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Principal themes included genetic therapies, advances in inherited neuropathies, myostatin biology, advances in mitochondrial disorders and the challenges posed in clinical trials with a particular emphasis of the use of biomarkers to measure the effectiveness of treatments and changes in the progression rate of disease impacts.
Several presentations were of relevance to Charcot-Marie-Tooth disease These were of a highly technical nature in many instances. For an overview of developments specific to Charcot-Marie-Tooth disease, Professor Mary Reilly’s presentation at the Festival is very strongly recommended.
Preliminary data was provided from a survey by the Queen Square team of Magdelena Dudziec, Mary Reilly and Gita Ramdharry (and strongly referencing the support given by UK!) on the use of walking aids by those with Charcot-Marie-Tooth disease together with exploring concerns about balance confidence and levels of physical activity. A cohort of 313 individuals aged between 6 and 94 started the survey with a marked preponderance of female respondents. Charcot-Marie-Tooth disease types were broadly as to be expected with 38% of those involved having Type 1A. Interestingly, 22% were unaware of their Type. Roughly 55% reported using a walking aid of which 30% used a stick, 4% used crutches, 4% used a wheelchair and 8% used one or two hiking poles. 78% of responders reported using other aids when walking including scooters and 45% had bought the aid item themselves. Falls have been identified as a significant issue – my interpretation is that around 75 out of the test cohort had a fall on the basis of between weekly and monthly. More work is continuing to increase knowledge and understanding of walking and physical supports to enable clinicians and patients to be informed of all the options for enhancing balance and mobility.
Newcastle University report that serum protein may act as a Charcot-Marie-Tooth disease biomarker – defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”- as blood proteins may be altered in tissue specific disorders. The group assessed the level of a range of blood proteins in a limited cohort of Newcastle patients including Type 1A, Type 2N and Type 2D mutations. Follow up work involved the use of enzyme-linked immunosorbent assays (ELISA) as an alternative means of measuring antibodies in addition to Polymerase Chain Reaction assay which amplifies DNA from extremely small samples and allows the measurement of cells of interest. Newcastle have identified several potential biomarkers including alterations to serum amyloid and serum transferrin – the former being specific to Type 1. Several proteins have been discovered which increase in Type 1 including biotinidase which has been found to increase in direct proportion to the severity of the disease. A wider evaluation over a longer period of time is proposed to further explore this.
Queen Square reported on the results of monitoring 111 pregnancies in 64 subjects where approximately 50% had been diagnosed with Type 1A and the remainder were spread across various Charcot-Marie-Tooth disease subtypes. Analysis has identified that issues reported so far were generally in line with those encountered across the general UK population. For example, 61% of deliveries were natural, 12% were assisted and 27% were caesarean. The most reported complications were high blood pressure or pre-eclampsia (4%), diabetes and bleeding before 20 weeks. Amongst the complications reported on delivery, slow progress was reported with the highest frequency and at 11% was slightly above the general UK level of 10.59%. Further research is aiming to increase the number of patients surveyed to 100 and the outcome of the survey is intended to inform future gynaecological guidelines on the standard of care.
A report on referrals to the Neuromuscular Complex Care Centre at Queen Square highlighted the need for the increased availability of psychological services to patients with neurological conditions. Referrals more than doubled between 2014 and 2016 and crucially, in the period March-September 2016, approximately 30% of the cases referred involved Charcot-Marie-Tooth disease. The themes arising in the research were anxiety arising from changes in physical condition, vulnerability, fears for the future, concerns over lost opportunities and acceptance by society. Furthermore, patients are worried about encountering barriers to actually accessing effective psychological help at a local level (including physical access to the premises), not meeting referral criteria and have concerns that the therapist did not understand their condition leading to under reporting of anxiety levels and uncertainty that the treatment was actually suitable to their needs.
The frequency of genetic variants in Charcot-Marie-Tooth disease is being researched by Queen Square because whilst next-generation sequencing techniques have significantly improved the rate of diagnosis, an individual human genome contains around 14000 protein-altering variants so making sense of and interpreting genetic variants remains challenging. In essence, the diagnostic challenge has moved from actually obtaining allele or genetic variants to interpreting them. In Charcot-Marie-Tooth disease the challenge is critical because it embraces such a diverse range of disorders and therefore there are more variants involved. It is argued that the frequency of a pathogenic variant in a population sample cannot be greater than the prevalence of the disease it causes. Experience has shown that this principle requires refining in the light of the use of generalised frequency cut-offs across genetic diseases despite the diseases all having unique genetic architectures such as prevalence in the population, inheritance mode, genetic and allelic heterogeneity and population penetration. This was demonstrated by reference to the difficulties around the diagnosis of Charcot-Marie-Tooth disease in the case of a family involving a novel myelin protein zero mutation was discovered in three generations.
