A Case of Charcot-Marie-Tooth Neuropathy Type 2E/1F Likely Due to A Novel NEFL Mutation



Poster Number: 178


Fang Sun, MD PhD, Department of Neurology, University of Pittsburgh School of Medicine, Sasha Živković, MD PhD, Department of Neurology, University of Pittsburgh; Department of Neurology, Yale School of Medicine, Paula Clemens, MD, University of Pittsburgh, David Lacomis, MD, UPMC/ Univ Pittsburgh

Hereditary neuropathy, commonly referred to as Charcot-Marie-Tooth disease (CMT), is associated with increasing numbers of causative genes, and a condition in need of targeted therapy. CMT type 2E/1F is caused by neurofilament light chain (NEFL) gene mutation. Various clinical phenotypes have recently been reported with this condition. In this study, we report a case of CMT neuropathy likely associated with a novel pathological variant in NEFL.

A 34-year-old right-handed white man presented to our clinic in 2008, with progressive right leg weakness and difficulty walking. He had tremors in the hands since childhood and was never athletic. He had trouble reading five years prior and was found with pallor of the right optic disk. He reported that a brother also had leg weakness. On examination, bilateral pes cavus, hammer toes and distal wasting were noted. He had decreased sensation in distal lower and upper extremities. Reflex was absent in the upper extremities, however, was preserved in the lower extremities.

Evaluation for potential central nervous system abnormality was unrevealing. EMG demonstrated evidence of a chronic length-dependent mixed axon loss and demyelinating sensorimotor polyneuropathy. There was no evidence of acquired demyelination. Motor nerve conduction velocities were intermediately slowed. EMG findings overall were thought compatible with CMT. Genetic testing for 9 known CMT associated genes was pursued in 2009, which was negative.

At subsequent clinic follow-up visits, his weakness slowly progressed. In 2020, he started to need a wheelchair for ambulation. Genetic testing for CMT was pursued again in 2018, with 72 known genes included at this time. It reported a heterozygous variant of uncertain significance in NEFL, c.668T>C (p. Leu223Pro). The patient was referred to genetic counseling, and a family pedigree was obtained. Genetic testing was subsequently performed on his brother and mother, which both revealed identical variant in NEFL as the patient. Of note, brother’s EMG reported similar features as the patient’s, while mother’s EMG findings were unremarkable.

Our findings in this case likely revealed a novel pathological variant in NEFL gene and have implications for expanding molecular diagnostics. Further functional characterization of this novel variant is needed.