Charcot-Marie-Tooth Type Research Articles

Ascorbic acid, myelination and associated disorders

Ascorbic acid has been considered, for a long time, only as an antioxidant. Since a few years, growing evidences, from literature, demonstrate that this molecule has other function. This is why different groups tried to find new targets for ascorbic acid, not only to prevent scurvy, but also as a drug. In this line of evidence, we report that high doses of ascorbic acid partially correct the phenotype of a Charcot–Marie–Tooth type 1A model, created in the lab. Based on this result, several clinical trials have been undertaken. Unfortunately, they have been controversial, primary outcomes never been reached, but tendencies observed. What conclusion could we draw? This will be discussed below.We published, in 2004, an article demonstrating that treatment of an animal model of CMT1A by high dose of ascorbic acid (AA), partially restores myelination and normal locomotion [1]. Our research was based on articles demonstrating that AA is necessary for myelination in co-culture of axon and Schwann cells [2–4]. This article was followed by clinical trials. Visioli et al. [5] recently published, in this journal, an article discussing AA treatment in Charcot–Marie–Tooth [5]. In this publication they use pharmacokinetics arguments to affirm that ascorbic acid could not be a treatment for CMT1A. In this paper, we will present arguments that demonstrate that this conclusion could be commented, as numerous arguments, based on literature, are not present in the article. We will thus expose these additional arguments, in the following sections.

Mutational analysis of PMP22, EGR2, LITAF and NEFL in Greek Charcot–Marie–Tooth type 1 patients

Clinical GeneticsVolume 83, Issue 4 p. 388-391 LETTERS TO THE EDITOR Mutational analysis of PMP22, EGR2, LITAF and NEFL in Greek Charcot–Marie–Tooth type 1 patients G Koutsis, Corresponding Author G Koutsis Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, Greece Correspondence: Dr G Koutsis Neurogenetics Unit Department of Neurology University of Athens Medical School Eginitio Hospital, 74 Vas. Sophias Avenue Athens 11528, Greece Tel.: +302107289118; fax: +302107289289; e-mail: gkoutsi2@otenet.grSearch for more papers by this authorA Pandraud, A Pandraud Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this authorG Karadima, G Karadima Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, GreeceSearch for more papers by this authorM Panas, M Panas Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, GreeceSearch for more papers by this authorMM Reilly, MM Reilly Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this authorP Floroskufi, P Floroskufi Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, GreeceSearch for more papers by this authorNW Wood, NW Wood Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this authorH Houlden, H Houlden Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this author G Koutsis, Corresponding Author G Koutsis Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, Greece Correspondence: Dr G Koutsis Neurogenetics Unit Department of Neurology University of Athens Medical School Eginitio Hospital, 74 Vas. Sophias Avenue Athens 11528, Greece Tel.: +302107289118; fax: +302107289289; e-mail: gkoutsi2@otenet.grSearch for more papers by this authorA Pandraud, A Pandraud Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this authorG Karadima, G Karadima Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, GreeceSearch for more papers by this authorM Panas, M Panas Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, GreeceSearch for more papers by this authorMM Reilly, MM Reilly Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this authorP Floroskufi, P Floroskufi Neurogenetics Unit, Department of Neurology, University of Athens Medical School, Eginitio Hospital, Athens, GreeceSearch for more papers by this authorNW Wood, NW Wood Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this authorH Houlden, H Houlden Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKSearch for more papers by this author First published: 19 April 2013 https://doi.org/10.1111/j.1399-0004.2012.01910.xCitations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume83, Issue4April 2013Pages 388-391 RelatedInformation

Prolonged high frequency electrical stimulation is lethal to motor axons of mice heterozygously deficient for the myelin protein P0 gene

