Hereditary motor and
sensory neuropathies, also called Charcot-Marie-Tooth (CMT) disease, comprise a group of inherited peripheral neuropathies. CMT affects one in 2,500 people (Skre, 1974
) and is the most common inherited neurological disorder (Kedlaya, 2012
Demyelinating CMT or CMT1, the most common form of the disease, accounts for more than 60% CMT cases (Numakura et al.
), and is characterized by lowered nerve conduction velocity (NCV) both in sensory and motor nerves. The other major form is axonal CMT or CMT2, distinguished by normal or mildly reduced NCVs.
CMT is a clinically and genetically heterogeneous group of diseases with rough genotype–phenotype correlation, so the final diagnosis requires extensive clinical and electrophysiological examination, family data, and gene mutation analysis. To date, about 30 genes and 50 loci have been associated with CMT (Inherited Peripheral Neuropathies Mutation Database - IPNMD, 2011). Among them, mutations in the PMP22
, and GJB1
genes are responsible for the vast majority of patients with CMT, while mutations in other genes are often present in rare, even individual cases (Mersiyanova et al.,
; Mostacciuolo et al.,
; Numakura et al.,
; Keckarevic Markovic et al.
are associated with autosomal dominant forms of CMT1 (and CMT2 for MPZ
), while GJB1
is responsible for X-linked CMT (IPNMD, 2011). Autosomal recessive (AR) forms are rare, but could be over-represented in small populations, due to a founder effect. Therefore, a founder mutation in the NDRG1
gene is responsible for CMT1 ARD (CMT4D), also known as CMT Lom, the most common peripheral neuropathy among Romani people (Kalaydieva, 2002
The genetic basis of CMT varies among populations, but the pattern is the same: the most frequent mutation in CMT1 is PMP22 duplication, then GJB1, MPZ, and PMP22 mutations. For CMT2, the gene mostly affected by mutations is MFN2, then GJB1, and MPZ. Therefore, the main algorithm for genetic testing of patients with CMT worldwide would be the same, suggesting genetic analyses in the order mentioned above. GJB1 gene analyses should not be done if there is male-to-male transmission of the disease.
Despite that, in general, the given algorithm is the best way to genetically evaluate most CMT cases, there could be some population differences that should be taken into account to facilitate analyses, to make them faster, cheaper, and easier.
Here, we present the algorithm for genetic testing in Serbian patients with demyelinating CMT, based on their genetic specificities.