Possible Genetic Component to MG Found in Large-scale North American Analysis

Possible Genetic Component to MG Found in Large-scale North American Analysis
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A large-scale analysis of people with myasthenia gravis (MG) in North America revealed a higher prevalence of MG and other autoimmune disorders among their families, suggesting there may be a genetic component to the neuromuscular condition, a study reported. 

The study, “Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America,” was published in the journal BMJ Open.

MG occurs when the immune system mistakenly attacks the neuromuscular junction — where nerve cell endings connect with muscles. 

Adult-onset MG is thought to be primarily a sporadic disease, which means not inherited. However, recent studies have suggested a genetic component, with some MG patients reporting a family history of the condition or of other autoimmune diseases.

To investigate further, researchers based at the National Institute on Aging’s Intramural Research Program, in collaboration with investigators from the U.S, Canada, and Italy, collected information between January 2010 and January 2011 for 1,032 patients with MG from specialized clinics at 14 centers across North America.

With this information, the team “approximated the prevalence of familial myasthenia gravis, compared the characteristics of familial disease with sporadic disease and assessed the comorbidity [co-conditions] of other autoimmune diseases among patients and among their families,” the scientists wrote. 

All of the patients had antibodies that attack acetylcholine receptors within the neuromuscular junction, the chief cause of MG.

Of note, acetylcholine is a chemical released by nerve endings when impulses travel down the nerve. It normally binds to receptors on the surface of muscle cells, causing muscle contractions. In MG, antibodies mistakenly block the receptors, impairing function and making the muscles become tired and weak.

Family histories of MG and other autoimmune diseases were collected using a questionnaire. Positive family history was defined as having first-degreesecond-degree, or third-degree relatives with the disease.

First-degree relatives include parents, siblings, and children — those who share about 50% of the patient’s genes. Meanwhile, second-degree family members include grandparents, grandchildren, aunts, uncles, nephews, nieces, or half-siblings, who generally share about 25% of the patient’s genes. Third-degree relatives include extended family members such as first cousins and great-grandparents.

Among the selected group, the age of MG onset ranged from 4 to 91 years. The median (middle) age of onset in females was 46, and in males was 62. Early-onset disease, meaning before age 40, was found in 248 participants (24%). Nearly one-third (29.6%) of patients had undergone a thymectomy — the surgical removal of the thymus.

The analysis revealed that 58 patients (5.6%) had a family history of MG.

“A prevalence of 5.6% represents a several hundred-fold increase for a disease with an overall prevalence of 1″ in 5,000–10,000, the researchers wrote. Normally the disease has a prevalence of 0.01-0.02%.

The most common types of familial relationships were sibling-sibling (31%) and parent-child (32.8%), followed by uncle/aunt–nephew/niece (13.8%), cousin–cousin (12.1%), and grandparent–grandchild (5.2%).

Notably, parent-child cases may be overestimated because neonatal MG cases, which are not believed to be genetic, could not be differentiated from non-neonatal cases, the team said.

Age at symptom onset was similar among patients with and without a family history. 

In turn, a personal history of an autoimmune disease other than MG was reported in 275 (26.6%) of participants, while 293 (28.4%) had a family history of an autoimmune disorder. 

“The prevalence of autoimmune disease in the general population is [approximately] 3%-9%, indicating that the rates observed among our myasthenia gravis subjects are significantly increased,” the investigators wrote. 

The most common autoimmune diseases found in the patients who also had MG were thyroid disease (11.4%), hematological disease (3.2%) — namely autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura and rheumatoid arthritis (2.7%).

In families of patients with MG, the three most frequent autoimmune conditions were thyroid disease (9.5%), rheumatoid arthritis (6.6%), and type 1 diabetes (3.5%).

In support of these findings, a literature review found five studies that discussed patients’ family histories of MG, with sample sizes ranging from 264 to 6,638 patients. A study in Taiwan reported a familial MG prevalence of 0.2%, while a Japanese study reported 0.7%. In addition, a study from Spain reported a frequency of 3.5%, and one from the U.S. showed 3.8%. A study conducted in Finland found a higher prevalence of 7.2%. 

Patient or family history of autoimmune diseases identified in three of these studies included thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome.

“The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease,” the scientists wrote. “Furthermore, a high proportion of patients had a personal or family history of autoimmune disease.”

“Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis,” they concluded.

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
Total Posts: 32
José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease
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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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