Abstract for presentation at 11th International Congress of Human Genetics

Clinical features of CMT associated with mutations in the neurofilament light chain polypeptide gene

  • Gabriel Miltenberger-Miltenyi, Dept. of Medical Genetics and Molecular and Clinical Pharmacology, Innsbruck Medical University, Austria, Austria
  • MD, PhD Wolfgang Loescher, University Clinic of Neurology, Innsbruck Medical University, Austria, Austria
  • Dr Julia Wanschitz, University Clinic of Neurology, Innsbruck Medical University, Austria, Austria
  • Dr Andreas Janecke, Dept. of Medical Genetics and Molecular and Clinical Pharmacology, Innsbruck Medical University, Austria, Austria
  • MD, PhD Michaela Auer-Grumbach, Medical Research Center, Medical University Graz, Austria, Austria
  • Dr Christian Windpassinger, Institute of Medical Biology and Human Genetics, Karl-Franzens-University Graz, Austria, Austria

    • Background: Mutations in the neurofilament light chain polypeptide (NEFL) were originally described in patients with the axonal form of Charcot-Marie-Tooth disease (CMT). Following the initial report, however, NEFL mutations were also associated with demyelinating and axonal variants. To date, 48 CMT patients from 15 families have been reported with NEFL mutations. We report 11 additional CMT patients harboring two different mutations in highly conserved regions of NEFL, one of which is novel.
    Methods: Standardized neuromuscular and nerve conduction studies were performed, and the coding regions of PMP22, MPZ and NEFL were analyzed by direct DNA sequencing in two families and one additional patient affected by severe CMT.
    Results: A novel NEFL mutation (p.L93P) was revealed in one family. The clinical phenotype was severe and similar in all 4 affected individuals and nerve conductions were intermediately slowed to 35-39 m/s. In the other family and in the sporadic patient, a p.P8R mutation was identified. p.P8R was associated with highly variable disease expression, classified as CMT1 in 2, and CMT2E in 5 cases.
    Conclusion: Our results argue against an obvious genotype-phenotype correlation regarding disease onset, degree of muscle weakness, as well as nerve conduction slowing caused by NEFL mutations. However, a more pronounced interfamilial than intrafamilial disease variation is apparent. Genetic testing of CMT patients should include a screen of the NEFL gene which should not be restricted to axonal or intermediate types of CMT.

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