Charcot-Marie-Tooth disease (CMT) is associated with a number of genetic mutations. In fact, the different mutations signify specific CMT subtypes, such as CMT1 or CMT3. According to Charcot-Marie-Tooth News, researchers recently explored the association between MPZ gene mutations and Charcot-Marie-Tooth disease type 1 subtype B (CMT1B). In the past, more than 200 MPZ gene mutations have been linked to CMT1B. However, researchers recently determined that loss of function MPZ mutations actually cause milder neuropathy than those with other mutations. Check out the full findings published in the Journal of the Peripheral Nervous System.

MPZ Mutations and CMT1B

As described above, researchers discovered how loss of function myelin protein zero (MPZ) mutations ultimately resulted in milder neuropathy. But how did this begin? According to MedLine Plus, the MPZ gene:

provides instructions for making a protein called myelin protein zero. It is the most abundant protein in myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses.

MPZ mutations prevent the production of MPZ protein. Normally, myelin helps protect nerves. The myelin sheath is the protective covering of nerves and also serves to help transmit nerve signals. Patients with CMT1B either do not have enough MPZ protein or have defective MPZ protein.

Ultimately, this can be caused by a loss-of-function mutation. As the name suggests, a loss-of-function mutation causes malfunctioning or defective proteins. MPZ deficiency, and CMT1B overall, result in neuropathy.

According to the National Institute of Neurological Disorder and Stroke (NINDS), neuropathy is defined as:

the many conditions that involve damage to the peripheral nervous system, the vast communication network that sends signals between the central nervous system (the brain and spinal cord) and all other parts of the body.

Nerve signaling in neuropathy is disrupted in three ways:

• loss of signals normally sent (like a broken wire)
• inappropriate signaling when there shouldn’t be any (like static on a telephone line)
• errors that distort the messages being sent (like a wavy television picture)

The Research

In the past, mice models with MPZ protein deficiencies showed symptoms of CMT1B, such as muscle weakness or nerve damage. But in this most recent study, researchers wanted to understand how MPZ deficiency impacted human patients with CMT1B. This study consists of 6 patients. Of these, 2 were female and 4 were male. None of the six patients were related to each other. While all six patients had CMT1B and MPZ haploinsufficiency, five patients (83%) had the c.306 del; p.Asp104fs mutation. Additionally, patients experienced adult-onset symptoms and mostly mild neuropathy. Only one patient had moderate neuropathy. Symptoms and characteristics of their conditions included:

• Sensation loss in legs, feet, and/or upper limbs
• Poor balance
• No deep tendon reflexes
• Muscle weakness in the limbs and hands
• Impaired fine motor skills

Additionally, one patient required mobility assistance. Finally, researchers determined that patients with MPZ haploinsufficiency did not transmit nerve signals quickly. Similar symptoms and signs were observed in mice models.

Ultimately, researchers determined that MPZ loss-of-function mutations cause mild sensory neuropathy in patients. In many cases, this neuropathy will not appear until adulthood. By understanding these mutations and how they work, researchers also believe that new treatments can be developed. These treatments could potentially be more targeted and focus on deficient MPZ proteins.

Charcot-Marie-Tooth Disease (CMT)

Charcot-Marie-Tooth disease (CMT) is a rare condition which causes peripheral nerve degeneration. Despite its “rare” status, CMT is also considered one of the most common inherited neurological disorders. While most cases are inherited, some patients develop CMT based on spontaneous gene mutations. As the peripheral nerves degenerate, it inhibits communication between the nerves and muscles. Typically, CMT onset occurs in adolescence or early adulthood. In rarer cases, like those explained above, symptoms may appear later in adulthood. Symptoms include:

• Curled toes (hammertoes)
• High arches
  • Note: In addition to the two physical characteristics listed above, CMT is also associated with a number of other foot deformities.
• Frequent tripping and/or falling
• Foot and lower leg muscle weakness
• Difficulty walking
• Fatigue
• Scoliosis (abnormal spinal curvature)
• Muscle weakness and atrophy in the hands
• Lower leg deformities caused by muscle loss
• Foot drop
• Poor circulation, resulting in cold hands and feet
• Difficulty with fine motor skills