Queen Square and the Sobell Department of Motor Neuroscience and Movement Disorders reported on an investigation of mitochondrial dysfunction in Charcot-Marie-Tooth disease . Based on the principle that the 80+ causative genes identified to date lead to mutations which affect proteins with wide ranging functions including the cytoskeleton, mitochondrial function, protein translation and vesicle trafficking as well as the cellular stress response, it is still unclear as to the underlying pathomechanisms of the disease. As a result, there is no disease modifying treatment currently available. It is possible that common pathomechanisms may be involved in different forms of Charcot-Marie-Tooth disease or indeed there may be greater specificity in the cell changes caused by different mutations. Using patient-derived fibroblasts the conclusion has been reached that a subset of Charcot-Marie-Tooth disease-causing mutations in both mitochondrial and non-mitochondrial genes causes defects in mitochondrial membrane potential and changes in network morphology. It is therefore possible that mitochondrial dysfunction could be a common pathomechanism in various forms of Charcot-Marie-Tooth disease.
Combined research by Queen Square, the Sahlgrenska Academy of Gothenburg University, the Trauma and Neuroscience Centre of the Blizard Institute and the London School of Medicine and Dentistry has followed up the negative trials of vitamin C in Charcot-Marie-Tooth disease which highlighted the lack of effective and sensitive outcome measures in the disease. It was proposed that as neurofilaments are neuronal cytoskeletal proteins which are found in abundance (and incidentally are very stable having been extracted from bodies more than 2600 years old) so their concentration in blood might reflect axonal breakdown and act as a biomarker. The theory was tested using 75 Charcot-Marie-Tooth disease patients and 67 age matched controls over a 12 month period. Plasma neurofilaments were found to be significantly higher in Charcot-Marie-Tooth disease patients and showed a direct correlation with disease severity as measured by the weighted CMT Examination and Neuropathy Scores. There was no significant movement in the levels over the period of the trial which was as expected as Charcot-Marie-Tooth is a slowly progressive disease and the timeframe of the trial was insufficient to allow substantial changes to develop. This approach clearly holds promise as a biomarker not only for Charcot-Marie-Tooth disease but for other peripheral neuropathies in general.
Although relating primarily to spinal muscular atrophy, Edinburgh Medical School reported on the targeting of ubiquitin pathways to develop new therapies for neuromuscular conditions. In around 95% of cases, the condition is caused by the deletion of the SMN1 gene which encodes the survival motor neuron protein. In other cases, proteins can be marked for mutation through changes in the ubiquitin-like modifier activation enzyme 1 gene (UBA1). It has been identified that UBA1 dependent pathways have a key role in controlling defective sensory-motor connectivity in spinal muscular atrophy. There is a suggested overlap between spinal muscular atrophy and some forms of Charcot-Marie-Tooth disease and that the restoration of UBA1 proposes a possible route capable of improving a range of disease-related phenotypes across a range of neuromuscular diseases.
The use of nuclear magnetic resonance imaging and spectroscopy as an outcome measure in neurological conditions received a caution from the Neuromuscular Investigation Centre of the Paris Institute of Myology that whilst it had a high reputation for effectiveness, there was a risk that it raised expectations on the part of both patients and consultants which were unrealistic. The measurement of fat fraction employing water-fat imaging is generally robust and precise, establishing the percentage of muscle which has been converted to fat and providing an indication of the disease’s process over time. However, for example, in conditions such as Duchenne muscular dystrophy where the progress of the disease is variable, the analysis of muscle conversion has a limited value as a biomarker. A direct relationship has been shown between muscle water T2 and fat transformation rates – the higher the level of T2, the higher the level of muscle to fat conversion and the higher the conversion progress rate over time. This has been demonstrated to be particularly clear in CMT1A and therefore can be seen as a further marker tool for identifying the progress of the disease.
Written by Mark Edwards, Chair of Charcot-Marie-Tooth UK, who attended the Conference.