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Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes.

May 16, 2010

J Neurol. 2010 May 12
Lee YC, Lin KP, Chang MH, Liao YC, Tsai CP, Liao KK, Soong BW.

Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.

Mutations in MPZ, which encodes myelin protein zero (P(0)), may lead to different subtypes of Charcot-Marie-Tooth disease (CMT). The aim of this study was to characterize the cellular manifestations of various MPZ mutations associated with CMT1, Dejerine-Sottas syndrome (DSS) and CMT2, and to correlate their cellular and clinical phenotypes.

Nine P(0) mutants associated with CMT1 (P(0)S63F, R98H, R277S, and S233fs), DSS (P(0) I30T and R98C), and CMT2 (P(0)S44F, D75V, and T124M), were investigated. Wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular localization.

An adhesiveness assay was used to evaluate the adhesiveness of the transfected cells. Protein localization and cell adhesiveness of each mutant protein were compared and correlated with their clinical phenotypes.

Three different intracellular localization patterns of the mutant P(0) were observed. Wild-type P(0), P(0)I30T, S44F, S63F, D75V, T124M, and R227S were mostly localized on the cell membrane, P(0)R98H, and R98C were found in the endoplasmic reticulum (ER) or Golgi apparatus, and P(0)S233fs formed aggregates within the ER.

Cells expressing mutant P(0), as compared with those expressing wild-type P(0), demonstrated variable degrees of reduction in the cell adhesiveness.

The molecular patho-mechanisms of MPZ mutations are likely very complex and the clinical phenotype must be influenced by many genetic or environmental factors.

This complexity may contribute to the highly variable clinical manifestations resulting from different MPZ mutations.

Bioavailability of Curcumin: Problems and Promises

November 21, 2007

Mol Pharm. 2007 Nov 14
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.
Cytokine Research Laboratory and Pharmaceutical Development Center, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination.
To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life.
Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn’s disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.

Oral Curcumin Mitigates the Clinical and Neuropathologic Phenotype of the Trembler-J Mouse: A Potential Therapy for Inherited Neuropathy

August 7, 2007

Author(s) Mehrdad Khajavi, Kensuke Shiga, Wojciech Wiszniewski, Feng He, Chad A. Shaw, Jiong Yan, Theodore G. Wensel, G. Jackson Snipes, and James R. Lupski
The American Journal of Human Genetics, volume 81 (2007), page 000
DOI: 10.1086/519926
Mutations in myelin genes cause inherited peripheral neuropathies that range in severity from adult-onset Charcot-Marie-Tooth disease type 1 to childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Many myelin gene mutants that cause severe disease, such as those in the myelin protein zero gene (MPZ) and the peripheral myelin protein 22 gene (PMP22), appear to make aberrant proteins that accumulate primarily within the endoplasmic reticulum (ER), resulting in Schwann cell death by apoptosis and, subsequently, peripheral neuropathy.
We previously showed that curcumin supplementation could abrogate ER retention and aggregation-induced apoptosis associated with neuropathy-causing MPZ mutants.
We now show reduced apoptosis after curcumin treatment of cells in tissue culture that express PMP22 mutants. Furthermore, we demonstrate that oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner.
Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons in sciatic nerves, leading to improved motor performance. Our findings indicate that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and improves the neuropathologic phenotype in an animal model of human neuropathy, suggesting a potential therapeutic role
in selected forms of inherited peripheral neuropathies.

Onset and duration of mivacurium-induced neuromuscular blockade in children with Charcot-Marie-Tooth disease. A case series with five children.

February 1, 2006

Filed under: Journal articles

Paediatr Anaesth. 2006 Feb;16(2):182-7.
Schmitt HJ, Wick S, Munster T.
Department of Anaesthesiology, The Department is part of the Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Summary Background: The Charcot-Marie-Tooth (CMT) disorders are a group of hereditary motor and sensory neuropathies characterized clinically by peripheral muscle wasting and weakness. We hypothesized that unknown involvement of the muscle used for monitoring neuromuscular block may account for the conflicting reports about the effect of nondepolarizing neuromuscular agents in these patients. The aim of this study was to compare onset and recovery from mivacurium-induced neuromuscular block on the adductor pollicis and orbicularis oculi muscles.
Methods: We used mivacurium 0.2 in five children (aged 7-12 years) with CMT type I undergoing propofol-fentanyl-oxygen-air anesthesia for orthopedic surgery. Using acceleromyography, neuromuscular transmission was monitored in parallel in the eye and thumb muscles, and onset and duration times were recorded.
Results: Following bolus administration of 0.2 of mivacurium the onset time ranged between 135 and 240 s and 75 and 165 s in the eye and in the thumb, respectively. The recovery time varied between 5.3 and 16 min and 6 and 31.3 min in the eye and in the thumb, respectively.
Conclusions: In our small series of patients with CMT the clinical duration of mivacurium-induced neuromuscular block was similar to data known from children without neuromuscular disease.

