Researchers in the United States and France, supported in part by MDA, have established that mutations in the titin gene are a cause of centronuclear myopathy (CNM), a group of muscle disorders characterized by variable degrees of weakness and cell nuclei that are abnormally located toward the center of muscle fibers rather than around the perimeter.
In November 2012, through a contest to further the science of genetic testing, titin mutations were found to be the underlying cause of CNM in 11-year-old Adam Foye of Pinebrook, N.J. The current study found titin mutations in five of 29 study participants (17 percent) with CNM of unknown origin.
Other genes that, when flawed, can cause CNM, include myotubularin, dynamin 2, amphiphysin 2 and ryanodine receptor 1.
The titin gene codes for the huge titin protein, located in the parts of muscle fibers that contract and relax in response to signals from the nervous system. The protein has been described as a "molecular spring," and it appears to participate in the contraction and relaxation process in both skeletal and heart muscle tissue.
Ozge Ceyhan-Birsoy at Boston Children's Hospital and Harvard Medical School, and colleagues, described their findings in Neurology (Aug. 23, 2013). MDA supported study coordinator Alan Beggs at Boston Children's and Harvard, and study participant Jocelyn Laporte at the University of Strasbourg in France.
Titin-related CNM — implications for care
CNM caused by titin gene mutations appears so far to be inherited in an autosomal recessive manner, meaning two gene flaws — one from each parent — are required for the full disease to appear. People with one gene flaw for an autosomal recessive disease are said to be carriers. They can be entirely symptom-free or develop some of the symptoms of the disease.
The researchers found a variety of titin gene mutations in five of the study participants whose CNM was known not to result from any of the previously recognized genetic causes of the disease. All five, who ranged in age from 5 to 19 years, had two titin gene mutations, one inherited from each parent. No two mutations were alike, but the result of each pair of mutations was a shorter-than-normal titin protein. Presumably, titin's functions were adversely affected by the shortening.
Three of the five participants were able to walk, and two had never walked independently. All but one had some loss of respiratory muscle function. Four had normal cardiac function, and one had a mild cardiac abnormality.
"Our findings have important implications for guiding the clinical care of patients with CNM carrying [titin] mutations," the authors write. "Mutations identified in various regions of [the titin gene] are known to cause adult-onset cardiomyopathy [cardiac muscle abnormalities], with an average age of diagnosis at 38 years. The oldest patient in our study was 19 years old when last followed. Because many of the mutations identified in our patients with CNM are also present in cardiac titin isoforms [forms of titin found in the heart], these patients, and their [carrier] parents, should be closely monitored for potential cardiac issues in the future."
More CNM findings expected
In his accompanying editorial, James Dowling says the new study "represents a beautiful merging" of new gene sequencing methods with careful clinical assessments of a group of patients.
He cautions, however, that the new methods have limitations and that 24 of the 29 participants (83 percent) who did not have known CNM-causing mutations at the start of the study remain without a molecular diagnosis. He says "it is certain that mutations in additional genes" will ultimately be identified in this group and that current methods of gene sequencing may not be the ultimate solution for genetic diagnosis.