Thanks to your support, over the past two years we have had the opportunity to carry out some exciting research on Charcot-Marie-Tooth disease and related neuropathies at the MRC Centre for Neuromuscular Diseases. We always strive towards translating our research findings into concrete patient benefit.
Over the course of this research project, we have mainly focused our efforts on CMT1A. While most CMT1A patients carry the same-sized duplication on chromosome 17, the severity of the disease is highly variable, even within a single family. Identifying genetic factors modifying disease severity will help in counselling patients and predicting disease course and in the future may help identify drug therapy targets. We have collected DNA samples and clinical descriptions of over 200 CMT1A patients. We have sequenced the PMP22 gene to determine whether certain variants might be associated with severe or mild disease. Although most variants were too rare to be able to correlate with disease severity in a meaningful way in our study, the variants identified will be carried forward to a larger study with international collaborators.
We have also identified 6 CMT1A patients in our cohort who have atypical, shorter duplications encompassing PMP22 on chromosome 17. This is a very important finding as these atypical duplications would have been missed by using the older diagnostic methods of detecting the CMT1A duplication.
Genetic modifiers are likely to play a role in other types of CMT and not solely in CMT1A. For example, in a CMT1 patient with a PMP22 mutation and a particularly severe phenotype, we have found a small deletion in a completely different part of the genome. This genetic abnormality is likely to be responsible for the additional disease features seen in this particular patient. We predict that such variations might explain some of the variability in disease severity.
Various cases of superimposed inflammatory neuropathy have been reported in CMT1A. We have therefore performed a genome-wide analysis of CMT1A patients compared to controls to ascertain whether common genetic variations associated with autoimmune and inflammatory diseases might account for some of the disease variability in CMT1A. Results are promising but still very preliminary, and will need to be confirmed in a larger cohort of CMT1A patients.
To gain a clearer idea of the frequency of different CMT subtypes in various populations, we have screened CMT genes in CMT cohorts coming from diverse geographical areas around the world. This study will assist clinicians in targeting genetic tests, and will also help to clarify the relationship between different genetic mutations and disease symptoms.
As some CMT patients do not have mutations in the genes known to be associated with CMT, we are using an exciting and recent technique called exome sequencing which allows us to sequence all the coding regions of the genome to search for novel genetic causes of CMT. Obtaining a genetic diagnosis is essential in providing accurate counselling and eventually in targeting disease treatments.
In order to provide more efficient and cost-effective genetic diagnostic tests, specifically for the rare subtypes of CMT which are not readily available for routine testing, we are developing panels of CMT genes which allow simultaneous testing of a large number of genes. Importantly, these panels will also allow us to identify disease modifiers.
Finally, we have begun working on a neuropathy related to CMT, called Brown-Vialetto-Van Laere syndrome (BVVL), which affects children at a very young age and also causes hearing loss and diaphragmatic paralysis. We all have genes encoding each of three riboflavin transporters. These transporters are all responsible for carrying vitamin B2 into the cell (to different extents depending on the cell type and location in the body). BVVL results from a mutation in any one of these three transporters (therefore vitamin B2 is no longer able to get into the cell quite as readily as normal when one transporter is mutated). We have identified several new cases of this rare disease, and have done some experiments on patient cells which have suggested a possible disease mechanism. Importantly, some of these patients have significantly improved upon treatment with high doses of vitamin B2.
Again, we would like to thank you for making this research possible. This research funded by CMTUK has already allowed us to improve our rate and accuracy of genetic diagnosis in the UK. It has also allowed us to identify the genes and a promising treatment for a rare genetic neuropathy, BVVL, which will help us understand the commoner forms of CMT. Most importantly our work on identifying genetic factors which affect the severity of CMT1A has become the basis for a large international research programme to study these factors further with a special aim to identify drug targets. Our study showed that we probably need about 2000 CMT1A patients to do this and this is now under way. We are confident that each small step we have taken has brought us closer to improving genetic diagnosis, patient counselling, our understanding of the disease mechanisms in CMT and related neuropathies and eventually to developing therapies.
(University College London Institute of Neurology)
This research project has been 50% funded by CMT United Kingdom (£30,000) over a 3 year period.