Molecular alterations resulting from frameshift mutations in peripheral myelin protein 22: Implications for neuropathy severity

November 9, 2005

Filed under: Journal articles

J Neurosci Res. 2005 Nov 4
Johnson JS, Roux KJ, Fletcher BS, Fortun J, Notterpek L.
Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida.
Alterations in peripheral myelin protein 22 (PMP22) expression are associated with a heterogeneous group of hereditary demyelinating peripheral neuropathies. Two mutations at glycine 94, a single guanine insertion or deletion in PMP22, result in different reading frameshifts and, consequently, an extended G94fsX222 or a truncated G94fsX110 protein, respectively. Both of these autosomal dominant mutations alter the second half of PMP22 and yet are linked to clinical phenotypes with distinct severities. The G94fsX222 is associated with hereditary neuropathy with liability to pressure palsies, whereas G94fsX110 causes severe neuropathy diagnosed as Dejerine-Sottas disease or Charcot-Marie-Tooth disease type IA. To investigate the subcellular changes associated with the G94 frameshift mutations, we expressed epitope-tagged forms in primary rat Schwann cells. Biochemical and immunolabeling studies indicate that, unlike the wild-type protein, which is targeted for the plasma membrane, frameshift PMP22s are retained in the cell, prior to reaching the medial Golgi compartment. Similar to Wt-PMP22, both frameshift mutants are targeted for proteasomal degradation and accumulate in detergent-insoluble, ubiquitin-containing aggregates upon inhibition of this pathway. The extended frameshift PMP22 shows the ability to form spontaneous aggregates in the absence of proteasome inhibition. On the other hand, Schwann cells expressing the truncated protein proliferate at a significantly higher rate than Schwann cells expressing the wild-type or the extended PMP22. In summary, these results suggest that a greater potential for PMP22
aggregation is associated with a less severe phenotype, whereas dysregulation of Schwann cell proliferation is linked to severe neuropathy.

Neurological and Neuromuscular Disease as a Risk Factor for Respiratory Failure in Children Hospitalized With Influenza Infection

November 2, 2005

Filed under: Journal articles

The Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccination for children with certain chronic medical conditions to prevent serious complications of influenza infection. Little is known about the relative contribution of each of these chronic medical conditions to the development of serious influenza-associated complications. [Read more]
And in plain English:

Kids With Neurological, Neuromuscular Diseases Need Flu Shot

While U.S. health officials already recommend that a number of children with chronic diseases, such as diabetes, heart disease and lung disorders, be vaccinated for influenza, a new study finds another group of children should be added to that list–those with neurological or neuromuscular diseases.
The reason, according to the study from the Children’s Hospital of Philadelphia and the U.S. Centers for Disease Control and Prevention, is that these children face a higher risk of serious flu-related complications. In fact, the study found that children with neurological or neuromuscular diseases (NNMD) are at a six-fold greater risk of flu-related respiratory failure. [Read more]

Structure and Stability of Internodal Myelin in Mouse Models of Hereditary Neuropathy

October 30, 2005

Filed under: Journal articles

Journal of Neuropathology & Experimental Neurology. 64(11):976-990, November 2005.
Avila, Robin L BS; Inouye, Hideyo PhD; Baek, Rena C BS; Yin, Xinghua MD; Trapp, Bruce D PhD; Feltri, M Laura MD; Wrabetz, Lawrence MD; Kirschner, Daniel A PhD
Peripheral neuropathies often result in abnormalities in the structure of internodal myelin, including changes in period and membrane packing, as observed by electron microscopy (EM). Mutations in the gene that encodes the major adhesive structural protein of internodal myelin in the peripheral nervous system of humans and mice-P0 glycoprotein-correlate with these defects. The mechanisms by which P0 mutations interfere with myelin packing and stability are not well understood and cannot be provided by EM studies that give static and qualitative information on fixed material. To gain insights into the pathogenesis of mutant P0, we used x-ray diffraction, which can detect more subtle and dynamic changes in native myelin, to investigate myelin structure in sciatic nerves from murine models of hereditary neuropathies. We used mice with disruption of one or both copies of the P0 gene (models of Charcot-Marie-Tooth-like neuropathy [CMT1B] or Dejerine-Sottas-like neuropathy) and mice with a CMT1B resulting from a transgene encoding P0 with an amino terminal myc-tag. To directly test the structural role of P0, we also examined a mouse that expresses P0 instead of proteolipid protein in central nervous system myelin. To link our findings on unfixed nerves with EM results, we analyzed x-ray patterns from unembedded, aldehyde-fixed nerves and from plastic-embedded nerves. From the x-ray patterns recorded from whole nerves, we assessed the amount of myelin and its quality (i.e. relative thickness and regularity). Among sciatic nerves having different levels of P0, we found that unfixed nerves and, to a lesser extent, fixed but unembedded nerves gave diffraction patterns of sufficient quality to distinguish periods, sometimes differing by a few A. Certain packing abnormalities were preserved qualitatively by aldehyde fixation, and the relative amount and structural integrity of myelin among nerves could be distinguished. Measurements from the same nerve over time showed that the amount of P0 affected myelin’s stability against swelling, thus directly supporting the hypothesis that packing defects underlie instability in “live” or intact myelin. Our findings demonstrate that diffraction can provide a quantitative basis for understanding, at a molecular level, the membrane packing defects that occur in internodal myelin in demyelinating peripheral neuropathies. [Read more]

Curcumin Treatment Abrogates Endoplasmic Reticulum Retention and Aggregation-Induced Apoptosis Associated with Neuropathy-Causing Myelin Protein Zero-Truncating Mutants

October 29, 2005

Filed under: Journal articles

Mehrdad Khajavi, Ken Inoue, Wojciech Wiszniewski, Tomoko Ohyama, G. Jackson Snipes, and James R. Lupski
The American Journal of Human Genetics, volume 77 (2005), pages 841–850
Mutations in MPZ, the gene encoding myelin protein zero (MPZ), the major protein constituent of peripheral myelin, can cause the adult-onset, inherited neuropathy Charcot-Marie-Tooth disease, as well as the more severe, childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Most MPZ-truncating mutations associated with severe forms of peripheral neuropathy result in premature termination codons within the terminal or penultimate exons that are not subject to nonsense-mediated decay and are stably translated into mutant proteins with potential dominant-negative activity. However, some truncating mutations at the 3 end of MPZ escape the nonsense-mediated decay pathway and cause a mild peripheral neuropathy phenotype. We examined the functional properties of MPZ-truncating proteins that escaped nonsense-mediated decay, and we found that frameshift mutations associated with severe disease cause an intracellular accumulation of mutant proteins, primarily within the endoplasmic reticulum (ER), which induces apoptosis. Curcumin, a chemical compound derived from the curry spice tumeric, releases the ER-retained MPZ mutants into the cytoplasm accompanied by a lower number of apoptotic cells. Our findings suggest that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and may potentially have a therapeutic role in treating selected forms of inherited peripheral neuropathies. [Read more]

Respiratory function assessment and intervention in neuromuscular disorders

September 20, 2005

Filed under: Journal articles

Current Opinion in Neurology. 18(5):543-547, October 2005.
Mellies, Uwe; Dohna-Schwake, Christian; Voit, Thomas
Purpose of review: Published research on neuromuscular respiratory failure has increased rapidly over the past decade. Progress in the management of respiratory complications and preventive care have improved outcomes and quality of life for many. In particular, noninvasive positive pressure ventilation (NIPPV) is effective in resolving respiratory failure and has dramatically changed the management of these patients. In this review we discuss recent studies assessing the course of respiratory failure, with a focus on non-Duchenne muscular dystrophy; investigating the impact NIPPV has when it is introduced before diurnal respiratory failure develops; and evaluating a device to treat insufficient cough – the mechanical insufflator-exsufflator (MI-E).
Recent findings: Studies in children with congenital muscular dystrophies and spinal muscular atrophies detected a high prevalence of respiratory complications and confirmed that respiratory failure can be predicted by measurement of vital capacity. NIPPV is an established treatment that is effective in the long-term management of end-stage diurnal respiratory failure. Additionally, recent studies showed improvement in symptoms, quality of life and prevention of respiratory complications when it is introduced for nocturnal hypoventilation before the development of diurnal respiratory failure. However, data on the efficiency of the MI-E are limited, and studies comparing it with other techniques of assisted coughing are needed.
Summary: Recent findings stress the importance of regular respiratory assessment in neuromuscular disease, including sleep studies; strongly support the introduction of NIPPV for management of symptomatic nocturnal hypoventilation; and suggest that prospective randomized trials are required to verify the usefulness of the MI-E.

Dejerine-Sottas syndrome and vestibular loss due to a point mutation in the PMP22 gene

July 6, 2005

Filed under: Journal articles

We describe a father and daughter with Dejerine-Sottas syndrome and bilateral vestibular loss due to an L71P missense mutation in the peripheral myelin protein 22 (PMP22). The combination of vestibular loss and peripheral neuropathy led to profound imbalance at a young age. It is important to recognize this combination of peripheral nerve and vestibular deficits since rehabilitation strategies and prognosis are different. [PubMed link]

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