TY  - JOUR
A1  - Hartmannsberger, Beate
A1  - Doppler, Kathrin
A1  - Stauber, Julia
A1  - Schlotter-Weigel, Beate
A1  - Young, Peter
A1  - Sereda, Michael W.
A1  - Sommer, Claudia
T1  - Intraepidermal nerve fiber density as biomarker in Charcot-Marie-Tooth disease 1A
JF  - Brain Communications
N2  - Charcot–Marie–Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case–control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot–Marie–Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot–Marie–Tooth type 1A was assessed by the Charcot–Marie–Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot–Marie–Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = −0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot–Marie–Tooth type 1A (P < 0.01, R = −0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot–Marie–Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot–Marie–Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot–Marie–Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot–Marie–Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot–Marie–Tooth type 1A disease progression on cutaneous innervation.
KW  - Charcot–Marie–Tooth disease type 1A
KW  - skin punch biopsy
KW  - intraepidermal nerve fibre density
KW  - Merkel cell density
KW  - reproducible outcome measure
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229538
VL  - 2
IS  - 1
ER  - 
TY  - JOUR
A1  - Niemann, Axel
A1  - Huber, Nina
A1  - Wagner, Konstanze M.
A1  - Somandin, Christian
A1  - Horn, Michael
A1  - Lebrun-Julien, Frédéric
A1  - Angst, Brigitte
A1  - Pereira, Jorge A.
A1  - Halfter, Hartmut
A1  - Welzl, Hans
A1  - Feltri, M. Laura
A1  - Wrabetz, Lawrence
A1  - Young, Peter
A1  - Wessig, Carsten
A1  - Toyka, Klaus V.
A1  - Suter, Ueli
T1  - The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease
JF  - Brain
N2  - The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot–Marie–Tooth disease. We found that Gdap1 knockout mice (\(Gdap1^{−/−}\)), mimicking genetic alterations of patients suffering from severe forms of Charcot–Marie–Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in \(Gdap1^{−/−}\) mice and mitochondrial transport is impaired in cultured sensory neurons of \(Gdap1^{−/−}\) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of \(Gdap1^{−/−}\) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged \(Gdap1^{−/−}\) mice compared with controls. Our findings demonstrate that Charcot–Marie–Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione.
KW  - animal models
KW  - Charcot-Marie-Tooth disease
KW  - mitochondria
KW  - axonal transport
KW  - demyelinating disease
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120731
VL  - 137
IS  - 3
ER  -