Charcot-Marie-Tooth disease, type 1B (CMT1B, OMIM 118200) is an autosomal dominant neuropathy caused by mutations in myelin protein zero (MPZ, OMIM 159440), a structural protein of peripheral myelin.
Family study revealed that de novo Ile62Phe mutation on the MPZ gene occurred in the proband and was inherited by her children with early onset slowly progressive neuropathy.
In this study we excluded all four regions for the presence of distal HMN II, indicating that this neuropathy is genetically different from CMT 1 and recessive SMA.
R98C mice, an authentic model of early onset Charcot-Marie-Tooth disease type 1B, develop neuropathy in part because the misfolded mutant myelin protein zero is retained in the endoplasmic reticulum where it activates the unfolded protein response.
Elegant studies with Ser63del mice suggest that Ser63delMPZ is retained in the ER where it activates the unfolded protein response (UPR) that contributes to the neuropathy.
This case illustrates the clinical heterogeneity that exists in neuropathies associated with MPZ mutations and highlights that in patients with mild hypotonia in the first months that develop a very severe demyelinating neuropathy, the MPZ gene must be taken into account.
We report a patient with Charcot-Marie-Tooth disease (CMT) due to the p.Ile112Thr mutation in myelin protein zero (MPZ) who presented with a patchy neuropathy with conduction block and tonic pupils.
Identifying molecular pathways involved in early and late onset CMT1B will be crucial to understand how MPZ mutations cause CMT1B so that rational therapies for both early and late onset neuropathies can be developed.
Moreover, we provide strong evidence that the Schwann cell-specific ablation of the ERAD factor Derlin-2 in S63del nerves exacerbates both the myelin defects and the UPR in vivo, unveiling a protective role for ERAD in CMT1Bneuropathy.
Molecular genetic testing and particularly screening for MPZ mutations in late onset neuropathies are important to differentiate acquired and inherited neuropathies.
The Pro132Leu mutation segregates with a severe early-onset dysmyelinating-hypomyelinating neuropathy, whereas the Ile135Thr substitution is associated with the classical phenotype of CMT1.
Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2).
Exenatide-induced phosphorylation of p38 and CREB was also totally blocked by the PKA inhibitor and siRNA/p38<i>β</i>, but not by siRNA/p38<i>α</i> Seven-day intrathecal injections of siRNA/p38<i>β</i> (but not siRNA/p38<i>α</i>) completely blocked exenatide-induced spinal p38 activation, <i>β</i>-endorphin expression, and mechanical antiallodynia in rats with established neuropathy, although siRNA/p38<i>β</i> and siRNA/p38<i>α</i> were not antiallodynic.
VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization.