First Portuguese Family Identified With CMT Type 2 Caused by NEFL Genetic Mutations

Researchers have identified the first Portuguese family with Charcot-Marie-Tooth disease type 2E — caused by rare mutations in the NEFL gene — with family members showing different symptoms.

The case report, “The first Portugese family with NEFL-related Charcot-Marie-Tooth type 2 disease,” was published in the journal Acta Myologica.

Mutations in the neurofilament light-chain polypeptide (NEFL) gene are the cause of 2% of all CMT cases, including the so-called axonal CMT (CMT2E) and demyelinating CMT (CMT1F). Neurofilaments are the structural elements that control the size and shape of nerve cells.

In CMT2, the mutations affect the axons (nerve fibers or the long projections of a nerve cell), and in CMT1, the defects are seen in the myelin protective layer, the fat-rich substance that wraps around nerve fibers. Both disease subtypes show clinical differences.

In the report, researchers describe the first case of NEFL-related CMT type 2 in Portugal with two related Portuguese adults carrying a mutation that causes CMT2E.

Both individuals had a missense mutation (an error which changes the encoded amino acid or protein building block) known as c.794A > G (p.Tyr265Cys) in the NEFL gene. This mutation had already been identified in an Australian family with CMT. Neurophysiological analysis was consistent with the patients having axonal CMT disease.

The first patient was a 68-year-old woman. At 42, she experienced feet numbness and gait difficulties, which worsened over time. A neurological examination when she was 66 showed that she had ataxic gait (staggering movements with a wide gait). However, she did not show muscle weakness in the upper and lower limbs. Stretch reflexes were absent in her lower limbs and decreased in her upper limbs.

The second patient was the woman’s 47-year-old daughter, who showed increasing gait difficulties at age 33 and was diagnosed later with bilateral pes cavus (a type of foot deformity), hammer toe deformity in the left foot, and an inverted champagne appearance of the legs. She also showed muscle weakness in specific feet muscles, and no stretch reflexes throughout her body.

“It has long been recognized that NEFL gene mutations are associated with intra-familial phenotypic [observable symptoms] variability,” the researchers wrote.

This was the case with the mother and daughter described in the study, “with the oldest patient presenting an ataxic sensory peripheral neuropathy and the youngest one a classical CMT phenotype,” they said.