Common Mutations Linked to CMT in Southern Italy Highlighted in Study

Charcot-Marie-Tooth disease type 1A (CMT1A) caused by a duplication in the DNA sequence of the PMP22 gene was the most common form of this disease found in a large group of patients in southern Italy, a study reports.

This finding supports suggestions that disease-causing mutations in CMT might differ by geographic region, possibly through a common ancestor, its researchers wrote, and may help to make genetic testing for CMT easier by spotting the most frequent mutations in a Mediterranean area.

The study, “Charcot-Marie-Tooth disease: experience from a large Italian tertiary neuromuscular center,” was published in the journal Neurological Sciences.

CMT, a heritable disease, affects the peripheral nervous system — the network of nerves responsible for controlling movement and sensation in the limbs. The disease can be caused by mutations in more than 80 different genes, and manifests at various ages depending on its type and subtype.

Previous research in the U.K., U.S., and Germany reported that mutations in PMP22, GJB1, MPZ, and MFN2 were responsible for more than 90% of all CMT cases.

But in “two recent CMT series both from the Mediterranean area, GDAP1 but not MFN2 was one of the four genes most frequently involved, suggesting that genetic distribution could possibly be influenced by geographical area,” the researchers wrote.

To explore this possibility, researchers at the University of Messina and colleagues at the University of Verona reviewed the medical records of 566 CMT patients who had been followed at the Neuromuscular Center of Messina University Hospital, in Italy, for at least 22 years (1994 to 2016).

After reviewing patient records containing genetic, clinical and electrophysiological data, investigators found that more than half of these people (62.19%, 352 people) had been given a genetic diagnosis, while the remaining 37.81% carried an unknown CMT-causing mutation. (Electrophysiology captures the generation and transmission of electrical signals in neurons, or nerve cells.)

Among patients with genetic diagnosis, more than half had CMT1A caused by a duplication in the PMP22 (51.3%) gene or by a deletion in that gene (15.05%).

Apart from CMT1A, the most common forms of CMT investigators found in this group of patients were CMT1B caused by a mutation in MPZ (10.22%), CMTX caused by a mutation in GJB1 (9.37%), and CMT2F associated with a mutation in HSPB1 (4%).

Because genetic screening for all genes that can cause CMT is time-consuming and expensive, “data on frequency of genetic CMT subtypes in a wide Mediterranean area in Southern Italy may contribute to help clinicians in addressing the genetic testing workup together with implementation of next generation sequencing with a targeted approach,” the investigators concluded.