Korean researchers have conducted a comprehensive analysis of the genetic and clinical features of GJB1 gene mutations in patients with X-linked Charcot-Marie-Tooth type 1 (CMTX1).
The results of the study were published in the Journal of the Peripheral Nervous System.
More than 400 mutations in the GJB1 gene have been linked to the development of CMTX1. This gene provides instructions for a protein called connexin32, or Cx32, essential for communication among Schwann cells, which produce the nerve cells’ protective myelin layer.
The previously identified genetic variants of GJB1 cause alterations in the Cx32’s sequence, affecting its function.
CMTX1, characterized by a reduction of nerve cells’ myelin protective layer and the degeneration of nerve cells, is a genetic disease inherited through the X chromosome. Its symptoms are more severe in male patients because they have just one X chromosome, whereas females, who have two X chromosomes, are commonly asymptomatic or have late-onset disease.
In the study “Clinical characterization and genetic analysis of Korean patients with X-linked Charcot-Marie-Tooth disease type 1,” a team of researchers conducted a genetic screen for mutations on GJB1 in Korean patients with CMTX1.
From a total of 655 unrelated CMT families of Korean origin, the team identified 128 patients who were carriers of GJB1 mutations. In total, they identified 43 mutations that were linked to CMTX1 development, of which six were new mutations that had not been previously identified. The team also identified 17 mutations that have exclusively been reported within the Korean population.
Among the 128 CMTX1 patients, 67 were males and 61 were females. Twenty-two female patients presented no symptoms, whereas in the remaining individuals, 87% presented high-arched foot, 41% had ataxia (uncoordinated muscle movements), and tremor was present in 35% of the patients. In addition, four patients experienced hearing loss and one patient had signs of reversible brain damage.
Similar to what had been previously reported, differences between genders were also observed in terms of clinical manifestations of the disease in the Korean patients.
Symptomatic females presented milder disease symptoms, as well as later disease onset compared to male patients. Males showed a poorer nerve cell response, with greater implications in motor function and the development of muscular deformities.
Interestingly, the team found the localization of the mutations on the Cx32 protein sequence were related to the outcome of male patients. Overall, patients who harbored mutations affecting the portion of the protein located outside the cell were those who experienced more severe symptoms.
“We suggest that the mutation site of GJB1 gene may be important in determining the clinical phenotype [presentation] of CMTX1,” the researchers stated.
The said that additional studies addressing the association between the localization of GJB1 mutations and disease severity in larger groups of patients are still necessary.
These data were the subject of two poster presentations at the 2017 World Congress of Neurology in Kyoto, Japan. The presentations were titled “Clinical and genetic analysis of Korean patients with CMTX1” and “Phenotypic characteristics in patients with X-linked dominant Charcot-Marie-Tooth disease of Korean origin.”
The abstracts were published in a supplemental issue of the Journal of the Neurological Sciences.