New Mutation on MPZ Gene Linked to Charcot–Marie–Tooth Disease in Three Generations of a Family

New Mutation on MPZ Gene Linked to Charcot–Marie–Tooth Disease in Three Generations of a Family

A mutation affecting the MPZ gene was found to be linked to Charcot–Marie–Tooth (CMT) disease in four members of a single family.

University of Vermont researchers published their case report on the family, titled “Novel Myelin Protein Zero Mutation in 3 Generations of Vermonters With Demyelinating Charcot–Marie–Tooth Disease,” in the Journal of Clinical Neuromuscular Disease.

The team presented the case of a family in which three generations were affected by progressive weakness of the legs. Family history also revealed a paternal great-aunt and paternal great-grandmother who were reported to have a phenotype of progressive weakness of the legs.

Based on this, the two daughters, the father and the paternal grandmother were further evaluated. Genetic analysis revealed a single alteration of one DNA unit — a C for a T — in the 314 position of the MPZ gene sequence. This mutation had already been described before, but no effect or disease association had been reported. Further studies are warranted to evaluate the molecular consequences of the MPZ mutation.

MPZ gene encodes a protein called myelin protein zero, which is a major component of the protective layer of nerve cells known as the myelin sheath. In the absence of this protein, the myelin layer will be defective and the electrical pulses used to communicate between nerve cells won’t flow normally.

Physical evaluation of all four members of the family confirmed that they experienced sensory loss, weakness of the legs and arms, and feet deformities. They also all had diminished lower leg tendon reflexes. Analysis of the nerve cells’ ability to transmit electrical impulses confirmed loss of myelin in the distal nerve cells, with consequent nerve cell death.

“The novel MPZ base-pair substitution in this family is associated with inherited distal demyelinating neuropathy and should be reclassified as pathogenic [disease-causing] for Charcot–Marie–Tooth,” the researchers stated.

Despite the similar symptoms presented by all family members, the onset of the disease was very different. The paternal grandmother experienced the first symptoms of leg weakness without cramping in her 40s, and the father developed cramping during adolescence and did not develop leg weakness until his third decade of life. In contrast, the two daughters first showed symptoms during early childhood, with one of child being born with tight heel cords that affected her walking ability.

The researchers could not find an explanation for this onset diversity and generational progressive presentation. Additional studies are required to clarify the link between the identified MPZ mutation and this progressive presentation of CMT.


  1. Barbara Woldin says:

    I am a medical writer, and my significant other has CMT (doctors believe it is CMT2). In the above article about the Vermont family, would this not be a case of anticipation, since this causes each succeeding family member to become symptomatic earlier or to have a more severe presentation of the disease?

  2. Jen Holdsworth says:

    our family has an MPZ gene fault, many generations and family members have this fault, all with different symptoms , told we have CMT1b

  3. Gesuina Scanu says:

    Io abito in Sardegna e sono affetta da CMT1A.
    Mai nonna paterna ve va tutti i miei sintomi, mio padre ha sviluppato la sindrome da adulto, la sua sorella divenne paralitica daiv28 anni fino ai 60 e poi morì.
    Io ho una figlia con CMT molto piú marcata della mia, 5 casi che io ho sperimentato di persona, 5 casi tutti differenti.

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