Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: CMT type 1 (CMT1; demyelinating form) and CMT type 2 (CMT2; axonal form). The objectives of this study were to systematically review and assess the quality of studies reporting the incidence and/or prevalence of CMT worldwide. Summary: A total of 802 studies were initially identified, with only 12 meeting the inclusion criteria. CMT prevalence was reported in 10 studies and ranged from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. The frequency of the main subtypes varied from 37.6 to 84% for CMT1 and from 12 to 35.9% for CMT2; the country with the lowest prevalence of CMT1 was Norway, and the country with the highest prevalence of CMT1 was Iceland; on the other hand, CMT2 was least prevalent in the United Kingdom and most prevalent in Norway. Key Messages: This review reveals the gaps that still exist in the epidemiological knowledge of CMT around the world. Published studies are of varying quality and utilise different methodologies, thus precluding a robust conclusion. Additional research focusing on epidemiological features of CMT in different nations and different ethnic groups is needed.

Charcot-Marie-Tooth disease (CMT) was first described in 1886 by Charcot and Marie in Paris, and Tooth in London, and was referred to as ‘peroneal muscular atrophy' [1,2.] It is part of a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies with a prevalence of 1/2,500 people; it is the most frequently inherited neuropathy and one of the most common neurogenetic disorders [3,4.]

The main clinical features of this disorder are typically childhood onset, familial occurrence, slowly progressive weakness, and muscular atrophy affecting the feet and legs; later on, the hands may also be affected, and additional clinical features may then include depression of tendon reflexes and slight to moderate distal sensory impairment [1,2,3,4].

The classification of CMT type 1 (CMT1), CMT type 2 (CMT2), and intermediate CMT is on the basis of median motor nerve conduction velocity: CMT1, <38 m/s; CMT2, >38 m/s; and intermediate CMT, 25-45 m/s [5,6,7].

The prevalence of CMT has been studied in western Norway, and 3 hereditary types were distinguished in the area: autosomal dominant CMT with an estimated prevalence of 36/100,000 X-linked recessive CMT with a prevalence of 3.6/100,000; and autosomal recessive CMT with a prevalence of 1.4/100,000 [3]. Furthermore, more than 40 CMT genes have been currently identified [8].

Few epidemiologic studies have reported the prevalence of CMT in the world. The apparent discrepancy in the results of the various prevalence studies may be caused by differences in methodology, including case identification. According to their importance, a systematic review of the literature was performed in order to analyse and synthetize the literature on epidemiologic studies, regarding the distribution of this disease among the worldwide population (countries and regions).

The current systematic review was performed in accordance with the guidelines for transparent reporting of systematic reviews and meta-analyses (PRISMA statement) [5].

Search Strategy

Four databases (Internet sources) were used to search for appropriate papers that fulfilled the purpose of this study. These included the National Library of Medicine (Medline-PubMed), Web of Science, Scopus, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) using different combinations of the following keywords: CMT disease, epidemiology, prevalence, public health, and cross-sectional studies. The databases were searched for studies conducted in the period from January 1990 to May 2015. The structured search strategy was designed to identify any published document that evaluated epidemiological studies on CMT disease. Additional papers were included in our study after analyses of all references from the selected articles. We did not contact the investigators, nor did we try to identify unpublished data.

Study Selection

All electronic search titles, selected abstracts, and full-text articles were independently reviewed by a minimum of 2 reviewers (L.C.L.S.B., P.S.N., I.M.P.F.C., and C.A.G.). Disagreements over inclusion/exclusion criteria were resolved by reaching a consensus. The following inclusion criteria were applied: epidemiological studies of CMT in different countries or global regions, and reported prevalence and/or frequency data of the disease and its most frequent CMT subtypes in the population. Exclusion criteria were as follows: inappropriate diagnoses, incomprehensive case ascertainment, review articles, meta-analyses, abstracts, conference proceedings, editorials/letters, and case reports. An exception was made for the article by Foley et al. [9], although it was in the form of a letter, due to the lack of epidemiological studies, which were consistent with the inclusion criteria available in the literature.

Quality Assessment

Each of the 2 reviewers independently completed a quality review for each study to assess the study eligibility for inclusion. The quality of the studies was evaluated using an assessment tool designed specifically for this study based on a scoring system suggested by Boyle [10] (table 1). The quality of studies was scored based on a scoring system composed of 8 questions. For studies based solely on registries, the reviewers were asked to mark ‘yes' for questions 3, 4, 5, and 6. For studies using multiple sources of ascertainment, the reviewers were asked to mark ‘not applicable' for question 4, and quality was thus scored out of 7. A score of 8/8 or 7/7 was considered high quality, while a score of 1/8 or 1/7 was considered low quality. A third reviewer was consulted in cases for which there was a lack of consensus between the primary reviewers.

