MORC2 Mutation Causes Severe Neuropathy in CMT2Z, Case Report Finds

Aisha I Abdullah PhD avatar

by Aisha I Abdullah PhD |

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MORC2 mutation and CMT2Z

Three people from two unrelated families were found to have Charcot-Marie-Tooth disease type 2Z (CMT2Z) caused by the same MORC2 mutation, called p.Ala406Val, which was linked to severe neuropathy, a case study reported. 

One patient’s condition also worsened following treatment with vinblastine for Hodgkin’s lymphoma, and scientists recommended use of this cancer medicine be carefully monitored in people with CMT.

“The identification of two additional, unrelated families with the same p.Ala406Val mutation demonstrates the pathogenic role of this mutation,” the investigators wrote. “In addition, we report the first case of vinblastine neurotoxicity in Charcot‐Marie‐Tooth disease type 2Z.

The study, “A recurrent MORC2 mutation causes CMT2Z,” was published in the Journal of the Peripheral Nervous System

CMT2Z results from mutations in the MORC2 gene that impair the activity of peripheral nerves, which connect the brain and spinal cord to the muscles in the limbs. The disease typically affects the distal nerves (those furthest from the body center) before progressing to proximal (body center) nerves. 

The most common MORC2 mutation linked to CMT2Z, called p.Arg252Trp, causes distal muscle weakness and loss of sensation. Other MORC2 mutations are associated with a variety of symptoms unrelated to neuropathy (damage to peripheral nerves). 

Now, researchers report the case of three individuals with CMT2Z — a father and son and an unrelated woman — all carrying the MORC2 mutation p.Ala406Val. 

The 33-year-old woman had a history of clumsiness as a child, and experienced cramping and fatigue as her earliest symptoms. She had severe distal muscle wasting and weakness in her distal muscles (hands, forearm, feet, and ankles), as well as a lack of response to stimuli in muscles in the feet, forearms, and left calf. Her father had neuropathy affecting his upper and lower limbs.

A man in a different family had difficulty lifting the front of his foot — a condition known as foot drop — which began when he was in his late 20s. By age 61, he had severe muscle weakness in his ankles, biceps, and shoulders, sensory loss in his toes and thumbs, and a lack of response to muscle stimuli.

The man’s son developed neuropathy and was diagnosed with CMT as a child. He experienced frequent ankle sprains, and, as a teenager, underwent surgical fusion of joints and surgery to replace poorly working muscles and tendons in the foot.

The son was also diagnosed with Hodgkin’s lymphoma while a college student, and given a variety of cancer medications. Among them was vinblastine, which belongs to a class of therapies called vinca alkaloids that have been linked to neurotoxicity in people with CMT. Following his treatment, the patient lost the ability to walk upstairs unsupported by a handrail. 

By age 31, he had mild-to-moderate muscle weakness in his hands, biceps, shoulders, and triceps, sensory loss in his toes, and a lack of response to muscle stimuli. Muscle weakness progressed, with him using a walker starting at 32 and a wheelchair at age 41, with severe nerve and sensory loss in his arms, and moderate CMT neuropathy.

Genetic tests revealed that all three patients had the same MORC2 mutation, p.Ala406Val (c.1217C>T). In all three cases, neuropathy and distal muscle weakness emerged relatively early and progressed to proximal muscle weakness.

These findings confirm “that the p.Ala406Val mutation in MORC2 causes severe neuropathy,” the researchers wrote.

Regarding the patient given vinblastine for his lymphoma, the team noted: “this may be the first case of neurotoxicity in a person with CMT2Z.” 

“Although [the vinca alkaloid] vincristine is well documented to cause neuropathy, this complication is less common for vinblastine … it seems prudent to carefully monitor a patient with CMT for whom therapy with any vinca alkaloid is being considered,” they added.