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- HMSN (Charcot–Marie–Tooth)
- mitochondrial disorders
- muscle disease
- mitochondrial disorders
- paediatric neurology
Charcot–Marie–Tooth disease (CMT) is a group of inherited disorders of the peripheral nerves.1 Clinical diagnosis of CMT can be made fairly accurately, and the clinical classification is very helpful in the identification of new disease genes. Thus far, approximately 40 genes have been implicated in CMT, but at present only a limited number of genes can be routinely tested worldwide, including the UK (http://www.ukgtn.nhs.uk/).
All types of CMT are thought to affect approximately 5–40 per 100 000 individuals.2 A previous epidemiological study in the northeast of England in 1978 identified a lower point prevalence of CMT of 4.9 per 100 000.3 We re-evaluated the prevalence of CMT in this region, and report prevalence data for hereditary neuropathy with liability to pressure palsies (HNPP) in Northern England for the first time.
Patients and methods
The population of Northern England (Northumberland, Durham, Cumbria, parts of Yorkshire and Lancashire) is estimated at 2.99 million people with 259 500 in Newcastle upon Tyne, based on the 2001 UK census (Office of National Statistics; http://www.ons.gov.uk/). The Northern Genetics Service is defined by the boundaries of primary care trusts (online supplementary material) and the Newcastle upon Tyne Hospitals Foundation Trust. We identified patients in the Northern region who were alive on the prevalence day (1 September 2010) and had a clinical diagnosis of CMT through three prospective databases curated between 1995 and 2010: the neurogenetics clinical service, the molecular diagnostic service and the clinical neurophysiology service. The diagnosis was confirmed by neurologists based on the clinical presentation, positive family history, electrophysiological studies and, when possible, molecular genetic testing. All patients including axonal CMT were screened for the common duplication/deletion in PMP22 and if family history did not exclude an X linked inheritance, for mutations in GJB1. In patients negative for these tests, MPZ analysis has been performed.
Patients from the clinical neurophysiology service were selected by the electrophysiology reports and if available by supporting family history. The type of neuropathy was defined by motor nerve conduction velocities (NCVs) of one upper limb nerve (medianus or ulnaris NCV<38 m/s, normal amplitudes: demyelinating; NCV>38 m/s, decreased amplitudes: axonal; NCVs between 25–45 m/s, both demyelinating and axonal: intermediate).
In both groups, we identified individuals with symptoms only and no attempt was made to identify family members who had not presented to clinical services. Data were cross-checked between databases to prevent duplication.
A total of 352 individuals from 275 families with a clinical diagnosis of CMT or HNPP were living in the Northern region on the census day, giving a minimal prevalence of 11.8 per 100 000 (95% CI 10.5 to 13.0). There was a slight male predominance (196 men/156 women), which cannot be only due to X linked CMT (12 men/7 women).
Detailed information was available in 244 individuals identified from the Northern Genetics Service (figure 1A).
Of 108 patients identified through the neurophysiology service, 15 had a molecular diagnosis (HNPP n=10, CMT1A (PMP22 duplication positive) n=5). The remaining patients had an electrophysiological diagnosis of axonal (n=17), demyelinating (n=43) or intermediate (n=8) neuropathy or HNPP (n=25).
Most CMT epidemiology studies were performed between 1970 and 1991, before the identification of causative genes (figure 1B).1 The lowest number, 4.9 per 100 000, was reported in the North of England in 1978.3 The data we present here indicate a higher combined prevalence of CMT and HNPP: 11.8 per 100 000 in the North of England and 23.5 per 100 000 in the city of Newcastle upon Tyne. The prevalence of CMT (15.2 per 100 000) and HNPP (7.3 per 100 000) independently were most accurately estimated by examining data from the city of Newcastle upon Tyne, where case ascertainment is likely to be more complete.
The frequently cited high prevalence data (41 per 100 000; 82.3 per 100 000) had been reported in Norway.2 4 These numbers reflect a much higher prevalence for CMT than in any other European countries (figure 1C). This may be due to the relatively isolated genetic population, although geographically close populations such as Iceland, Sweden and Finland show much lower prevalence rates. We rather think that the difference is due to selection criteria, since family members of index cases were intensively investigated in the Norwegian study. If we compare our data (figure 1C) with the prevalence of CMT in other populations (figure 1B), we think that more a realistic minimal prevalence for CMT in Europe is likely to be 10–28 per 100 000.
We emphasise that these data reflect minimal prevalence and by our selection method we are most likely missing some patients with CMT for the following reasons. We collected data from the tertiary referral centre, and some individuals may access services elsewhere in the region. Some individuals may have had clinical and electrophysiological work-up before 1995. Since electrophysiology cannot be used to definitely diagnose CMT, some patients may have been labelled as chronic inflammatory demyelinating polyneuropathy (CIDP). Additionally, some individuals may have few symptoms and have not presented to services.
By looking at the 222 patients seen at the neurogenetic clinic (56.7% CMT1, 17.6% CMT2, 8.7%, CMTX), the frequency of CMT1 is lower than usually quoted,1 but is comparable with data previously reported in the UK and Spain (56% South Wales; 54% Spain). In all, 42.8% of CMT patients have CMT1A, which is also slightly lower compared with previous studies (50%). It is possible that patients without a genetic diagnosis were more likely referred to our service. Other CMT types (CMT4, intermediate) were detected in 17.1%.
We estimated that the prevalence of HNPP in Newcastle is 7.3 per 100 000. This is likely to be an underestimate due to the insidious nature and variable penetrance of the disease. One comprehensive study in Finland identified a much higher prevalence of 16 per 100 000.5 As HNPP and CMT1A are believed to be due to a reciprocal recombination event, the population frequency should be similar, although the lower prevalence of HNPP may be explained by lower penetrance.
In conclusion, CMT is a chronic disease requiring long-term medical and social support. The prevalence figures give some indication of the burden of disease in the region and could be used to guide the allocation of resources for clinical management and for research into new therapies.
We are very thankful for the orthotic work of Paul Charlton (Peacock's) and the support of Dr David Bourne and Judith Goodship from the Northern Genetics Service.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
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Funding This work was supported by the Medical Research Council Translational Neuromuscular Centre. RH is supported by the Medical Research Council (G1000848) and the Academy of Medical Sciences, UK (BH090164). PFC is a Wellcome Trust Senior Fellow in Clinical Science, and also receives funding from the Parkinson's Disease Society (UK), the Medical Research Council Translational Muscle Centre and the UK NIHR Biomedical Research Centre in Ageing and Age-related Disease.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was approved and performed under the ethical guidelines issued by our institutions for clinical studies.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The corresponding author declares that all authors and contributors have agreed to conditions about data sharing noted on the Authorship Agreement Form.
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