Abstract
BackgroundCurrent genetic test algorithms for Charcot Marie Tooth (CMT) disease are based on family details and comprehensive clinical and neurophysiological data gathered under ideal conditions for clinical assessment. However, in a diagnostic laboratory setting relying on external test requisitions and patient samples, such conditions are not always met. Our objective was therefore to perform a retrospective evaluation of the data given in laboratory request forms and to assess their quality and applicability with regard to the recommended algorithms for CMT diagnostics. As we are the main test centre for CMT in Norway our results also provide an overview of the spectrum of gene defects in the Norwegian CMT population.MethodsGenetic testing was performed according to polyneuropathy type; demyelinating/mixed: PMP22 duplication, MPZ, EGR2, LITAF, NEFL, PMP22, GJB1, axonal: MFN2, MPZ, NEFL, and GJB1.ResultsDiagnostic testing of index patients was requested in 435 of the 549 cases. Seventy-two (16.6%) positive molecular genetic findings were made. The majority (94.6%) of mutation positive cases showed disease onset before 50 years of age. PMP22 (duplication), MPZ, GJB1 and MFN2 mutations constituted 95.8% of the positive findings. Within the nerve conduction study groups, mutation detection rates were; demyelinating 33.8%; mixed 29.0%; axonal 8.8%; unspecified 16.5%.ConclusionWe suggest a simplified algorithm intended for referral centres, dealing with DNA/blood samples, which involves the assessment of age at onset and neurophysiological data followed by testing of four genes; PMP22 (duplication), MPZ, GJB1 and MFN2. Patients negative for mutations in those four genes should be subjected to evaluation at an interdisciplinary inherited neuropathy clinic with the capacity for extended molecular genetic analysis by next generation sequencing.
Highlights
Current genetic test algorithms for Charcot Marie Tooth (CMT) disease are based on family details and comprehensive clinical and neurophysiological data gathered under ideal conditions for clinical assessment
To investigate to which extent available clinical information is influencing the success of genetic diagnostics we found it necessary to stratify our patient population in 9 clinical categories as follows; 1: polyneuropathy/CMT − no further information; 2: Symptoms of classical CMT specified; 3: as 2, but more severe; 4: as 2, but with additional hearing impairment, pyramidal features, fasciculations, tremor or white matter changes on MRI; 5: Symptoms of atypical CMT, hereditary sensory and autonomic neuropathy (HSAN) or hereditary motor neuronopathy (HMN) specified; 6: polyneuropathy with additional features not usually seen in association with CMT; 7: healthy; 8: testing with regards to a family mutation, symptoms not specified; 9: requesting physician primarily suspects alternative diagnosis (CIDP, congenital myopathy, etc.)
The present study strongly indicates that none of the genes that have been reported elsewhere to be involved in rare cases of CMT
Summary
Current genetic test algorithms for Charcot Marie Tooth (CMT) disease are based on family details and comprehensive clinical and neurophysiological data gathered under ideal conditions for clinical assessment. As we are the main test centre for CMT in Norway our results provide an overview of the spectrum of gene defects in the Norwegian CMT population. Charcot Marie Tooth disease (CMT) is the most prevalent hereditary neuropathy [1]. The classic clinical picture of Charcot Marie Tooth disease is characterized by muscular atrophy and weakness in the distal parts of the legs, absence of Achilles tendon reflexes, pes cavus, hammertoes and loss of touch and vibratory sensation. Autosomal recessive CMT is called CMT4 and X-linked CMT CMTX independent of the NCV. The recessive CMT4 is associated with an early onset and severe symptoms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
