Charcot-Marie-Tooth Diseases: An Update
Charcot-Marie-Tooth Diseases: An Update
To date, numerous genes have been implicated in hereditary neuropathies, particularly in CMT and dHMN, which share a clinical and molecular overlap with CMT: altogether, >60 genes have been identified. In spite of this genetic heterogeneity, all forms of CMT have quite a homogeneous clinical phenotype: PMA, skeletal deformities (including pes cavus), and usually decrease or absence of tendon reflexes. Other signs, such as pyramidal tract involvement (CMT5) or optic neuropathy (CMT6), may also be observed. Some specific features (clinical, biological or pathological) can be suggestive of some particular genes. For example, the association of a CMT phenotype with proteinuria and/or abnormal elongated expansions of Schwann cell cytoplasms (as evidenced by electron microscopic examination of a nerve sample) is strongly suggestive of INF2-related CMT. When additional signs are found, some authors have proposed the term of 'CMT plus' (eg, as CMT5 and CMT6), but the individualisation of such a supplemental subtype does not add any meaningful information in our opinion.
The majority of CMT subtypes have AD inheritance, although X-linked and AR transmission also exist. Most of the CMT diseases are demyelinating (CMT1 for the AD forms and CMT4 for the AR ones), and up to one-third are primarily axonal (type 2: AD-CMT2 and AR-CMT2). In CMT, information of families in term of diagnostic certainty, mode of inheritance, prognosis and sometimes therapeutic trials (see further) requires an accurate genetic diagnosis. Recently, Saporta et al, in a personal series of >500 patients with CMT, reported that the most prominent CMT subtypes identified were CMT1A (duplication of PMP22), CMTX1 (mutations of GJB1), hereditary neuropathy with liability to pressure palsies (deletion of PMP22), CMT1B (mutations of MPZ) and CMT2A (mutations of MFN2); other CMT subtypes accounted for <1% of all patients with genetically defined CMT; only 1.8% of patients with CMT1 were without a genetic diagnosis, although 65.6% of patients with CMT2 were in the same situation. Murphy et al (on 916 patients) have found that four common genes (PMP22, GJB1, MPZ and MFN2) account for >90% of all CMT molecular diagnoses. Finally, Fridman et al (on 997 patients) have confirmed that the most frequent CMT subtypes are CMT1A, CMTX1, CMT2A, CMT1B and HNPP, these genes being affected in 89.2% of all genetically confirmed mutations.
Among CMT2 patients, the most frequent mutated gene is MFN2 and, at the present time, it is said to account for 10–30% of these cases; otherwise, mutations in NEFL gene have been recently found as unexpectedly frequent in CMT2 patients of Chinese origin. Concerning AR forms, many of the reported families and patients originated from Mediterranean countries as a consequence of the high rate of consanguinity (especially in Maghreb and the Middle East).
At last, a close relationship between CMT2 and dHMN was noticed before the identification of mutated genes: first, CMT2 is generally a peripheral nerve disease with predominant motor involvement, patients having sometimes no or little sensory symptoms; in addition, families were identified in which some patients had CMT2 and other dHMN. Identification of genes responsible for dHMN confirmed the existence of an overlap between the two conditions.
CMT Disease: A Heterogeneous Genetic Syndrome
To date, numerous genes have been implicated in hereditary neuropathies, particularly in CMT and dHMN, which share a clinical and molecular overlap with CMT: altogether, >60 genes have been identified. In spite of this genetic heterogeneity, all forms of CMT have quite a homogeneous clinical phenotype: PMA, skeletal deformities (including pes cavus), and usually decrease or absence of tendon reflexes. Other signs, such as pyramidal tract involvement (CMT5) or optic neuropathy (CMT6), may also be observed. Some specific features (clinical, biological or pathological) can be suggestive of some particular genes. For example, the association of a CMT phenotype with proteinuria and/or abnormal elongated expansions of Schwann cell cytoplasms (as evidenced by electron microscopic examination of a nerve sample) is strongly suggestive of INF2-related CMT. When additional signs are found, some authors have proposed the term of 'CMT plus' (eg, as CMT5 and CMT6), but the individualisation of such a supplemental subtype does not add any meaningful information in our opinion.
The majority of CMT subtypes have AD inheritance, although X-linked and AR transmission also exist. Most of the CMT diseases are demyelinating (CMT1 for the AD forms and CMT4 for the AR ones), and up to one-third are primarily axonal (type 2: AD-CMT2 and AR-CMT2). In CMT, information of families in term of diagnostic certainty, mode of inheritance, prognosis and sometimes therapeutic trials (see further) requires an accurate genetic diagnosis. Recently, Saporta et al, in a personal series of >500 patients with CMT, reported that the most prominent CMT subtypes identified were CMT1A (duplication of PMP22), CMTX1 (mutations of GJB1), hereditary neuropathy with liability to pressure palsies (deletion of PMP22), CMT1B (mutations of MPZ) and CMT2A (mutations of MFN2); other CMT subtypes accounted for <1% of all patients with genetically defined CMT; only 1.8% of patients with CMT1 were without a genetic diagnosis, although 65.6% of patients with CMT2 were in the same situation. Murphy et al (on 916 patients) have found that four common genes (PMP22, GJB1, MPZ and MFN2) account for >90% of all CMT molecular diagnoses. Finally, Fridman et al (on 997 patients) have confirmed that the most frequent CMT subtypes are CMT1A, CMTX1, CMT2A, CMT1B and HNPP, these genes being affected in 89.2% of all genetically confirmed mutations.
Among CMT2 patients, the most frequent mutated gene is MFN2 and, at the present time, it is said to account for 10–30% of these cases; otherwise, mutations in NEFL gene have been recently found as unexpectedly frequent in CMT2 patients of Chinese origin. Concerning AR forms, many of the reported families and patients originated from Mediterranean countries as a consequence of the high rate of consanguinity (especially in Maghreb and the Middle East).
At last, a close relationship between CMT2 and dHMN was noticed before the identification of mutated genes: first, CMT2 is generally a peripheral nerve disease with predominant motor involvement, patients having sometimes no or little sensory symptoms; in addition, families were identified in which some patients had CMT2 and other dHMN. Identification of genes responsible for dHMN confirmed the existence of an overlap between the two conditions.
