Kompendium 2020 Forschung & Klinik

TOP-Studien
The Genetic Landscape
of Axonal Neuropathies:
Focus on MME
55
Study:
Senderek J, Lassuthova P,
Kabzińska D, Abreu L, Baets J,
Beetz C, Braathen GJ, Brenner
D, Dalton J, Dankwa L, Deconinck
T, De Jonghe P, Dräger B,
Eggermann K, Ellis M, Fischer
C, Stojkovic T, Herrmann DN,
Horvath R, Høyer H, Iglseder
S, Kennerson M, Kinslechner
K, Kohler JN, Kurth I, Laing
NG, Lamont PJ, Wolfgang N
L, Ludolph A, Marques W Jr,
Nicholson G, Ong R, Petri
S, Ravenscroft G, Rebelo A,
Ricci G, Rudnik-Schöneborn S,
Schirmacher A, Schlotter-
Weigel B, Schoels L, Schüle R,
Synofzik M, Francou B, Strom
TM, Wagner J, Walk D, Wanschitz
J, Weinmann D, Weishaupt
J, Wiessner M, Windhager
R, Young P, Züchner S,
Toegel S, Seeman P, Kochański
A, Auer-Grumbach M. The
genetic landscape of axonal
neuropathies in the middleaged
and elderly: Focus on
MME. Neurology. 2020 Dec
15;95(24):e3163-e3179
The genetic diversity of Charcot-Marie-Tooth (CMT) syndrome,
a hereditary motor-sensory neuropathy, is still not fully explored.
CMT consists of several subtypes, however, CMT1 (demyelinating
form) and CMT2 (axonal form) are the most common types 1 .
The disease onset of CMT usually starts in childhood, but lateonset
forms have been described 2 . For the latter, rare variants
in MME, encoding the metalloprotease neprilysin, have been
published earlier by our group 3 . Here, this international and interdisciplinary
study reveals new gene variants of CMT2 for midelderly
and individuals older than 65 years, leading to late-onset
manifestations.
To investigate unexplained axonal neuropathies and disease onset in
patients older than 35 years, 230 individuals were included into this study.
From 2012 until 2016 clinical and electrophysiological screenings were
conducted and genetic analyses were performed. For the latter, DNA was
isolated from patient’s blood and samples underwent either whole-exome
sequencing (WES, n = 126) or MME single-gene sequencing (n = 104).
Furthermore, the concentration of neprilysin was measured by ELISA in
patients’ blood.
Genetic Causes Identified by WES
126 DNA samples were screened by WES and for 23 samples rare nonsynonymous
likely pathogenic variants were identified, related to CMT2
or resembling the CMT2 phenotype. The most frequently involved gene
was MME (n = 8), followed by LRSAM1 (n = 3), MPZ (n = 2), TTR (n = 2)
and HMBS, VCP, WARS, AARS, DHTKD1, GARS, HARS and HSPB8 (n = 1,
respectively). Concerning the MME gene, three patients carried rare
biallelic variants consistent with autosomal recessive inheritance, while
five patients carried single heterozygous loss-of-function (frameshift,
nonsense or splice) variants.
Targeted sequencing of the MME gene
104 DNA samples were screened independently for MME variants and
revealed private or rare variants in 14 patients. One individual was consistent
with autosomal recessive inheritance, four patients carried single