Native American Myopathy (NAM), also known as STAC3 disorder, is a rare, inherited muscle condition that primarily affects skeletal muscles. It is a congenital myopathy, meaning its characteristics are present from birth or early infancy. The condition was first identified in 1987, and initially described in a three-month-old infant. It was reported among individuals of the Lumbee Native American tribe in North Carolina, though cases have since been recognized globally.
What is Native American Myopathy?
Native American Myopathy is a congenital myopathy, characterized by muscle weakness and poor muscle tone present at birth or in early infancy. This muscle weakness impacts motor development and physical capabilities from a young age. Affected individuals often experience delays in achieving motor milestones like sitting, crawling, standing, and walking.
The condition manifests with various physical characteristics. Many individuals present with “myopathic facies,” a specific set of facial features that can include drooping eyelids (ptosis), sunken cheeks, and an open mouth with downturned corners. Other distinctive facial features may include a small lower jaw (micrognathia), a cleft palate, low-set ears, or shorter eye openings.
Musculoskeletal involvement is also a prominent feature. Joint deformities that restrict movement, known as contractures, can be present at birth, particularly affecting the knees, ankles, neck, and elbows. Many individuals also develop an abnormal curvature of the spine, such as scoliosis or kyphoscoliosis. Respiratory involvement can occur due to muscle weakness, sometimes requiring noninvasive respiratory support.
Individuals with Native American Myopathy have an increased susceptibility to malignant hyperthermia. This life-threatening reaction can be triggered by certain anesthetic drugs used during surgical procedures. It can lead to a rapid rise in body temperature, severe muscle rigidity, and metabolic acidosis, requiring immediate medical intervention.
The Genetic Origin
Native American Myopathy is caused by mutations in the STAC3 gene. This gene provides instructions for producing the STAC3 protein, which plays a role in the excitation-contraction coupling process within skeletal muscles. This process converts electrical signals into muscle contractions, allowing for movement.
The STAC3 protein is involved in the mechanical coupling of voltage-gated calcium channels (CaV1.1) and the Ryanodine Receptor 1 (RyR1) in muscle cells. The RyR1 protein forms a channel that releases calcium ions stored inside muscle cells, a step essential for muscle contraction. When the STAC3 protein is impaired or reduced due to mutations, it can prevent the proper release of these calcium ions by RyR1 channels, leading to the characteristic muscle weakness observed in Native American Myopathy.
The inheritance pattern of Native American Myopathy is autosomal recessive. This means an individual must inherit two copies of the mutated STAC3 gene—one from each parent—to develop the condition. Parents who carry one copy of the mutated gene are typically unaffected themselves, but they can pass the gene to their children.
The condition was initially identified primarily within the Lumbee Native American population in North Carolina, where its estimated prevalence is approximately 1 in 5,000 individuals. This higher prevalence suggests a “founder effect,” where a disease-causing mutation originated in a common ancestor within an isolated community. While first described in this specific Native American group, the condition has since been diagnosed in individuals of African, Middle Eastern, and South American descent outside the United States.
Diagnosis and Management
Diagnosing Native American Myopathy involves a thorough clinical evaluation, genetic testing, and sometimes a muscle biopsy. The diagnostic process typically begins with a clinical assessment of the characteristic symptoms, such as congenital muscle weakness, joint contractures, and specific facial features. A detailed medical and family history is also gathered to identify potential patterns of inheritance.
Muscle biopsy findings can provide additional insights, showing structural abnormalities in muscle tissue consistent with a myopathy. However, the definitive diagnosis is confirmed through molecular genetic testing, such as DNA sequencing, to identify pathogenic variants in the STAC3 gene. For individuals of Lumbee Native American ancestry, targeted analysis for a specific STAC3 pathogenic variant (c.851G>C) may be performed first.
Currently, there is no cure for Native American Myopathy; therefore, management focuses on supportive care to address the symptoms and improve the individual’s quality of life. A multidisciplinary approach involving various medical specialists is generally recommended. Physical therapy and occupational therapy are used to improve muscle strength, range of motion, and overall mobility, often incorporating adaptive devices for daily living activities.
Respiratory support may be necessary if individuals experience weakness in their breathing muscles. Orthopedic interventions, including surgical correction, might be required for severe joint contractures or spinal deformities like scoliosis or kyphoscoliosis. Nutritional support is also important, particularly for infants who may have feeding and swallowing difficulties due to oral hypotonia or cleft palate, sometimes requiring gastrostomy tube placement.
Due to the risk of malignant hyperthermia, individuals with Native American Myopathy and their families are counseled on avoiding triggering anesthetics during any surgical procedures. If surgery is necessary, a specific protocol to prevent or manage malignant hyperthermia, including the use of dantrolene, is followed. Ongoing surveillance monitors growth, musculoskeletal complications, and respiratory function to adjust care plans as needed.