Page 30 - 2021 Spring CMTA Report - Special Research Edition
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The CMTA’s Type 2 Gene Discovery Initiatives
Some 95 percent SORD, or SORD1, is responsible for Drs. Cortese, Scherer, Züchner and
of CMT patients coding an enzyme that converts others studied over 1,100 database
with a demyelinat- sorbitol, a type of sugar, to fructose, entries and identified 48 CMT patients
ing type can get a another type of sugar, in a two-step whose genetic test results failed to
genetic confirma- process. It does this via the same identify an underlying genetic cause
tion of their CMT. pathway that is implicated in diabetic for their CMT, but who all had the
In contrast, only neuropathy. In diabetes, this pathway same recessive SORD1 gene
about 35 to 50 is disrupted, leading to the loss of mutation, found with either whole
percent of patients sorbitol being converted into fructose, exome sequencing (WES) or whole
with an axonal increasing intracellular sorbitol levels genome sequencing (WGS), and
CMT are able to and decreasing intracellular fructose who all had similar clinical findings
Dr. Stephan Züchner
obtain genetic levels. consistent with an axonal CMT.
confirmation. Scientists have already The CMT-causing mutation in the From there, Dr. Züchner and his
identified more than 100 genes that SORD1 gene causes the same loss fellow CMTA-supported scientists
cause CMT and they believe there of sorbitol conversion as diabetic were able to determine that the
are still over 100 causes waiting to be neuropathy. Dr. Züchner is designing VUS finding in the SORD1 gene was
discovered. a study to investigate the candidate indeed responsible for causing the
Why is knowing one’s type so diabetic neuropathy therapy as a associated CMT
important? Developing success- potential SORD-CMT treatment. THE MODIFIER GENES
ful treatments and a cure for CMT THE VUS INITIATIVE
depends on being able to target INITIATIVE
therapies to a patient’s particular Genetic tests for CMT often identify The CMTA is also pursuing an initia-
CMT-causing genetic mutation. only a variant of unknown or uncer- tive to identify “modifier genes,” which
CMT is caused by mutations in genes, tain significance—or VUS. Because of are secondary to the CMT-causing ge-
which are responsible for coding—or this, the CMTA is focused on studying netic mutation. The secondary genes
instructing—certain processes within VUS findings from CMT genetic tests. are believed to play a role in symptom
the peripheral nerves. Each unique It can be very frustrating for CMT onset and/or disease severity.
type of CMT is caused by a patients when their much-anticipated CMT affects everyone differently, even
disruption in normal cell function, result does not identify the underly- within the same family. While some of
and each disruption is caused by the ing responsible mutation and instead the reasons for this are environmental,
underlying genetic mutation. returns only a VUS finding. some might be due to modifier genes.
THE SORD GENE VUS findings are common and CMTA SARM1, whose presence is required
researchers have begun adding them
DISCOVERY to a massive international database, for axonal degeneration, is a modifier
gene.
In 2019, with CMTA support, Dr. stripped of any and all identifying Scientists posit that if deleting SARM1
Stephan Züchner and his team at the information, and then studying that allows for the preservation of periph-
University of Miami discovered an database in-depth to see if any of eral nerve axons, then a therapeutic
autosomal recessive mutation in the these VUS findings are actually approach that mimics a SARM1 dele-
SORD gene that causes an axonal connected to CMT diagnoses. This tion has the potential to be a success-
type of CMT (Type 2). More than is what led to the discovery of the ful treatment for axonal types of CMT.
3,000 patients in the United States SORD1 gene mutation causing CMT. This discovery also demonstrates that
have this mutation. targeting modifier genes like SARM1
may be more effective than targeting
the underlying genetic mutation itself.
Scientists have already • Less than 50 percent of CMT 2 patients know their gene.
identified more than 100 genes • No known gene -> no therapy development.
that cause CMT and • No known gene -> ongoing “diagnostic odyssey.”
they believe there are still • CMTA supports the most important genomic initiative
by the INC and the GENESIS project.
over 100 causes waiting to • In 2020, the most common axonal CMT was discovered -
be discovered. SORD neuropathy, which is likely treatable.
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