Current profile of Charcot‐Marie‐Tooth disease in Africa: A systematic review

Abstract Background and aims Charcot‐Marie‐Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were described in populations with Caucasian ancestry, genetic research on CMT in Africa is scant. Only a few cases of CMT have been reported, mainly from North Africa. The current study aimed to summarise available data on CMT in Africa, with emphasis on the epidemiological, clinical, and genetic features. Methods We searched PubMed, Scopus, Web of Sciences, and the African Journal Online for articles published from the database inception until April 2021 using specific keywords. A total of 398 articles were screened, and 28 fulfilled our selection criteria. Results A total of 107 families totalling 185 patients were reported. Most studies were reported from North Africa (n = 22). The demyelinating form of CMT was the commonest subtype, and the phenotype varied greatly between families, and one family (1%) of CMT associated with hearing impairment was reported. The inheritance pattern was autosomal recessive in 91.2% (n = 97/107) of families. CMT‐associated variants were reported in 11 genes: LMNA, GDAP1, GJB1, MPZ, MTMR13, MTMR2, PRX, FGD4/FRABIN, PMP22, SH3TC2, and GARS. The most common genes reported are LMNA, GDAP1, and SH3TC2 and have been found mostly in Northern African populations. Interpretation This study reveals that CMT is not rare in Africa, and describes the current clinical and genetic profile. The review emphasised the urgent need to invest in genetic research to inform counselling, prevention, and care for CMT in numerous settings on the continent.

reported variable prevalence, 3 with a crude global estimate of 1/2500. 4 Yet, despite being described more than 130 years ago and the genetic cause identified about 30 years ago, 5,6 there remains a paucity of information on its global prevalence and genetic epidemiology due largely to challenges in diagnosis, especially in countries with limited resources. Studies of CMT in Africa, particularly genetic epidemiology are notably scarce, 7 because of the unavailability of neurologists and diagnostic tools. 8 Classically, CMT is divided into two main types: type 1 (CMT1) when the disease is primarily demyelinating with the median motor nerve conduction velocities (MNCVs) <38 m/s, and type 2 (CMT2) when the disease is axonal with MNCVs >38 m/s. 9  Other sub-classifications are based on the inheritance pattern, which can be autosomal dominant (AD), autosomal recessive (AR), or X-linked (CMTX). 9,10 Over 100 genes have been associated with CMT, 9 and it is reported that over 90% of all genetically diagnosed cases are due to mutations in four genes: PMP22, GJB1, MFN2, and MPZ. 9, 10 The 1.4 Mb duplication on chromosome 17 (17p) accounts for over 60% of all genetically diagnosed cases of CMT in Europe and America. 9 This region contains nine genes including the peripheral myelin protein 22 gene (PMP22), which is emendable to therapeutic manipulation of CMT1A, mainly aiming at reducing PMP22 transcription. 2 Still, no curative treatment exists for these CMTs, although several clinical trials are ongoing. [11][12][13] Interestingly, PMP22 has been associated with CMT in only four families in Africa. [14][15][16] This may be due to the limited studies on CMT in the continent or, alternatively, the genetic architecture of CMT among people of African and non-African ancestries is significantly different, as demonstrated with a higher proportion of CMT4B in Tunisia. 15,16 Substantial genetic architectural differences among people of African and non-African ancestries have been extensively documented, 14,17,18 and the highest genetic diversity among Africans should be expected to be associated with numerous unreported variants in known genes, and offer the opportunity for novel genes discovery, as shown in congenital hearing impairment research. 19,20 Hence, current therapeutic strategies under trial may not be beneficial to Africans, unless the relevant genetic variants for these populations are fully identified. 21 Therefore, given the extensive genetic diversity in Africa, 22 the high consanguinity in numerous regions 23,24 and fertility rates, 25 African populations present a unique opportunity to discover novel disease variants 25 and, specifically to better understand CMT pathophysiological mechanisms. 26 In this review, we report the scarcity of research on CMT in Africa, the current clinical profiles, the specificity in the pattern of inheritance, and available genetic data of reported CMT cases in Africa.

| METHODS
The present review was performed in accordance with the guidelines for transparent reporting of systematic reviews and meta-analyses (PRISMA statement 2020).

| Search strategy
We searched four databases for articles reporting CMT in Africa that fitted with the aim of this study. These databases included

| Selection criteria
We included observational studies published from database inception until April 2021 that report data on the epidemiology, clinical, and genetic features of CMT in Africa. In case of duplicate studies, we selected the most recent or more informative studies. We excluded qualitative studies, letters to the editor, reviews, and commentaries.
Also, studies with unavailable full text or missing key data were removed from this review. In the case of articles reporting on patients both from Africa and outside Africa, we extracted the data of interest.