Table 1

Quality assessment scores of CMT disease incidence and prevalence studies

Quality assessment scores of CMT disease incidence and prevalence studies
Quality assessment scores of CMT disease incidence and prevalence studies

Data Extraction

Data were extracted by one reviewer using standardised forms and were checked by a second reviewer. Extracted information included data regarding setting, source (authors, year), objective and study design, country, population denominator, affected individuals/families, timescale (prevalence date), case ascertainment method, diagnostic method, outcome (prevalence per 100,000 population), prevalence of CMT1 and CMT2 subtypes, and potential bias/methodological limitations.

In the literature search, we found 1,158 titles. After excluding 301 duplicate articles and 57 review articles, we proceeded with the reading of 802 titles and abstracts; these included 567 articles on PubMed; 117 on Scopus; 86 on Web of Science and 32 on CINAHL. Thirty articles were selected for full reading. After the assessment of articles not shown in full; duplicates; case studies; articles not in English, Spanish, or Portuguese; and articles with objectives that were not relevant to this study, 12 remaining articles were finally selected (fig. 1).

Fig. 1

Flow diagram of selection of CMT disease incidence and prevalence studies during the period January 1, 1990-May 31, 2015.

Fig. 1

Flow diagram of selection of CMT disease incidence and prevalence studies during the period January 1, 1990-May 31, 2015.

Close modal

The most common types of studies were epidemiological and they reported the prevalence and frequency of the genetic subtypes; 4 were retrospective, 3 were prospective, 3 were transversal, 1 was a cohort study, and 1 was a cross-sectional community-based study (table 2). The longest time interval investigated was 27 years (1960-1987), in the retrospective study of Mostacciuolo et al. [11]. A high level of heterogeneity among studies precluded a firm conclusion.

Table 2

Details of included studies

Details of included studies
Details of included studies

The selected studies were performed in different countries, including Egypt, England, Germany, Iceland, Italy (2), Japan, Norway, Serbia, Sweden, Turkey, and the United Kingdom. The studies were conducted between 1991 and 2013. The number of participants per study varied widely, ranging from 5 to 776 individuals with CMT and from 1 to 275 families (table 3).

Table 3

Genetic epidemiology of CMT in the general population

Genetic epidemiology of CMT in the general population
Genetic epidemiology of CMT in the general population

The most commonly used diagnostic tools were family history, neurological and neurophysiological investigations, and molecular genetic investigations. Ten studies assessed the prevalence of CMT, with reported rates ranging from 9.7/100,000 in Serbia to 82.3/100,000 in Norway (table 3).

The frequency of the main CMT subtypes in countries varied from 37.6 to 84% for CMT1 and from 12 to 35.9% for CMT2; CMT1 was least prevalent in Norway and most prevalent in Iceland; on the other hand, CMT2 had the lowest prevalence in the United Kingdom and the highest prevalence in Norway. A disproportion in the CMT1/CMT2 relationship was observed in different countries; for example, Iceland, which had the greatest difference, had a CMT1 to CMT2 ratio of 5:1, while Norway had the most homogenous sample with a 1:1 ratio. Among the included studies, only 3 did not report information on CMT1 and CMT2 subtypes; Kandil et al. [12] performed a study on various peripheral neuropathies in Egypt, Kurihara et al. [13] reported data on CMT prevalence in the general population, and Mostacciuolo et al. [11] presented only CMT1 data.

Regarding the different strategies for collecting epidemiological data, the studies used self-administered questionnaires, and clinical and electrophysiological data analysis in retrospective, prospective, and databases studies. Note that self-administered questionnaires and interviews are common ways to obtain morbidity information, frequency of symptoms, and prevalence of variables.

Although there is a growing interest in CMT research, epidemiological studies of this disease are still scarce, and knowledge of CMT epidemiology in different parts of the world remains extremely limited.

It is difficult to assess the prevalence of CMT due to a wide variation of clinical symptoms and the different forms of the disease [14]. These difficulties account for the high variability in the prevalence rates reported in epidemiological studies. The problem with estimating minimal prevalence in chronic disorders is to identify all the patients in the general population/geographical region. According to Mladenovic et al. [15], CMT prevalence varies in different populations and different regions within countries.

In our review, we found articles from several countries, but most studies were performed in European countries. This is probably due to the fact that there are major centres for CMT diagnostics in Europe.

Regarding the types of studies included in this review, it seems that the retrospective study was the most predominant, which is due to the fact that the review of medical records is a widely used method of data collection, despite certain limitations [16]. Prior knowledge about certain characteristics of what is being observed introduces distortions in the record of an event, and years later, for the conduction of a historical cohort study, verification may aggravate these distortions for the same reasons [17].