The relationship between dysmyelination and the progression of neuropathy in Charcot–Marie–Tooth (CMT) hereditary polyneuropathy is unclear. Mice heterozygously deficient for the myelin protein P0 gene (P0+/−) are indistinguishable from wild-type (WT) at birth and then develop a slowly progressing demyelinating neuropathy reminiscent of CMT Type 1b. Accumulating evidence suggests that impulse conduction can become lethal to acutely demyelinated central and peripheral axons. Here we investigated the vulnerability of motor axons to long-lasting, high-frequency repetitive stimulation (RS) in P0+/− mice as compared to WT littermates at 7, 12, and 20months of age. RS was carried out in interrupted trains of 200Hz trains for 3h. Tibial nerves were stimulated at the ankle while the evoked compound muscle action potentials (CMAPs) and the ascending compound nerve action potentials (CNAPs) were recorded from plantar muscles and the sciatic nerve, respectively. In 7-month old mice, there was recovery of CMAP and CNAP following RS. When mice were about one year old, electrophysiological recovery following RS was incomplete and in P0+/− also associated with morphological signs of partial Wallerian degeneration. The effect of RS was larger in P0+/− as compared to age-matched WT. When mice were about 2years old, the effect was stronger and became similar between WT and P0+/−. RS was followed by a transient hyperpolarization, which decreased with age and was smaller in P0+/− than in WT. Our data suggest that both aging and the dysmyelinating disease process may contribute to the susceptibility to activity-induced axonal degeneration. It is possible that in aging mice and in P0+/− there is inadequate energy-dependent Na+/K+ pumping, as indicated by the reduced post-stimulation hyperpolarization, which may lead to a lethal Na+ overload in some axons.

Czech family confirms the link between FBLN5 and Charcot–Marie–Tooth type 1 neuropathy

Sir, The article by Auer-Grumbach et al. (2011) reporting that fibulin 5 ( FBLN5 ) mutations are also linked to inherited neuropathies helped us to clarify the cause of autosomal dominant, demyelinating hereditary motor and sensory neuropathy (HMSN I) in our long-time known, but unsolved, Czech family. Before this study was published, mutations in FBLN5 were associated only with the connective tissue disorder cutis laxa (Loeys et al. , 2002; Markova et al. , 2003; Lotery et al. , 2006; Nascimento et al. , 2010) and age-related macular degeneration leading to vision loss in those aged >50 years (Stone et al. , 2004; Lotery et al. , 2006). Auer-Grumbach et al. (2011) were the first to describe a large family with demyelinating Charcot–Marie–Tooth (CMT1) and linkage with the interval on chromosome 14. Subsequent resequencing of this region revealed only one novel variant c.1117 C > T (p.R373C) segregating with the disease in the family. Additional screening of 112 patients with Charcot–Marie–Tooth disease showed two other sequence variations in two patients with pure motor neuropathy and hyperelastic skin. The linkage with log of odds score >3.31 indicates the FBLN5 mutation as highly probably causal for HMSN I, but no functional study to confirm this was performed, and no other study on FBLN5 mutations in a family with HMSN has been published to date. This Austrian HMSN I family is the only one reported worldwide. We report a second family with non-syndromic inherited demyelinating motor and sensory neuropathy (HMSN I) with FBLN5 mutation and confirm FBLN5 mutations as the new cause of HMSN I. We used exome sequencing for clarification of the cause of HMSN I in a Czech family recruited in 2001 (Fig. 1A). The most frequent causes of CMT1 (CMT1 duplication/HNPP …

Oral Health, Temporomandibular Disorder, and Masticatory Performance in Patients with Charcot-Marie-Tooth Type 2

Background. The aim of this study was to evaluate the oral health status of temporomandibular disorders (TMD) and bruxism, as well as to measure masticatory performance of subjects with Charcot-Marie-Tooth type 2 (CMT2). Methods and Results. The average number of decayed, missing, and filled teeth (DMFT) for both groups, control (CG) and CMT2, was considered low (CG = 2.46; CMT2 = 1.85, P = 0.227). The OHIP-14 score was considered low (CG = 2.86, CMT2 = 5.83, P = 0.899). The prevalence of self-reported TMD was 33.3% and 38.9% (P = 0.718) in CG and CMT2 respectively and for self-reported bruxism was 4.8% (CG) and 22.2% (CMT2), without significant difference between groups (P = 0.162). The most common clinical sign of TMD was masseter (CG = 38.1%; CMT2 = 66.7%) and temporalis (CG = 19.0%; GCMT2 = 33.3%) muscle pain. The geometric mean diameter (GMD) was not significantly different between groups (CG = 4369; CMT2 = 4627, P = 0.157). Conclusion. We conclude that the CMT2 disease did not negatively have influence either on oral health status in the presence and severity of TMD and bruxism or on masticatory performance.

Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease

ObjectivePreimplantation genetic diagnosis (PGD) is an assisted reproductive technique for couples carrying genetic risks. Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy, with a prevalence rate of 1/2,500. In this study, we report on our experience with PGD cycles performed for CMT types 1A and 2F.MethodsBefore clinical PGD, we assessed the amplification rate and allele drop-out (ADO) rate of multiplex fluorescent polymerase chain reaction (PCR) followed by fragment analysis or sequencing using single lymphocytes. We performed six cycles of PGD for CMT1A and one cycle for CMT2F.ResultsTwo duplex and two triplex protocols were developed according to the available markers for each CMT1A couple. Depending on the PCR protocols, the amplification rates and ADO rates ranged from 90.0% to 98.3% and 0.0% to 11.1%, respectively. For CMT2F, the amplification rates and ADO rates were 93.3% and 4.8%, respectively. In case of CMT1A, 60 out of 63 embryos (95.2%) were diagnosed and 13 out of 21 unaffected embryos were transferred in five cycles. Two pregnancies were achieved and three babies were delivered without any complications. In the case of CMT2F, a total of eight embryos were analyzed and diagnosed. Seven embryos were diagnosed as unaffected and four embryos were transferred, resulting in a twin pregnancy. Two healthy babies were delivered.ConclusionThis is the first report of successful pregnancy and delivery after specific PGD for CMT disease in Korea. Our PGD procedure could provide healthy babies to couples with a high risk of transmitting genetic diseases.

Charcot–Marie–Tooth type 2B disease-causing RAB7A mutant proteins show altered interaction with the neuronal intermediate filament peripherin

Charcot–Marie–Tooth type 2B (CMT2B) is a peripheral ulcero-mutilating neuropathy caused by four missense mutations in the rab7a gene. CMT2B is clinically characterized by prominent sensory loss, distal muscle weakness leading to muscle atrophy, high frequency of foot ulcers and infections that often results in toe amputations. RAB7A is a ubiquitous small GTPase, which controls transport to late endocytic compartments. Although the biochemical and functional properties of disease-causing RAB7A mutant proteins have been investigated, it is not yet clear how the disease originates. To understand how mutations in a ubiquitous protein specifically affect peripheral neurons, we performed a two-hybrid screen using a dorsal root ganglia cDNA library with the purpose of identifying RAB7A interactors specific for these cells. We identified peripherin, an intermediate filament protein expressed primarily in peripheral neurons, as a putative RAB7A interacting protein. The interaction was confirmed by co-immunoprecipitation and pull-down experiments, and established that the interaction is direct using recombinant proteins. Silencing or overexpression of wild type RAB7A changed the soluble/insoluble rate of peripherin indicating that RAB7A is important for peripherin organization and function. In addition, disease-causing RAB7A mutant proteins bind more strongly to peripherin and their expression causes a significant increase in the amount of soluble peripherin. Since peripherin plays a role not only in neurite outgrowth during development but also in axonal regeneration after injury, these data suggest that the altered interaction between disease-causing RAB7A mutants and peripherin could play an important role in CMT2B neuropathy.

Molecular basis of Charcot–Marie–Tooth type 2B disease

CMT2B (Charcot-Marie-Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway. In neurons, Rab7 is important for endosomal trafficking and signalling of neurotrophins, and for retrograde axonal transport. Recent data on CMT2B-causing Rab7 mutant proteins show that these proteins exhibit altered koff rates and, as a consequence, they are mainly in the GTP-bound state and bind more strongly to Rab7 effector proteins. Notably, expression of CMT2B-causing Rab7 mutant proteins strongly inhibit neurite outgrowth in several cells lines and alter NGF (nerve growth factor) trafficking and signalling. These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. In the present paper, we discuss the current understanding of the molecular and cellular mechanisms underlying CMT2B, and we consider possible hypotheses in order to explain how alterations of Rab7 function lead to CMT2B.

Genetics of the Charcot‐Marie‐Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy‐Russe in depth

Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range.

