the typical form, often requiring wheelchair and ventilation support by the pre-teen years.
- Childhood-onset: Weakness develops in the first or second decade of life.
- Adult-onset: The mildest form, with symptoms emerging between ages 20 and 50.
- Amish nemaline myopathy: A distinct, severe form that is typically fatal within the first two years.
The Diagnostic Process
Diagnosing nemaline myopathy involves a combination of clinical assessment and specialized testing. The process begins when a physician observes characteristic symptoms, like delayed motor milestones in a child, and considers any family history of neuromuscular disorders. Because symptoms can overlap with other conditions, specific tests are needed for confirmation.
A muscle biopsy has historically been a primary diagnostic tool. This procedure involves taking a small sample of muscle tissue, usually from the thigh, for examination under a microscope. Using a special stain, pathologists can identify the nemaline rods inside the muscle cells, and the presence of these rod-like structures confirms the diagnosis.
Genetic testing is now a common first-line diagnostic method. A blood sample is analyzed for mutations in the genes known to cause the disorder. Identifying a specific genetic mutation can confirm the diagnosis, often making a muscle biopsy unnecessary. This testing is also valuable for determining the inheritance pattern and for genetic counseling.
Other tests may be used to support the diagnosis or rule out other conditions. Electromyography (EMG) measures the electrical activity of muscles and can help distinguish myopathy from nerve-related problems. Blood tests for creatine kinase (CK) are normal or only slightly elevated, which helps differentiate it from muscular dystrophies.
Management and Supportive Care
There is currently no cure for nemaline myopathy, so treatment focuses on managing symptoms, preventing complications, and providing supportive care to improve quality of life. This requires a proactive, multidisciplinary approach involving a team of specialists to manage the disorder’s progression and maintain function.
Physical and occupational therapy are central to management. These therapies help maintain muscle strength, prevent joint stiffness (contractures), and preserve mobility. Therapists may recommend specific exercises and assistive devices like braces or walkers to support movement. A wheelchair may become necessary to conserve energy and ensure mobility.
Respiratory support is another aspect of care due to weakness in breathing muscles. Regular monitoring of respiratory function, sometimes through sleep studies, can detect nocturnal hypoventilation. Many individuals benefit from non-invasive ventilation, such as a BiPAP machine, to assist breathing at night. In more severe cases, invasive mechanical ventilation through a tracheostomy may be required.
Nutritional management is addressed for those with feeding and swallowing difficulties. A speech therapist can help with swallowing techniques, and a dietitian can ensure adequate caloric intake. For individuals who cannot safely swallow or consume enough food, a gastrostomy tube (G-tube) may be placed to deliver nutrition directly to the stomach. This ensures proper growth and energy levels.