Regarding epidemiological studies, most have investigated the prevalence of general CMT; most of the remaining studies have investigated the prevalence of CMT1, the most common subtype of the disease [18]. Prevalence studies evaluating only CMT2 are rare. Patients and families affected by CMT2 may be more difficult to identify than those affected by CMT1. The age of onset for CMT1 is often during the younger years, while that for CMT2 is often during the older years. The presence of other hereditary neuropathies is more frequent with advancing age, and CMT may thus be more difficult to discern from other neuropathies.

The clinical diagnosis of peripheral neuropathies can be difficult [19]. However, in relation to diagnostic methods used in studies, neurophysiological findings and family history with multiple affected individuals can further support the diagnosis of CMT, which is the most common inherited neuropathy [20]. The systematic screening of multiple close relatives is important [21,22].

According to Gudmundsson et al. [21], there have recently been major advances in understanding the genetics of CMT. Genetic testing is helpful in subdividing CMT, but this is not a prerequisite for the diagnosis of CMT. DNA abnormalities are not known to exist for some forms of CMT, or corresponding tests are not commercially available. Gess et al. [22] reported that the genetic heterogeneity of CMT is enormous, and over 40 genes have been shown to cause CMT. Thus, it is important to design rational diagnostic procedures, including the evaluation of the most common causative genes. In particular, the most common genes and their cumulative rates in CMT are of interest.

When analysing the prevalence of CMT (9.37-20.1/100,000), it can be inferred that the lower prevalence rate (9.37/100,000) was reported in an older study [11], in which the only diagnostic methods were nerve biopsies and electromyography; this was also a retrospective study. The second study with the lowest prevalence was also a retrospective study [15], and diagnosis was confirmed only by clinical and CMT diagnosis established according to European CMT Consortium criteria.

In addition to this difference in the diagnostic method used in each study, another factor that may have changed the prevalence reported in each study is that some affected individuals may have mild or no symptoms. This presents a problem in identifying cases of CMT, and most prevalence studies have included a number of individuals with few or no symptoms that were only discovered when seemingly unaffected family members were studied. This may explain the somewhat higher prevalence found in some studies [21].

In the study by Braathen et al. [23], a meticulous effort was made to include all people with CMT in eastern Akershus County, Norway; perhaps that is the reason why their study reported the highest prevalence of CMT (82.3/100,000).

Gudmundsson et al. [21] also reported a high prevalence of CMT in Iceland (12/100,000 population), and improved methods were discussed when comparing another Icelandic study performed in the 1960s, with a reported CMT prevalence of 1.6/100,000.

Regarding the prevalence of CMT subtypes (CMT1 and CMT2), a majority of studies found through genetic testing that CMT1 was more prevalent than CMT2; in most studies, the duplication of chromosome 17p11.2 occurred more frequently, indicating a diagnosis of CMT1 [14,15,22].

The only study that found that CMT2 was more prevalent than CMT1 was from Braathen et al. [23], but there was a relatively small difference (CMT2, 49.4% and CMT1, 48.2%). The authors found an equal distribution of CMT1 and CMT2 in the general Norwegian population, and this was in contrast to previous studies based on clinical populations, which found that CMT1 was significantly more frequent than CMT2.

According to Sackett [24], the different neurophysiological distribution in the general and clinical populations are probably caused by ascertainment differences, as selection bias is more pronounced in clinical populations than in the general population. Thus, Braathen et al. [23] reported that it is likely that their results are more representative than the results from clinical populations, reinforcing this statement by the fact that the ratio between the total number of affected people and the total number of families was similar for both CMT1 and CMT2 (2.3:1 and 2.1:1, respectively).

In conclusion, most studies were performed in European countries, and this is probably due to the fact that there are major centres for CMT diagnostics in Europe. Also, the most widely used diagnostic method was surveying family history with multiple affected individuals, and the survey was further associated with other methods, since the systematic screening of multiple close relatives is important. The prevalence of CMT varied in different populations and different regions within countries, as did the relative frequency of subtypes CMT1 and CMT2. However, most studies found that CMT1 is the most prevalent subtype of CMT. However, the retrospective nature of these studies might contribute to biases in data collection. Future studies using uniform diagnostic criteria and longitudinal follow-up can help identify temporal trends and geographic variations of the epidemiologic features of CMT in different regions of the world.

This review reveals the gaps that still exist in the epidemiological knowledge of CMT in the world. Published studies are of varying quality and utilize different methodologies, thus precluding a robust conclusion. Future research focusing on epidemiological features of CMT in different nations and different ethnic groups is therefore needed.

We would like to thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico/CNPq/Brazil and Fundação de Amparo à Pesquisa do Estado de Sergipe/FAPITEC-SE for the financial support. We would like to thank Editage (www.editage.com.br) for their English language editing services.

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