| Data extraction process and assessment of methodological quality
One researcher (A.Y.) extracted data from the studies included in this review. A second researcher (K.E.) checked the accuracy of the extraction process. Any discrepancy was resolved through discussion and consensus. We extracted data included the last name of the first author, the year of publication, the country of origin of the patients, the prevalence, the incidence, the study setting, the study design, the sex ratio, age ranges, the sample size, the number of affected individuals, type of CMT, the age onset, the starting symptoms, the major neurological signs, the inheritance pattern, the technique used to identify genes, the identified gene or/and variants, and the reporting journal. We also extracted data from the available histological studies. The

| RESULTS
An initial 395 records were identified. We removed 364 articles after screening for titles and abstracts. The remaining 31 records were considered for the full review, after which we removed six records for reasons of missing key data, the letter to the editor, or review articles.
In addition, three articles were found through other sources. Finally, a total of 28 articles fulfilled our selection criteria and were included in the review ( Figure 1).

| Clinical expression
A total of 185 patients were described in the studies reviewed, and the sex ratio was 1.2 (99 males vs 86 females). The demyelinating CMT type was reported in 58.3% of the studies, 16,31-37 followed by the axonal type in 37.5% (n = 28) 23,38-42 and the intermediate form in 4.2%. 43 The disease started mostly in the first two decades of life but cases with later onset were also reported. 35  and kyphosis) ( Figure 3C-F), and sensory impairment were reported. 34 Reflexes were reduced to absent in most of the cases. However, a case with upper motor neuron involvement with brisk reflexes was reported. 38 A severe case associated with marked stridor during inspiration causing dyspnoea and abdominal respiration, and a vocal cord paralysis was reported in a family with three affected sibs 37 ( Figure 3A-C).
A rare case of the AR demyelinating form of CMT associated with early-onset glaucoma was reported from Tunisia. 31 Moreover, an unusual phenotype associating CMT1A with macular oedema was first reported in a South African girl. 46 Only one sporadic case of intermediate motor NCV in a female from Morocco was reported with a mutation in the GJB1 gene. 43 The phenotype was more severe in the recessive cases with early onset, and patients were wheelchairdependent by the time of diagnosis. 23,33,34,37,39 Similar to other reports, intra and interfamilial phenotype variability were seen in African patients as the cases reported from Algeria. 36,42 Also, a case of CMT associated with hearing impairment was reported in an Algerian family. 44 The disease course was slowly progressive in most of the cases, but a rapidly progressive case was found in an Algerian family. 44 The demyelinating type was the most reported (Table 2).  Nerve biopsy was performed in select cases and showed the classic aspect of "onion bulbs." 34,36,40,44,45 In addition, some axonal cases were reported with an important loss of large myelinating fibres and a few clusters of regeneration. 23, 47 The main characteristics of the clinical profile are highlighted in Table 2.

| Pedigrees' analysis
The pattern of inheritance was AR in most cases (91.2%, n = 97) ( Figure 3G-I) while AD represented 4.9%, and X-linked and unknown patterns were seen in 3.9% each. Consanguinity was reported in 62% (n = 66) of families. 34,37

| Genetic analysis
Several techniques were used to identify the causative genes associated with CMT over the time (Table 2) 49 In other studies, most of the variants reported were novel 7,32,34,35,37,43 and no genes have been identified in a few studies. 16,39,44,50 This is not surprising since most of these studies were conducted more than two decades ago, and the techniques used were less efficient compared to NGS. NGS with a CMT gene panel testing was performed in only one study. 7 All the genes and variants reported are summarised in Table 2.

