In a 15-year study, South Korean researchers examined the clinical, genetic, and imaging features of Charcot-Marie-Tooth (CMT) disease in more than 1,100 families with this group of peripheral nervous system disorders who had undergone gene sequencing that revealed on the focused NEFL Gene.
The team identified 10 mutations in NEFL Gen, three of which had never been reported.
These insights can help in evaluating NEFL mutations and help diagnose different CMT subtypes, they found.
The study, “Phenotypic heterogeneity in patients with NEFL– related Charcot-Marie-Tooth disease,‘ was published in the magazine molecular genetics and genome medicine.
Mutations in neurofilament light chain polypeptide (NEFL) Genes are a cause of CMT, including one form called axonal CMT (CMT2E) and another form called demyelinating CMT (CMT1F). They are also a cause of an intermediate subtype that includes both axonal (nerve fiber damage) and loss of myelin, the insulating layer around nerve fibers—traits known as CMTDIG. In particular, CMTDIG is characterized by slow progression and variable age at onset.
Neurofilaments are nerve cell-specific components that control size and shape. mutations on NEFL affect the neurofilament network, affect transport in nerve fibers and the maturation of regenerating nerve fibers. As such, they can lead to multiple CMT manifestations.
In this study, researchers assessed the clinical characteristics of 37 CMT patients – 20 males and 17 females – from 17 families harboring disease-causing or probable disease-causing mutations in the NEFL Gene.
Data were collected from a cohort of 1,889 CMT patients by gene sequencing. Analysis revealed the presence of 10 mutations in the NEFL Gene, three of which were classified as new because they had not been reported in genetic databases. The three new mutations are now known as p.L312P, p.Y443N and p.K467N.
The p.L312P mutation was found in one CMTDIG patient, while the other two new mutations were found in individuals with CMT2E.
Four previously reported mutations were identified in CMT1F patients, while two additional mutations were found in participants with CMTDIG alongside p.L312P.
A specific mutation – p.E396K – has been detected in both CMT1F and CMTDIG patients. Two other mutations in addition to p.Y443N and p.K467N were found in the CMT2E group.
Most patients wear NEFL Mutations revealed the classic CMT trait of peripheral neuropathy, or damage to nerves outside the brain and spinal cord, and additional symptoms. These other symptoms included delayed walking, incoordination, difficulty swallowing, speech disorders, dementia, drooping of the upper eyelid, waddling gait, tremors and hearing loss.
Motor abnormalities were observed early, at or before 3 years of age, in five patients. Problems with coordination were the most common symptom in NEFL-related CMT patients detected in 78% of patients with CMT1F, 79% in the CMTDIG group and half of CMT2E patients.
Neuroelectrophysiology studies – which examine how electrical signals are transmitted through nerves in the body – showed that peroneal nerve responses were often significantly reduced in CMT1F patients. The peroneal nerve is a branch of the sciatic nerve that provides movement and sensation to the lower legs, feet, and toes. In contrast, only one in four CMT2E patients showed similar changes, while the CMTDIG group showed intermediate results.
MRI analyzes of the legs showed varying degrees of fat infiltration in the muscle. Comparing patients with similar disease duration (19 to 20 years) but different clinical characteristics, one patient with CMT1F showed severe fat infiltration in the thigh, while one participant with CMT2E and another with CMTDIG showed mild or minimal fat infiltration. In the calf muscles, the same patients showed different patterns of fat infiltration affecting all muscle compartments of the participant with CMT1F.
Overall, “The clinical, genetic, and imaging results of this study may be helpful in evaluating novels NEFL Variants and differential diagnosis versus other CMT subtypes,” the scientists concluded.