In vivo, Pikfyve generates PI(3,5)P 2 , which serves as both a signaling lipid and the major precursor for PI5P

Mutations that cause defects in levels of the signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P(2)] lead to profound neurodegeneration in mice. Moreover, mutations in human FIG4 predicted to lower PI(3,5)P(2) levels underlie Charcot-Marie-Tooth type 4J neuropathy and are present in selected cases of amyotrophic lateral sclerosis. In yeast and mammals, PI(3,5)P(2) is generated by a protein complex that includes the lipid kinase Fab1/Pikfyve, the scaffolding protein Vac14, and the lipid phosphatase Fig4. Fibroblasts cultured from Vac14(-/-) and Fig4(-/-) mouse mutants have a 50% reduction in the levels of PI(3,5)P(2), suggesting that there may be PIKfyve-independent pathways that generate this lipid. Here, we characterize a Pikfyve gene-trap mouse (Pikfyve(β-geo/β-geo)), a hypomorph with ~10% of the normal level of Pikfyve protein. shRNA silencing of the residual Pikfyve transcript in fibroblasts demonstrated that Pikfyve is required to generate all of the PI(3,5)P(2) pool. Surprisingly, Pikfyve also is responsible for nearly all of the phosphatidylinositol-5-phosphate (PI5P) pool. We show that PI5P is generated directly from PI(3,5)P(2), likely via 3'-phosphatase activity. Analysis of tissues from the Pikfyve(β-geo/β-geo) mouse mutants reveals that Pikfyve is critical in neural tissues, heart, lung, kidney, thymus, and spleen. Thus, PI(3,5)P(2) and PI5P have major roles in multiple organs. Understanding the regulation of these lipids may provide insights into therapies for multiple diseases.

Three Routes to Suppression of the Neurodegenerative Phenotypes Caused by Kinesin Heavy Chain Mutations

Kinesin-1 is a motor protein that moves stepwise along microtubules by employing dimerized kinesin heavy chain (Khc) subunits that alternate cycles of microtubule binding, conformational change, and ATP hydrolysis. Mutations in the Drosophila Khc gene are known to cause distal paralysis and lethality preceded by the occurrence of dystrophic axon terminals, reduced axonal transport, organelle-filled axonal swellings, and impaired action potential propagation. Mutations in the equivalent human gene, Kif5A, result in similar problems that cause hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth type 2 (CMT2) distal neuropathies. By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5A HSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin-1. Our results reveal the value of large-scale complementation analysis for gaining insight into protein structure-function relationships in vivo and point to possible paths for suppressing symptoms of HSP and related distal neuropathies.

G.P.87 Demyelinating neuropathy caused by point mutations in PMP22 gene: Phenotype variability

Abstract Charcot–Marie–Tooth type 1A (CMT1A) is the main form of a dominant hereditary demyelinating neuropathy, caused by a duplication of the PMP22 gene. This gene, encodes the protein of the myelin membrane expressed on the Schwann’s cells of the peripheral nerves. Point mutations of PMP22 gene are less frequent and have been associated with a wide range of phenotypes that may vary from mild hereditary neuropathy to the Dejerine–Sottas syndrome. The aim of the present study is to describe the clinical and electrophysiological features of six patients with CMT neuropathy with a point mutations in PMP22 gene. Clinical cases: We describe six patients with point mutations in the PMP22 gene; three of them (two siblings) have the Thr118Met mutation. The mean age of the patients was 13 years (range: 9–22). Four of the patients developed the first symptoms between the age of 2 and 3 years, showing an unstable gait and frequent falls, and evolved in a stable way, developing cavous feet and distal atrophy. The other two cases, showed a more severe phenotype, starting their first symptoms in the neonatal period, with hypotonia and arreflexia; one of them, developed Dejerine–Sottas syndrome and was not able to reach an autonomous gait due to the severe ataxia; the other patient, presented frequent pneumonias during the first years of age due to diaphragmatic paralysis and developed a proximal and distal weakness that impeded her to climb stairs and to stand up from the floor; her brother, affected by the same mutation, showed a milder phenotype. The electrophysiology study showed a demyelinating neuropathy in all the cases. Conclusions: There is a wide clinical spectrum in patients with a point mutation on PMP22 gene. We recommend the study of point mutations once the duplication of the PMP22 gene has been ruled out. We confirm that the Thr118Met mutation recently described, causes a demyelinating neuropathy with different degrees of severity,even between members of the same family.

Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN). A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function. Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme. We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.

Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controls

BackgroundTRPV4 mutations have been identified in Charcot–Marie–Tooth type 2 (CMT2), scapuloperoneal spinal muscular atrophy and distal hereditary motor neuropathy (dHMN).ObjectiveWe aimed to screen the TRPV4 gene in 422 British patients...

