Page 32 - 2021 Spring CMTA Report - Special Research Edition

CMT2A P
ublished in BRAIN, A Journal of Neurology, in January, the study

concluded that current clinical outcome measures, namely the CMT

Examination Score v2 (CMTESv2) and the CMT Pediatric Scale
Researchers put researchers on track to becoming trial-ready.
(CMTPedS), along with the development of responsive biomarkers,
on THE Way Led by Menelaos Pipis and Mary M. Reilly of the Centre for Neuromuscular
Diseases, UCL Queen Square Institute of Neurology, London, UK, the
cross-sectional and longitudinal study involved the largest CMT2A cohort
to Being reported to date (196 patients). Clinical information from patients was collected
as a part of the ongoing Inherited Neuropathy Consortium (INC) natural
Trial-Ready history study of CMT. The study’s aim was to provide guidance for interpreting
mutations of uncertain significance in mitofusin-2 (MFN2), inform prognosis
and also provide natural history data that will guide clinical trial design.

A large international Pipis said the study, which was funded by the National Institutes of Health,
the INC and the CMTA, among others, exemplifies the power of international
study of patients with multi-center collaborations.
It also illustrates the close relationship between the clinical and research
CMT2A demonstrated functions at the CMTA’s Centers of Excellence: Patients were evaluated at one
of the 19 INC Centers between 2009 and 2019 and at Wayne State University
that researchers are between 1996 and 2009. Antecedent clinical data was collected retrospec-
tively from patient history while longitudinal follow-up data (clinical history and
“in a good position to examination with or without neurophysiological studies) was collected during
annual visits.
perform clinical trials CMT2A, the commonest axonal form of CMT, affects some 25 percent of
as candidate therapies CMT2 patients. It is caused by mutations in mitofusin-2 (MFN2). In comparison
to CMT1A, the commonest form of CMT, CMT2A is associated with a more
become available.” severe, motor-predominant phenotype that usually manifests earlier in life and
carries a greater burden of disability. Additional symptoms include optic nerve
atrophy in up to 9 percent of patients, vocal cord involvement and upper motor
neuron dysfunction.
Earlier, smaller studies of CMT2A described the phenotypic spectrum, or
physical characteristics, of the disease, but longitudinal natural history studies
were lacking until now.
The study found that childhood onset of autosomal dominant CMT2A is the
most predictive marker of significant disease severity, independent of
disease duration. When compared to adult onset autosomal dominant
CMT2A, childhood onset is associated with significantly higher lifetime rates
of use of ankle-foot orthoses, full-time use of a wheelchair and dexterity
difficulties. Patients with a childhood onset of symptoms had a similar disease
duration compared to those whose symptoms started in adulthood, yet the
former had a significantly higher CMT Examination Score (CMTESv2) and CMT
Neuropathy Score (CMTNSv2) at initial assessment.
The longitudinal data revealed that over one year, the CMTESv2 increased
significantly in autosomal dominant CMT2A. Over two years, both the
CMTESv2 and the CMTESv2-R increased significantly, much more than
the increase observed in CMT1A over the same duration.
Longitudinal changes in the pediatric CMT2A population (autosomal
dominant and autosomal recessive CMT2A grouped together) were even more
pronounced, increasing significantly both over one year and two years. In
practical terms this means that the CMTESv2 and CMTPedS as bedside clinical
assessment tools are sensitive enough to pick up significant progression
of the disease over one and two years, despite CMT being a very slowly
progressive disease. Therefore, the CMTESv2 /CMTPedS can be used as
clinical outcome measures in future clinical trials as they will be able to identify
if a trial therapy is effective or not, given that a sufficient number of patients
Jeanne has CMT2A. are recruited for the trial.
She wants to educate people The study’s findings and the ongoing work in developing novel blood and
about CMT so they don’t skin biomarkers are significant milestones in the preparedness of the CMT
have to endure a 20-year community for clinical trials and could not have come at a better time for
journey to diagnosis like patients with CMT2A.
she did.

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