| DISCUSSION
To the best of our knowledge, this review is the most comprehensive and complete report on the epidemiological, clinical, and genetic features of CMT in Africa. It revealed the lack of data from most African countries, especially from SSA. The review has also allowed us to identify the genetic profile of CMT in Africa and suggests a difference from what is reported to date in the Western countries characterised by a lower contribution of PMP22-associated variants in Africa, higher rate of novel and founder variants in known genes, likely related to higher consanguinity rates. In contrast to the high-income countries, the prevalence or incidence of CMT in Africa is still largely unknown.
Two clinical studies published in the 1980s have reported prevalence rates of 8/100 000 and 10/100 000 in Libya 51 and in Nigeria, 52 respectively. More recently, an estimated prevalence of 12/100 000 was reported in Egypt. 29 Most of the studies included in this review were case reports on familial or isolated cases, illustrating a widely variable regional epidemiological description of CMT in Africa. 28,47 Similarly, the clinical description was similar to other reports worldwide. In most patients, symptoms appear during the first or second decade of life with an insidious onset and a slowly progressive weakness that starts in the lower extremities and later involves upper extremities. [53][54][55] Diverse phenotypes were reported in Africa including asymptomatic, mild, moderate, and severe forms of CMT. 7,23,34,37,40 These data confirm its clinical heterogeneity reported in other populations. 9,55 However, the clinical presentation seems more severe in the African families 39 than reported elsewhere. 56 This could be due to other genetic modifiers, environmental factors, the differences in the care, or the high frequency of the reported recessive cases of CMT, known to be more severe. The distribution of muscle weakness is mainly in the distal part but can also be proximal as reported in some studies. 45,57 In addition to muscle weakness, other motor signs include decreased or absent tendon reflexes, amyotrophy, and walking difficulties with steppage gait. Similar to other reports, some rare cases can cause respiratory failure or breathing difficulties like the case reported by Nouioua et al. 37,58,59 Sensory impairment is typically associated with the phenotype, affecting generally the distal part in "gloves and socks" pattern. 57, 60 The disease course is slowly progressive in most cases, but in exceptional cases, it can progress rapidly. 44 In this study, most families segregated CMT disease in its recessive form associated with a high rate of consanguinity. This is different from the dominant manner inheritance pattern that is the most common reported worldwide, 42 but could be due to the underreported cases in Africa.
The histological study has a role in identifying underlying genetic aetiology in sporadic cases, and it helps distinguishing CMT from acquired peripheral neuropathies. 57 Nerve biopsy may also support a functional association when the genetic tests detect "variants of uncertain significance" or a novel variant. 57 However, these were not performed as standard procedures in the studies reviewed here. 7,30,32,36,41 Nerve conduction studies are an important step in the algorithm of CMT diagnosis, and allow the classification of different CMT types. 57 This testing was performed in almost all the studies, though not all patients in each study were screened. 30,50 The present review highlighted some regional specificity with LMNA and GDAP1 genes mostly found in North Africa where most of the studies were reported from, a region known for its high consanguinity rates as confirmed in this review. 61 The consanguinity rate YALCOUY was also high in Mali, Morocco, Algeria, and Egypt, [23][24][25]39 26 Recent studies reported that the increasing insights into the molecular-genetic mechanisms have revealed potential therapeutic targets. 26 These will enable the development of novel therapeutics for genetic neuropathies that remain, in their majority, without effective treatment. 9 The techniques used in Africa in the past were mostly MLPA, Recent studies have confirmed the efficiency of NGS in diagnosing CMT cases. 9 In a cohort of pre-excluded PMP22dup/del from Japan, authors identified the causative genes in 30% of the cases, and the most common genes were GJB1, MFN2, and MPZ. 55 The overall diagnosis rate is higher in demyelinating CMT compared to the axonal type. 8,55 The molecular profile of CMT is sparse but globally PMP22, GJB1, MFN2, MPZ genes explain at least 90% of CMT cases. 3,9,10 36,46,48 Moreover, an AR CMT case (CMT4B) was first mapped in a family from Africa, before the gene was identified in subsequent studies done abroad 16 ; suggesting that the African population harbours specific gene variants for CMT but the limited access to diagnosis tools may delay the molecular diagnosis confirmation.
The scarcity of the most common CMT genes in Africa might be associated with the limited number of studies as it is expected that the prevalence of CMT1A (and HNPP) could be similar in populations worldwide. It is possible CMT1A might be under reported because the phenotype is already well known, and only the most severely affected patients come to the medical attention in many African regions, owing to the limited access to diagnostic tools, and to scarce neurology specialists. It is also possible that the findings of the current review may be due to the genetic diversity of African populations, the population structure, the consanguinity rates, or the genetic drift. Therefore, this stresses the need for more studies on the genetics of CMT in Africa using NGS, with the potential of uncovering novel genes or variants important for the function of the peripheral nerve system. CMT is a disabling condition that does not have a cure, but the advances in the understanding of its pathophysiology have advanced research in the identification of therapeutic targets in human and animal models. 11,55,65,66 The extension of such studies to Africa could be especially beneficial and equitable.

| STRENGTHS AND LIMITATIONS
To the best of our knowledge, this review provides the most compre-

| CONCLUSION
This study reveals that CMT is not rare, and likely underreported in Africa and describes the current clinical and genetic profile. Large and multicentric cohort studies in Africa would not only inform the genetic epidemiology of CMT in this region but could also lead to new discoveries important to the global research effort for therapeutic perspectives. The increasing access to NGS technologies offers to African scientists a unique opportunity to fully describe relevant variants in known genes and to discover novel CMT-associated genes that may improve our understanding and care of this condition in Africa.