Clinical Variability of Charcot-Marie-Tooth Disease and its Association with Neurofilament and Genetic Type of Disease. Summary of the Doctoral Thesis
Authors:   ,   Rīga Stradiņš University, Kalniņa Elīna 
Published: May 2023

Charcot-Marie-Tooth (CMT) disease is a slowly-progressing, clinically and genetically very heterogeneous disease. There are disease causing variants associated with CMT in almost 100 different genes, which may have very different phenotypes between subtypes and within a single subtype. Until now no specific treatment for the disease is currently available. The lack of specific disease progression biomarkers limits the execution of clinical trials, however, different biomarkers have been studied. One of the most promising is neurofilament light chain (NfL) that has been suggested as a potential biomarker for peripheral nervous system disorders, although previously more studied in central nervous system disorders. Aim of this study was to determine and describe the association between clinical variability of CMT disease and the neurofilament light chain concentration as well as the genetic type of CMT. In this study the genetic type of disease and NfL concentration association to the clinical heterogenity has been evaluated. The study included 101 CMT patients, aged 5 to 81 year old as well as a control group (n = 60), aged 5 to 62 year old. Genetic testing included peripheral myelin protein 22 (PMP22) gene copy number detection and exome sequencing (ES). In the clinical evaluation CMT disease-specific severity scales was used as well as aditional neuropathic and musculosceletal pain, anxiety level, and memory / cognitive abilitiy testing was done. Neurophysiological analysis included evaluation of nerve condution study data. Blood plasma NfL concentrations were measured using the single-molecule array (Simoa) NfL assay. After determining the PMP22 copy number variations, the CMT diagnosis was confirmed in 45.8 % of cases, while after ES – in 77.8 % cases. Most common confirmed genetic type was CMT1A, caused by PMP22 duplication, followed by CMTX1, caused by GJB1 gene disease causing variant. Evaluation of disease severity indicated high clinical variability between genetic groups as well as within one genetic type group. At least mild anxiety level was present in fifth (20.7 %) of patients, twice as much (41.0 %) patients reported pain – these patients had significantly more common at least low levels of anxiety. The time from the onset of the first symptoms to the CMT diagnosis was more than 13 years. The NfL concentration was significantly higher in the CMT disease patient group than in the controls (p < 0.001). Of the CMT disease patients, those with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (p = 0.0498). The NfL concentration had a significant, but weak correlation with the disease severity score (rs = 0.25, p = 0.012). Receiver operating characteristic (ROC) analysis showed that an NfL concentration of 8.9 pg/ml could be used to discriminate CMT disease patients from controls. The study raises awerness of the CMT clinical and genetic profile in the Latvian population, as well as confirms the high clinical heterogenity of the disease. The time spend from first symptoms to confirm diagnosis should be improved by the initial testing of PMP22 duplication / deletion followed by ES. Genetic type was not associated with clinical severity, however CMTX1 patients tended to have more severe phenotype compared to other CMT types, especially in males. The data confirms that plasma NfL levels in patients with CMT are significantly higher than in controls, in addition, plasma NfL levels are significantly, albeit weak, reflecting the disease severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT disease.