In Spain, a young child showed signs of muscle atrophy and difficulty walking; she wasn’t quite stable on her feet and struggled with balance and coordination. But it wasn’t until she was 47 years old that the woman was diagnosed with chronic nerve damage. Then, it took 7 more years before she received a diagnosis of Charcot-Marie Tooth disease (CMT). Researchers found that she had a novel gene mutation in EGR2, called P397H. But their research showed something groundbreaking: despite the mutation not causing CMT directly, its concurrent presence alongside a non-disease causing LITAF gene mutation ultimately caused CMT development in this woman and her family. Find the full case study in Neurology Genetics.
Family Disease
When the woman first visited the doctor about her condition, she displayed:
- High foot arches
- A shortened Achilles tendon
- Muscle weakness
- Moderate/severe muscle atrophy in her upper and lower limbs
- Loss of fine motor skills
- Poor reflexes
Next, doctors performed genetic analyses to determine whether the woman’s condition was caused by previously known CMT-related mutations. However, they found no disease-causing variants. At the same time, they did find two non-disease causing mutations: the novel EGR2 mutation, and an LITAF mutation.
Normally, the EGR2 gene stimulates myelin production by Schwann cells. For context, myelin is a combination of proteins and phospholipids which forms a protective shield around nerves. Normally, EGR2 mutations cause CMT type 1D, while LITAF mutations cause CMT type 1C. But again, in this situation, neither mutation was disease-causing – at least not on its own.
Studying CMT and Genetic Mutations within the Family
After isolating these mutations, researchers then performed genetic tests on the woman’s family. Altogether, they discovered:
- Family members with just the LITAF mutation OR the EGR2 mutation had no CMT-related symptoms.
- However, those with both mutations developed CMT.
Next, researchers tested the ERG2 mutation on lab-grown cells. Although the mutation didn’t affect protein levels or stability, it did make proteins less active. Because of this, myelin production was inhibited. When EGR2 mutations are alone, the body can still produce enough myelin. However, combined with LITAF, which altered protein abundance, Schwann cells were unable to produce myelin.
Charcot-Marie-Tooth (CMT) Disease
Charcot-Marie-Tooth disease (CMT) is an inherited motor disorder, also referred to as hereditary motor and sensory neuropathy. Gene mutations cause the disorder, and symptoms vary based on mutation type. In fact, over 40 different genetic mutations have been linked to CMT development.
These genetic mutations cause peripheral nerves (on the brain and spinal cord) to degenerate. This prevents the nerves and muscles from communicating, leading to muscle weakness or issues with coordination.
Generally, symptom onset occurs in adolescence or early adulthood. However, in some cases, symptoms may not appear until mid-adulthood. Symptoms of CMT include:
- Difficulty with walking, grasping objects, writing, or other activities requiring fine motor skills
- Foot and lower leg deformities, including high arches and hammertoes
- Muscle cramping
- Nerve pain
- Muscle weakness and atrophy in the hands, lower legs, and feet
- Foot drop, or difficulty lifting the foot at the ankle
- Frequent tripping
- Cold hands and feet
Learn more about Charcot-Marie-Tooth disease.