An MBoC Favorite: Axonal membrane proteins are transported in distinct carriers: a two-color video microscopy study in cultured hippocampal neurons

Neuronal cell bodies supply the axon and nerve terminal with organelle precursors, such as synaptic vesicle precursors, by means of membrane-bound carriers propelled by motors mounted on cytoskeletal tracks. Several neurodegenerative diseases, such as CharcotMarie-Tooth type 2 disease and hereditary spastic paraplegia, involve the defective delivery of organelles from the cell body and impaired bidirectional trafficking in long axons. The diversity of causative genetic mutations affecting, for example, endosome traffic proteins, such as the WASH complex, molecular motors and their cargo adaptors, and the shared clinical features of axonal degeneration suggest a corresponding diversity of precursor organelles that traffic in axons. In 2000, Kaether et al. were among the first to show that more than one type of precursor organelle is delivered to nerve terminals (Kaether et al., 2000). This seminal study directly demonstrated the sorting and bidirectional transport of two fluorescent-tagged axonal membrane proteins, amyloid precursor protein and synaptophysin, into different membrane-bound carriers in hippocampal neurons. These carriers possess morphological features and transport speeds that clearly differentiate them. Thus, diverse precursor carriers share a common function of providing axonal and synaptic compartments with their constituents.

Hereditary motor neuron disease in a large Norwegian family with a “H46R” substitution in the superoxide dismutase 1 gene

Mutant genes associated with Charcot Marie Tooth type 2, distal hereditary motor neuropathy and familial amyotrophic lateral sclerosis may cause overlapping clinical phenotypes. We performed whole genome linkage analysis, haplotype analysis, sequencing and detailed clinical and neurophysiological investigations in a large Norwegian kindred with a condition that clinically had been classified as Charcot Marie Tooth type 2. The mutation c.140A>G, p.His47Arg (alias p.His46Arg or H46R) in the superoxide dismutase 1 gene (SOD1) segregated with the disease. The patients present a hereditary motor neuropathy-like clinical picture and long survival (mean 29years). To our knowledge, this is the first extensive report describing a large non-Japanese kindred. The prognostic implications of the condition seen in this family have little in common with what is normally associated with sporadic amyotrophic lateral sclerosis and illustrates the complexity of the genetic etiology of lower motor neuron disease.

Pain assessment in Charcot-Marie-Tooth (CMT) disease

ObjectiveThe objective of our study was to describe and evaluate the prevalence of chronic pain in persons with Charcot-Marie-Tooth (CMT) disease during a multidisciplinary consultation at the Center of Reference for Neuromuscular Diseases. MethodologyThis prospective study was conducted between 2008 and 2010, it was a partnership between a Center of Reference for Neuromuscular Diseases (Centre de référence des maladies neuromusculaires [CRMD]) and a Department for the Assessment and Treatment of Pain (Département d’évaluation et de traitement de la douleur [DETD]). The evaluation consisted in a complete assessment of each patient during the first multidisciplinary consultation, with a previously established diagnosis validated by genetic testing, by various specialists: neurologist, PM&R physician, pain management specialist and physiotherapist. The evaluation tools used were Visual Analogical Scale (VAS), Hospital Anxiety and Depression Scale (HAD), DN4 scale, Neuropathic Pain Symptom Inventory (NPSI) (if DN4≥4), Pain Questionnaire of Saint Antoine (QDSA) (if DN4<4), body representation to define the painful areas, Overall Neuropathy Limitations Scale (ONLS), Medical Research Council scale (MRC), Short Questionnaire on Pain (QCD), VAS during transfers, self-care, getting dressed and physiotherapy sessions and quantified use of analgesics. ResultsA total of 50 patients were included (28 women, 22 men); two patients (one man and one woman) were discarded from the study because of missing pain assessment data. Mean age was 47years (R: 14–85), in average the symptoms had been present for the past 20years (R: 0.3–68), most patients had little impairment, the mean MRC was 53 (R: 36–60), with CMT1A being predominant (CMT1A: 76.9%, CMTX: 13.5%, CMT2: 5.8%, CMT4: 3.8%). It is noted that 65.4% of patients reported some pain with a mean duration of pain at 140months (R: 5–660). The mean VAS was 5.5 (R: 1–10), greater than 4 in 79.4% of cases, requiring the use of analgesics in 38.4% of cases (step 1: 60%, step 2: 40% on the WHO pain relief ladder). The predominant location of the pain was distal, peripheral and symmetric (64.7%); furthermore the feet were affected in 80% of cases. DN4 was positive in 40.6% of painful patients. In 62.5% of the cases, the pain did not have an underlying mechanical origin. The emotional impact remained quite modest (HAD: A=8; D=5). Patients with CMT1A seemed less affected by pain (P=0.03). ConclusionThis original study describes the pain in patients with CMT disease during a primary multidisciplinary consultation. We see that in 66% of cases, patients do report some pain, this pain is usually moderate, preferentially located in the extremities and is symmetric. In 62.5% of cases, the pain has a neuromuscular origin with a positive DN4 in 50% of cases in this etiology. In our study, patients with CMT1A report less pain than patients with other CMT types. This disease being quite rare (rare disease), the number of patients did not allow us to bring up statistically significant results. The pain must be thoroughly screened for because of its frequency in persons with CMT.

