Page 62 - Read Online

Page 346 Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04

The historical deficit in the diagnostic rate of SORD cases is a consequence of SORD2P, a SORD
pseudogene. The homology between them is quite high, with an identity of 2295 out of 2320 bases, with
three gaps. Pseudogenes are usually not actively transcribed or translated, and they can be recognized by the
[142]
presence of nonsense mutations or a frameshift that interrupts the open reading frame .

Biallelic mutations in SORD gene were initially described in May 2020 and, until now, 14 mutations have
[141]
been identified . Among them, the most prevalent mutation is c.757delG, which is common to all the
reported patients (either in homozygous or heterozygous states, except for one patient with dHMN).
Among these 14 variants, most are frameshift or splicing mutations causing a loss of function of sorbitol
dehydrogenase.

Some studies have found a complete loss of SORD protein and increased intracellular sorbitol levels in
fibroblasts derived from patients. Some inhibitors of aldose reductase led to the rescue in Drosophila of
[141]
synaptic degeneration and motor deficiency caused by SORD orthologs deletion . However, the exact
mechanism that produces the axonal damage that can be seen in SORD cases has not been elucidated yet.
Mechanisms such as the increase of sorbitol levels, cellular osmolarity, oxidative stress, and the decrease of
[141]
NADPH levels have been proposed as responsible for the phenotype . Few data on nerve pathology are
available. Recently, Chen et al. (2022) described the neuropathology in the sural nerve of a 25-year-old
woman with dHMN phenotype, which confirmed slight changes, including thin myelin sheath fibers and
separation from the myelin sheath in very few fibers . These authors identified microvascular basement
[143]
membrane thickening, something that has also related to diabetic neuropathy.

In a clinical setting, some efforts should be made to reanalyze those undiagnosed patients suffering from
hereditary axonal neuropathies since it has been proven that SORD might play an important causative role.
The recognition of the biallelic variants in this gene would help to increase the diagnostic rates of autosomal
recessive and axonal types of neuropathies .
[144]
To check SORD-related CMT cases, it is important to consider three different aspects: (1) the clinical
homogeneity of cases with an onset in the second or third life decade and axonal neuropathy with distal
muscle weakness and atrophies; (2) the c.757del variant, which is common and facilitates genetic screening;
and (3) if direct analysis of this gene is selected, the primers should be designed with special attention to
discriminate SORD and SORD2P. Furthermore, in the case of NGS techniques, an optimization of the
analysis pipeline should be considered, selecting proper parameters, especially regarding alignment
settings .
[144]

Although we are far from understanding the exact mechanism of pathogenesis of SORD variants, there is no
doubt that this gene is a key role player in axonal neuropathies. The analysis of its sequence should help to
reduce the diagnostic deficit in cohorts of neuropathic patients.

CONCLUSION
Over the last decades, there have been significant advances in deciphering the genetic causes of CMT
disease. The number of genes associated with this peripheral neuropathy increased markedly, and
improvements have been made in the genetic diagnosis. To manage such a heterogeneous group of
disorders, it is essential to make a correct classification of its different types and elucidate which is the
particular mechanism that underlies the pathological effect of the variants in the associated genes. Thanks to
the efforts made to characterize them, it is clear that CMT-associated genes are closely related to the
formation, compaction, and maintenance of myelin, the neuronal soma, axon and cytoskeleton