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Page 336 Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04

Because CMT1A (PMP22) duplication represents 50% of CMT patients (around 70.7% of demyelinating
CMT), the very first step is to analyze them by multiplex ligation-dependent probe amplification (MLPA).
This is the current technique for genetic testing of the CMT1A duplication (and hereditary neuropathy with
liability to pressure palsies or HNPP deletion) in postnatal and prenatal diagnosis. However, in the case of
preimplantation genetic diagnosis (PGD), segregation analysis of CMT1A linked microsatellites is still a
molecular technique for genetic testing. After that, if negative, different algorithms help to perform
sequential testing of individual genes using Sanger sequencing [26,27] . In this scenario, the most promising
candidate gene is analyzed and, if negative, the next most likely candidate is tested. Several publications
provide the scientific community with algorithms and pipelines designed to maximize efficiency when
diagnosing CMT disease [14,27] .

Nevertheless, this is a very expensive and time-consuming workflow, especially in those cases where the
causative gene is individually rare. With the evolution of next generation sequencing (NGS, or massive
parallel sequencing) techniques, it is now possible to analyze all CMT genes by a selection of genes (panels),
the exome (containing only the protein-coding sequences), or the genome, and this strategy has become the
most cost-efficient approach [14,28,29] . This means that, as technology has advanced and the cost has dropped,
these approaches have replaced the traditional screening gene by gene. Therefore, NGS technologies have
helped not only to identify genes in association with CMT but also to develop more efficient workflows to
couple a clinical diagnosis with the genetic diagnosis.

However, some challenges remain to be solved and are responsible for deficits in the diagnostic rates. A
critical issue in this two-step process (clinical exam and genetic testing) is the analysis and interpretation of
genomic data generated by NGS . Depending on different criteria, geneticists have to evaluate the
[29]
relationship between a variant and the described phenotype to identify causative variants. Sometimes, the
chosen criteria allow them to find a variant that could be considered causative in achieving the etiological
diagnosis. However, the same workflow may be inconclusive, generally because of the identification of
variants of uncertain clinical significance or VUS [according to the American College of Medical Genetics
[30]
and Genomics (ACMG) and the Association for Molecular Pathology (AMP)] .
Treatment
Historically, inherited peripheral neuropathies have been challenging to treat. There is little specific therapy
for these neuropathies other than genetic counseling as well as symptomatic treatment, physical therapy,
and rehabilitation [31,32] . This represents supportive treatment, limited to rehabilitative therapy and surgical
[33]
treatment of skeletal deformities and/or abnormalities of soft tissues . There are no established disease-
modifying therapies to date. In clinical practice, patients are often evaluated and managed by a
multidisciplinary team that includes adult and pediatric neurologists, physiatrists, orthopedic surgeons, and
physical and occupational therapists .
[34]
On the one hand, these supportive treatments are usually based on rehabilitation to improve patient’s
posture and balance and shoe modifications, orthoses, or other assistive devices that have been shown to
[35]
improve patient’s walking economy . Although data are limited, there is evidence that mild to moderate
exercise is effective and safe for CMT patients and that it could be interesting to consider it as a therapeutic
intervention . Moreover, many different approaches have been used to treat skeletal deformities (especially
[36]
[37]
of the feet) from a surgical point of view .
On the other hand, different pharmacological therapies have been considered in the treatment of CMT
patients. First, a symptomatic drug therapy approach can be selected: pain can be an emerging feature of