The study highlights the importance of electromyography (EMG) for family members who have no symptoms but may have disease-related muscle or nerve problems that would otherwise go unnoticed.
The study, “A novel GJB1 mutation associated with X‐linked Charcot–Marie–Tooth disease in a large Chinese family pedigree,” was published in the journal Molecular Genetics & Genomic Medicine.
Charcot-Marie-Tooth (CMT) disease is the term for a group of inherited disorders that affect the peripheral nerves, the network of nerves that supply movement and sensation to the body. Patients experience muscle weakness, muscle wasting, and sensory loss, as well as reduced tendon reflexes and slower nerve conduction velocities.
CMT is heterogeneous, and there are several types: CMT1, CMT2, CMT3, CMT4, CMTX, and DI-CMT. Each form is classified according to its genetic cause, pattern of inheritance, age of onset, severity, signs, and symptoms.
X-linked CMT (CMTX) is the second most common form, affecting about 10%-16% of all cases. It is characterized by damage to myelin, a protective fatty substance that covers nerve fibers and is essential for the proper transmission of nerve impulses.
Common symptoms are muscle weakness, muscle wasting atrophy, and loss of sensation, mostly in the feet, lower legs, hands, and forearms.
The root cause of CMTX is some form of mutation in the GJB1 gene, a gene located on the X chromosome that encodes a protein called connexin-32 (also known as gap junction beta 1). This protein forms channels between cells, which are important for cells to communicate with each other.
In the nervous system, connexin-32 is located in the membrane of specialized cells called Schwann cells, which produce myelin. For that reason, most GJB1 mutations will likely result in loss of myelin, or demyelination, and disturb the way nerve fibers work.
More than 400 GJB1 mutations have been linked to CMTX. Many of these mutations are single-point mutations, meaning they change only a single amino acid (one of the building blocks of proteins) of connexin-32.
CMTX is inherited in an X-linked manner. Females carry two X chromosomes, while males carry one X and one Y chromosome. This means a female with a GJB1 mutation has a 50 percent chance of passing the disease on to her children. Male carriers do not transmit the disease to their sons, as they only pass them the Y chromosome, but they may transmit the disease to their daughters.
Females usually tend to have mild symptoms to no symptoms at all, because they have a second X chromosome inherited from the other parent to compensate for the faulty gene. Males have more severe symptoms, because they only have a single X chromosome.
Researchers studied a GJB1 mutation found on a large Chinese family with CMTX. Based on muscle weakness symptoms and abnormal electromyography (EMG) findings (electrical activity in muscles and associated nerves) several members of the family, spanning four generations, were clinically diagnosed with CMT.
Fifteen of them underwent genetic tests to sequence the DNA stretch containing the GJB1 gene.
The tests identified a new missense mutation in GJB1, named c.605T>A (p.Ile202Asp), which caused one of the amino acids in the protein to be substituted by another.
Of the 15 family members tested, the mutation was present in five males and three females. All the females were asymptomatic — meaning they had no symptoms — but passed on the disease to their sons, who were more severely affected.
Even though these females had no obvious symptoms, they had abnormal EMG results, indicating subclinical CMT.
Using a more extensive genetic analysis called whole‐exome sequencing, researchers found no other suspicious mutations in the family.
The study represents the first time this GJB1 mutation was reported. It seems to be directly linked with CMTX, as it was not detected in 120 unrelated, healthy people who served as controls.
The mutation was classified as pathogenic, or disease-causing. That was supported by lab studies showing that mutated cells could not assemble the connexin-32 channels used for cell-to-cell communication.
“Our findings demonstrate that a novel mutation (c.605T>A) in GJB1 is associated with CMTX, and adds to the repertoire of GJB1 mutations related to CMTX,” the researchers said.
They recommended that CMTX family members without symptoms receive EMG tests to confirm the pattern of disease inheritance, and that they seek genetic counseling.