Researchers have demonstrated the genetic and clinical characteristics of a rare form of Charcot Marie Tooth Disease (CMT), an incurable genetic disease of the nerves that causes progressive and debilitating muscle weakness and sensory loss.
A team led by Professor Mary Reilly carried out a literature review and studied cases of CMT caused by mutations in the neurofilament light (NEFL) polypeptide gene, which account for less than 1% of cases. NEFL-related CMT can be detected from a DNA sample extracted from blood.
Results of the case study literature review showed:
- Five new unrelated patients with CMT carrying the NEFL mutations P8R and N98S and the novel variant L311P
- Four common mutations (P8R, P22S, N98S and E396K)
- Three mutational hotspots accounting for 37 (55%) and 50 (75%) kindreds, respectively.
- Eight patients had de novo mutations (a genetic alteration that is present for the first time in one family member)
- Loss of large-myelinated fibres was a uniform feature in a total of 21 sural nerve biopsies and ‘onion bulb’ formations and/or thin myelin sheaths were observed in 14 (67%) of them.
- The neurophysiological phenotype was broad but most patients with E90K and N98S had upper limb motor conduction velocities <38 m/s. Age of onset was ≤3 years in 25 cases.
UCLH clinicians have seen a number of patients with NEFL mutations present with a range of symptoms including: early motor development delay, hearing loss, muscle weakness and cerebellar ataxia. As a result of the literature review, published in the Journal of Neurology, Neurosurgery, and Psychiatry, the team discovered 7 patients were initially diagnosed with or tested for inherited ataxia. Professor Reilly said: ““Our review of the literature identified 62 other kindreds with NEFL mutations. What was striking, because of the complexity of the phenotype and pyramidal tract signs, was that 7 out of the 62 had initially been diagnosed or tested for spinocerebellar ataxia or Freidreich’s ataxia. Therefore, it is important to highlight this phenotype to prevent misdiagnosis.”
