MARS Mutations Linked to Axonal, Intermediate Early-onset Forms of CMT

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Mutations in the MARS gene can cause axonal and intermediate childhood-onset forms of Charcot-Marie-Tooth disease (CMT), according to a study of two unrelated Chinese families.

While MARS mutations were reported initially to cause an axonal form of CMT, these findings add to previous studies suggesting a link between such mutations and a wide range of clinical manifestations that also includes intermediate forms of CMT.

The study, “Clinicopathological features in two families with MARS-related Charcot–Marie–Tooth disease,” was published in the journal Neuropathology.

CMT comprises a group of inherited progressive diseases that affect the peripheral nervous system, which controls movement and sensation in the limbs. It is divided mainly into “demyelinating CMT,” also known as CMT type 1, and “axonal CMT,” or CMT type 2 (CMT2).

Demyelinating CMT is characterized by progressive demyelination, or the loss of myelin, the protective sheath around nerve fibers, or axons, that allows fast transmission of signals to the next nerve or muscle cell. Axonal CMT is characterized by the degeneration of these axons.

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This differentiation is based on results of nerve conduction velocity tests, which measure how quickly electrical impulses move along a nerve cell. Markedly slow velocities reflect myelin damage, while higher velocities indicate axonal damage. Intermediate values suggest an intermediate form of CMT, with both demyelination and axonal injury.

Mutations in the MARS gene, which provides instructions to generate an enzyme involved in protein production, have been reported to cause CMT type 2U (CMT2U), a slowly progressive axonal form with a late-adult onset.

However, other studies described cases of MARS-associated CMT that did not fulfil the diagnostic criteria of axonal CMT. These reports suggest that MARS mutations may cause a large range of clinical and neurological features within the CMT spectrum.

Now, a team of researchers in China described the genetic, clinical, and neurological characteristics of two unrelated families with members diagnosed with MARS-associated CMT.

In one family, an 18-year-old male was affected by an axonal form of the disease (based on nerve conduction studies), while both of his parents were healthy. Genetic testing showed that he and his mother carried the previously reported, disease-causative p.P800T mutation in one of the two copies of the MARS gene.

Since his mother did not develop the disease, the team hypothesized there was incomplete penetrance of the disease, which occurs when some people carrying a disease-associated mutation develop the disease, while others do not.

In the other family, CMT affected three generations: a 10-year-old girl, her 32-year-old mother, and her deceased grandmother. Nerve conduction tests highlighted intermediate axonal and demyelinating features in both the girl and her mother, who were found to carry a new mutation (p.R199Q) in one of MARS copies.

Due to its location and resulting swap of an amino acid (proteins’ building blocks) in the generated enzyme, this mutation is likely to disrupt the enzyme’s normal structure, which ultimately may affect its function and the production of other proteins.

All patients presented with childhood-onset, length-dependent sensory and motor nerve damage with pes cavus, or feet with an abnormally high arch. Length-dependent nerve damage means that it affects the farthest nerve endings in the feet first.

Patients from both families also showed signs of demyelination and onion bulbs, which are specific structures associated with repeated cycles of myelin loss and repair. However, demyelinating signs were more pronounced in the family with the intermediate form of CMT.

Moreover, both MARS mutations were associated with the abnormal accumulation of neurofilaments close to damaged mitochondria inside axons — a feature not reported in previous cases of MARS-related CMT. Neurofilaments are major structural proteins of nerve cells; mitochondria are cells’ powerhouses.

MRI revealed significant differences between the two forms, with thickened spinal nerve roots — the fiber bundles that come off the spinal cord — being detected only in the two females with intermediate CMT.

Previous research suggests this “may be caused by the demyelination and remyelination [myelin repair] processes as well as the disruptions in the blood–nerve barriers,” the researchers wrote.

These findings expanded the clinical spectrum of MARS-associated CMT and highlighted that “MARS mutations cause not only the known axonal type but also intermediate type,” the team added.

This information may be “useful for the differential diagnosis of CMT patients with unknown MARS variants,” the researchers wrote.