Mutations in More Than One Gene May Explain Symptom Differences

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by Patricia Inacio PhD |

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The co-occurrence of mutations that affect more than one gene may explain more severe cases of Charcot-Marie-Tooth (CMT) within members of the same family, a small Chinese study says.

According to the researchers, this should be considered whenever CMT patients within the same family show differing symptoms.

The report “One PMP22/MPZ and Three MFN2/GDAP1 Concomitant Variants Occurred in a Cohort of 189 Chinese Charcot-Marie-Tooth Families” was published in Frontiers in Neurology.

CMT is caused by gene mutations that affect the normal functioning of peripheral nerves, which supply movement and sensation to the arms and legs. The disease can be classified into several types based on the genes that are mutated, the inheritance pattern, and the extent of nerve damage.

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CMT1, also known as demyelinating CMT, is the most common type and is characterized by defects that damage the myelin sheath, the fat-rich layer covering nerve fibers. A second type, CMT2, also called axonal CMT, is caused by mutations in genes important for the structure and function of nerve fibers.

Mutations in more than 100 genes have been linked with CMT, with changes in PMP22 and MFN2 being the most frequent causes of CMT1 and CMT2, respectively.

It’s generally accepted that CMT is a monogenic disease, meaning it’s triggered by inheriting mutations in a single gene. However, patients often display differing symptoms, such as in the age of onset, disease severity, and clinical progression.

“Thus, a single mutation may not completely explain the intrafamilial heterogeneity [diversity] of CMT,” the scientists wrote.

To see if mutations exist in two or more genes, the team analyzed 189 unrelated Chinese CMT families followed at a single hospital in central China. Patients were diagnosed with either CMT1 or CMT2 by two experienced neurologists and according to the diagnostic criteria of the European CMT Consortium.

The researchers used blood samples collected from all of the patients to conduct next-generation sequencing, a high-throughput technique for genetic analysis.

Results identified four families (2.1%) carrying a mutation in two distinct CMT genes.

In one family, a 6-year-old girl had a mutation in the PMP22 gene — specifically, a gene duplication — and another in the MPZ gene, which contains the instructions for myelin protein zero (MPZ), the most abundant protein within myelin.

The girl had delayed motor development since early childhood, with symptoms progressing into her upper limbs, and showed difficulties buttoning at age 6. Her father, 28, had a mutation in the MPZ gene and in adolescence had reduced athletic ability and impaired balance.

In the second family, a 22-year-old man had mutations in the genes MFN2 and GDAP1, which are associated with subtype CMT2K.

He was unable to stand on his heels since he was 5, and at 20 had difficulty climbing stairs. His mother, who carried the same mutation in the MFN2 gene, developed only one CMT symptom — pes cavus, or high foot arch.

In the third family, a girl was identified as a carrier of MFN2 and GDAP1 gene mutations. She developed symptoms early on, including delayed motor development and muscle weakness at age 3. Her father carried the same MFN2 mutation, and had diminished tendon reflexes in the limbs.

Finally, the fourth case involved a 29-year-old man who had a de novo, or spontaneous, mutation in a germ cell (egg or sperm) in the MFN2 gene and another mutation in the GDAP1 gene. While both of his parents were healthy, he developed weakness on both sides of his body when he was 7. The disease progressed to severe muscle wasting that affected his legs and arms, pes cavus in both feet, and tendon reflexes that were absent in the legs and reduced in the arms.

These results show that mutations in more than one gene may co-exist, and are usually linked with more severe clinical presentations among those with CMT.

The possibility of underlying multiple mutations “should be taken into consideration when significant clinical heterogeneity is observed,” the scientists concluded.