Knee MRI showing thickened peripheral nerves in Charcot–Marie–Tooth disease

A 16-year-old boy with 3-year history of knee pain was initially seen in the orthopedic clinic. He was then referred to the pediatric neurology clinic after an abnormal magnetic resonance imaging (MRI) of the knee (Figs. 1, 2). Axial and sagittal T2 weighted with fat suppressed MRI images obtained at the level of midline patella demonstrated diffuse enlargement of the sciatic (solid arrow) and tibial (dotted arrow) nerves with increased signal intensity. The knee joint was normal on MRI. On examination, the significant clinical findings were thoracic scoliosis, pes cavus, weakness of ankle and toe dorsiflexors, generalized areflexia, distal sensory loss in the legs and thickened peripheral nerves. The family history was negative for any neuromuscular disease or foot deformities. Electrodiagnostic studies were consistent with hereditary demyelinating sensorimotor polyneuropathy. DNA analysis identified the duplication of peripheral myelin protein 22 (PMP22) gene on chromosome 17. This confirmed the diagnosis of Charcot–Marie–Tooth (CMT) type 1A disease. CMT is a genetically heterogeneous group of inherited neuropathies with variable age of presentation [1]. The typical clinical presentation is that of slowly progressive distal lower extremity weakness and peroneal muscles atrophy with characteristic foot abnormalities (pes cavus, hammer toes), followed by weakness and atrophy of upper extremity muscles and sensory loss [2]. Genetically CMT type 1A is the most common form and is associated with 1.4 Mb duplication at chromosome 17p11.2 [1]. The family history may be negative in autosomal recessive or potentially new dominant mutations as noted in our case. In our patient the clinical features, electrodiagnostic studies and genetic studies confirmed CMT type 1A. However, the patient’s presentation with knee pain was atypical. We think that the knee pain was secondary to the foot deformities and muscle weakness due to CMT.

A Recurrent loss-of-function alanyl-tRNA synthetase (AARS ) mutation in patients with charcot-marie-tooth disease type 2N (CMT2N)

Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl-tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family. Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity. Genotyping analysis indicated that this mutation arose on three distinct haplotypes, and the results of bisulfite sequencing suggested that methylation-mediated deamination of a CpG dinucleotide gives rise to the recurrent p.Arg329His AARS mutation. Together, our data suggest that impaired tRNA charging plays a role in the molecular pathology of CMT2N, and that patients with CMT should be directly tested for the p.Arg329His AARS mutation.

A novel MPZ mutation in Charcot–Marie–Tooth disease type 1B with focally folded myelin and multiple entrapment neuropathies

Charcot–Marie–Tooth type 1B (CMT1B) is a demyelinating neuropathy caused by mutations in the myelin protein zero (MPZ) gene. Here, we describe a patient with CMT1B with focally folded myelin, a rarely reported phenotype of CMT1B, who initially presented with multiple entrapment neuropathies. She complained of palmar dysesthesia on both sides and on both soles of her feet in her 30’s. She underwent bilateral carpal and tarsal tunnel release at age 44, which provided transient relief from the symptoms. A sural nerve biopsy performed at age 49 revealed focally folded myelin. Molecular genetic analysis revealed a novel Asn131Ser mutation in MPZ.