Charcot-Marie-Tooth Disease (CMT) is a family of inherited disorders of the peripheral nervous system, affecting approximately one in 2,500 Americans. Its most common iteration, CMT1, comes in many forms, most of which have to date been linked to a small set of causative genes. Now, a study from researchers from the University of Pennsylvania and the Children’s Hospital of Philadelphia maps a new genetic cause of CMT1. The team state that their findings expand the number of genes known to cause CMT1, further helping the global medical community and patients find the genetic underpinnings of their neuropathy.
Previous studies show that Charcot-Marie Tooth Disease is a progressive debilitating neurodegenerative disorder that strikes in the second or third decade of life. This disease results in numbness and weakness in the hands and feet. There are two categories of CMT, those caused by the loss of axons in the peripheral nerves (CMT2), and those characterized by a malfunction in the Schwann cells that make up the myelin sheath, the protective coating that surrounds the nerve fibers and allows them to conduct nerve signals at high speeds (CMT1). The current study uses whole exome sequencing on a patient with Charcot–Marie–Tooth disease type 1 to identify a de novo mutation in PMP2, the gene that encodes the myelin P2 protein.
The current study investigated a father and son with CMT1 who did not carry a mutation in any of the five genes known to cause CMT1. The father’s parents did not have the disease, suggesting that a new random mutation occurred, not shared by either parent, which he then passed on to one of his three sons.
Through complex genetic sequencing of the father’s 20,000 genes, the lab was able to identify 49 mutations that could be the cause of the pair’s CMT. Results show that one mutation, a change in the peripheral myelin protein 2 gene (PMP2), emerged as the most likely culprit. The group explain that PMP2 encodes a protein that transports fatty acids, which are the building blocks of the myelin sheath and known to be one of the most abundant proteins in peripheral nervous system myelin. Data findings show that the father and his one affected son were the only family members to carry this mutation; this was strong evidence that mutations in PMP2 cause CMT1, slowing nerve conduction and resulting in weakness and numbness in the hands and feet.
To provide further evidence of an association between PMP2 mutation and CMT1, the lab screened an additional 136 European families with CMT1 for mutations in PMP2. These identified an Austrian family with several affected members who share a mutation in PMP2.
The team surmise that their findings demonstrate that dominant PMP2 mutations cause Charcot–Marie–Tooth disease type 1. For the future, the researchers state that it should be noted that next-generation sequencing technology has allowed them to find new causes of genetic diseases in much smaller families. They go on to conclude that traditional genetic techniques would never have allowed them to find the cause of this family’s CMT.