Abstract
ObjectiveCharcot-Marie-Tooth 1A (CMT1A) disease is the most common inherited neuropathy that lacks of therapy and of molecular markers to assess disease severity. Herein, we have pursued the identification of potential biomarkers in plasma samples and skin biopsies that could define the phenotype of CMT1A patients at mild (Mi), moderate (Mo) and severe (Se) stages of disease as assessed by the CMT neuropathy score to contribute to the understanding of CMT pathophysiology and eventually inform of the severity of the disease.MethodsWe have used: (i) a high-throughput untargeted metabolomic approach of plasma samples in a cohort of 42 CMT1A patients and 15 healthy controls (CRL) using ultrahigh liquid chromatography coupled to mass spectrometry and (ii) reverse phase protein microarrays to quantitate the expression of some proteins of energy metabolism and of the antioxidant response in skin biopsies of a cohort of 70 CMT1A patients and 13 healthy controls.ResultsThe metabolomic approach identified 194 metabolites with significant differences among the four groups (Mi, Mo, Se, CRL) of samples. A multivariate Linear Discriminant Analysis model using 12 metabolites afforded the correct classification of the samples. These metabolites indicate an increase in protein catabolism and the mobilization of membrane lipids involved in signaling inflammation with severity of CMT1A. A concurrent depletion of leucine, which is required for the biogenesis of the muscle, is also observed in the patients. Protein expression in skin biopsies indicates early loss of mitochondrial and antioxidant proteins in patients’ biopsies.ConclusionThe findings indicate that CMT1A disease is associated with a metabolic state resembling inflammation and sarcopenia suggesting that it might represent a potential target to prevent the nerve and muscle wasting phenotype in these patients. The observed changes in metabolites could be useful as potential biomarkers of CMT1A disease after appropriate validation in future longitudinal studies.
Highlights
Charcot-Marie-Tooth (CMT) disease, referred as hereditary motor and sensory neuropathy, is the most common group of inherited neuromuscular disorder with a prevalence of 1/2,500 [1]
We have used: (i) a high-throughput untargeted metabolomic approach of plasma samples in a cohort of 42 CMT is type 1A (CMT1A) patients and 15 healthy controls (CRL) using ultrahigh liquid chromatography coupled to mass spectrometry and (ii) reverse phase protein microarrays to quantitate the expression of some proteins of energy metabolism and of the antioxidant response in skin biopsies of a cohort of 70 CMT1A patients and 13 healthy controls
A multivariate Linear Discriminant Analysis model using 12 metabolites afforded the correct classification of the samples
Summary
Charcot-Marie-Tooth (CMT) disease, referred as hereditary motor and sensory neuropathy, is the most common group of inherited neuromuscular disorder with a prevalence of 1/2,500 [1]. The most common form of CMT is type 1A (CMT1A), which is due to a 1.4 Mb duplication of chromosome 17 containing the PMP22 gene [3, 4]. Progesterone antagonists or recombinant human neuregulin-1 have been investigated as therapies in rodent models [8,9,10]. To date, the clinical trials using ascorbic acid in humans have not shown an effect on disease severity and progression [11, 12] and the need of biomarkers [13] for assessing CMT disease severity, progression and response to therapy are urgently required
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