Neurology Central

New genetic cause of Charcot-Marie-Tooth disease identified

New research, published this week in Brain, has widened understanding of the inheritance of Charcot-Marie-Tooth disease (CMT). The team, based at the University of Pennsylvania (PA, USA), successfully indentified de-novo mutations associated with the most common form of CMT, termed CMT type 1 (CMT1), which affects nearly one in 2,500 Americans.

To date, CMT1, caused by a malfunction in the Schwann cells of the myelin sheath, has only been linked to a limited set of five causative genes.

Neurologists at the University of Pennsylvania initiated the study by analyzing the genetics of a father and son who were both being treated for CMT1 in Pennsylvania, but did not possess a mutation in any of the five known genes. In addition, the father’s parents did not experience CMT1, suggesting that a novel random mutation may have occurred within the father.

Exome sequencing of approximately 20,000 genes within the father highlighted 49 different mutations that were potential contributors to both the father and son’s CMT. In particular, a de novo mutation in the peripheral myelin protein 2 gene (PMP2 ) emerged as the primary contributor to disease inheritance. Following sequencing of further family members, it was revealed that the father and son with CMT1 were the only individuals to possess the mutation.

Given the role of PMP2 in transporting fatty acids, which are the most abundant proteins in peripheral nervous system myelin, the findings provide strong evidence for a causative link between PMP2 and CMT1, resulting in reduced nerve conduction speed and numbness and weakness in the hands and feet, among other symptoms.

William Motley (University of Pennsylvania) commented: “The fact that [the individual’s]parents did not have the disease allowed us to narrow the number of possible mutations, as so few arise between generations.” He went on: “Next-generation sequencing technology has allowed us to find new causes of genetic diseases in much smaller families.”

To investigate the association between PMP2 and CMT1 further, the team consulted with an international consortium of CMT researchers to try and identify other patients across the globe with a PMP2 mutation.  As part of this, an additional 136 European probands with uncharacterized genetic causes of Charcot–Marie–Tooth disease were investigated.

From the sample of 136, one family was eventually identified in which several individuals shared a mutation in PMP2. Unexpectedly, the mutation was shown to affect an adjacent amino acid (p.Thr51Pro) to that seen in the original family investigated at the University of Pennsylvania.

Senior author, Steven Scherer commented on the study outcomes: “This has been a highly fulfilling effort. We were able to track down the cause of this family’s CMT, help another family, and find a new genetic cause of CMT in the process.”

Sources: University of Pennsylvania press release