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1.  Inherited Peripheral Neuropathies 
Neurologic clinics  2013;31(2):597-619.
SYNOPSIS
Charcot Marie Tooth disease (CMT) is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder, as opposed to diseases in which the neuropathy is part of a more generalized neurological or multisystem syndrome. Due to the great genetic heterogeneity of this condition, it can be challenging for the general neurologist to diagnose patients with specific types of CMT. Here, we review the biology of the inherited peripheral neuropathies, delineate major phenotypic features of the CMT subtypes and suggest strategies for focusing genetic testing.
doi:10.1016/j.ncl.2013.01.009
PMCID: PMC3646296  PMID: 23642725
Charcot Marie Tooth; Inherited Neuropathy; Genetic Testing
2.  Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice 
Brain  2012;135(12):3551-3566.
Charcot–Marie–Tooth disease type 1B is caused by mutations in myelin protein zero. 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. Because oral curcumin, a component of the spice turmeric, has been shown to relieve endoplasmic reticulum stress and decrease the activation of the unfolded protein response, we treated R98C mutant mice with daily gastric lavage of curcumin or curcumin derivatives starting at 4 days of age and analysed them for clinical disability, electrophysiological parameters and peripheral nerve morphology. Heterozygous R98C mice treated with curcumin dissolved in sesame oil or phosphatidylcholine curcumin performed as well as wild-type littermates on a rotarod test and had increased numbers of large-diameter axons in their sciatic nerves. Treatment with the latter two compounds also increased compound muscle action potential amplitudes and the innervation of neuromuscular junctions in both heterozygous and homozygous R98C animals, but it did not improve nerve conduction velocity, myelin thickness, G-ratios or myelin period. The expression of c-Jun and suppressed cAMP-inducible POU (SCIP)—transcription factors that inhibit myelination when overexpressed—was also decreased by treatment. Consistent with its role in reducing endoplasmic reticulum stress, treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin was associated with decreased X-box binding protein (XBP1) splicing. Taken together, these data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response and by promoting Schwann cell differentiation.
doi:10.1093/brain/aws299
PMCID: PMC3577101  PMID: 23250879
Charcot-Marie-Tooth disease 1B; curcumin; myelin protein zero; peripheral neuropathy; unfolded protein response
3.  Neuropathy in Human and Mice with PMP22 null 
Archives of neurology  2011;68(6):814-821.
Background/Objective
Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies (HNPP). However, the biological functions of PMP22 in humans are largely unexplored due to the absence of patients with PMP22 null mutations.
Design, Setting and Participants
We have evaluated a 7-year-old boy with PMP22 null. Findings were compared with those from nerves of Pmp22 null mice.
Results
Motor and sensory deficits in the proband were non-length dependent. Weakness was found in cranial muscles, but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and DRG during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells that were more significant in motor nerve fibers than in sensory nerve fibers.
Conclusions
Taken together, these data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with absence of PMP22.
doi:10.1001/archneurol.2011.110
PMCID: PMC3711535  PMID: 21670407
4.  MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot–Marie–Tooth disease type 1B 
Brain  2012;135(7):2032-2047.
Mutations in myelin protein zero (MPZ) cause Charcot–Marie–Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C ‘knock-in’ mouse model of Charcot–Marie–Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/+) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/+ mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/+ mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results provide a potential link between the accumulation of MpzR98C in the endoplasmic reticulum and a developmental delay in myelination. These mice provide a model by which we can begin to understand the early onset dysmyelination seen in patients with R98C and similar mutations.
doi:10.1093/brain/aws140
PMCID: PMC3381724  PMID: 22689911
Charcot–Marie–Tooth type 1B; demyelination; neuromuscular disorders; glial cells; neuropathy
5.  Conduction Block in PMP22 Deficiency 
Patients with PMP22 deficiency present with focal sensory and motor deficits when peripheral nerves are stressed by mechanical force. It has been hypothesized that these focal deficits are due to mechanically induced conduction block (CB). To test this hypothesis, we induced 60-70% CB (defined by electrophysiological criteria) by nerve compression in an authentic mouse model of HNPP with an inactivation of one of the two pmp22 alleles (pmp22+/−). Induction time for the CB was significantly shorter in pmp22+/− mice than that in pmp22+/+ mice. This shortened induction was not found in the mice with deficiency of myelin protein zero (MPZ), a major structural protein of compact myelin. Pmp22+/− nerves showed intact tomacula with no segmental demyelination in both non-compressed and compressed conditions, normal molecular architecture, and normal concentration of voltage-gated sodium channels by H3-saxitoxin binding assay. However, focal constrictions were observed in the axonal segments enclosed by tomacula, a pathological hallmark of HNPP. The constricted axons increase axial-resistance to action potential propagation, which should hasten the induction of CB in pmp22 deficiency. Taken together, these results demonstrate that a function of Pmp22 is to protect the nerve from mechanical injury.
doi:10.1523/JNEUROSCI.4264-09.2010
PMCID: PMC3676309  PMID: 20071523
PMP22; conduction block; paranode; tomacula; hereditary neuropathy with liability to pressure palsies (HNPP); Schwann cell; myelin; Charcot-Marie-Tooth disease; axonal constriction
6.  Induced pluripotent stem cells in the study of neurological diseases 
Five years after their initial derivation from mouse somatic cells, induced pluripotent stem (iPS) cells are an important tool for the study of neurological diseases. By offering an unlimited source of patient-specific disease-relevant neuronal and glial cells, iPS cell-based disease models hold enormous promise for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery. The present review focuses on the recent advancements in modeling neurological disorders, including the demonstration of disease-specific phenotypes in iPS cell-derived neurons generated from patients with spinal muscular atrophy, familial dysautonomia, Rett syndrome, schizophrenia and Parkinson disease. The ability of this approach to detect treatment effects from known therapeutic compounds has also been demonstrated, providing proof of principle for the use of iPS cell-derived cells in drug discovery.
doi:10.1186/scrt78
PMCID: PMC3308034  PMID: 21936964
7.  Shortened internodal length of dermal myelinated nerve fibres in Charcot–Marie-Tooth disease type 1A 
Brain  2009;132(12):3263-3273.
Charcot–Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot–Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot–Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot–Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot–Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot–Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot–Marie-Tooth disease type 1A.
doi:10.1093/brain/awp274
PMCID: PMC2800385  PMID: 19923170
CMT1A; internodal length; Schwann cell; skin biopsy; Charcot–Marie-Tooth disease

Results 1-7 (7)