Charcot-Marie-Tooth Research Articles

A National French Consensus on Gene List for the Diagnosis of Charcot-Marie-Tooth Disease and Related Disorders Using Next-Generation Sequencing.

Next generation sequencing (NGS) is strategically used for genetic diagnosis in patients with Charcot–Marie–Tooth disease (CMT) and related disorders called non-syndromic inherited peripheral neuropathies (NSIPN) in this paper. With over 100 different CMT-associated genes involved and ongoing discoveries, an important interlaboratory diversity of gene panels exists at national and international levels. Here, we present the work of the French National Network for Rare Neuromuscular Diseases (FILNEMUS) genetic diagnosis section which coordinates the seven French diagnosis laboratories using NGS for peripheral neuropathies. This work aimed to establish a unique, simple and accurate gene classification based on literature evidence. In NSIPN, three subgroups were usually distinguished: (1) HMSN, Hereditary Motor Sensory Neuropathy, (2) dHMN, distal Hereditary Motor Neuropathy, and (3) HSAN, Hereditary Sensory Autonomic Neuropathy. First, we reported ClinGen evaluation, and second, for the genes not evaluated yet by ClinGen, we classified them as “definitive” if reported in at least two clinical publications and associated with one report of functional evidence, or “limited” otherwise. In total, we report a unique consensus gene list for NSIPN including the three subgroups with 93 genes definitive and 34 limited, which is a good rate for our gene’s panel for molecular diagnostic use.

From Negative to Positive Diagnosis: Structural Variation Could Be the Second Mutation You Are Looking for in a Recessive Autosomal Gene.

Next-generation sequencing (NGS) allows the detection of plentiful mutations increasing the rate of patients getting a positive diagnosis. However, while single-nucleotide variants (SNVs) or small indels can be easily detected, structural variations (SVs) such as copy number variants (CNVs) are often not researched. In Charcot–Marie–Tooth disease (CMT), the most common hereditary peripheral neuropathy, the PMP22-duplication was the first variation detected. Since then, more than 90 other genes have been associated with CMT, with point mutations or small indels mostly described. Herein, we present a personalized approach we performed to obtain a positive diagnosis of a patient suffering from demyelinating CMT. His NGS data were aligned to the human reference sequence but also studied using the CovCopCan software, designed to detect large CNVs. This approach allowed the detection of only one mutation in SH3TC2, the frequent p.Arg954*, while SH3TC2 is known to be responsible for autosomal recessive demyelinating CMT forms. Interestingly, by modifying the standard CovCopCan use, we detected the second mutation of this patient corresponding to a 922 bp deletion in SH3TC2 (Chr5:148,390,609-Chr5:148,389,687), including only one exon (exon 14). This highlights that SVs, different from PMP22 duplication, can be responsible for peripheral neuropathy and should be searched systematically. This approach could also be employed to improve the diagnosis of all inherited diseases.

Validation of the Spanish version of the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS)

The Charcot-Marie-Tooth Pediatric Scale (CMTPedS) is a validated and change-sensitive tool for assessing the severity of neuropathy in children and adolescents between 3 and 20 years of age. The aim of this article is to translate and validate a Spanish version of the CMTPedS in order to disseminate its use in Spanish-speaking countries. The process used to translate the CMTPedS into Spanish was the reverse parallel translation method based on the principles of good practice for translation and the cultural adaptation process of the Food and Drug Administration Guidelines. A direct translation of the original source of the CMTPedS into Spanish was performed first and reviewed by experts in Charcot-Marie-Tooth (CMT) disease trained in the use of the CMTPedS tool. The Spanish version was then translated back into English by a linguist specialised in translation. The preliminary Spanish version of the CMTPedS was evaluated in 18 children with CMT aged 6-20 years (mean: 13.27). The scale was well tolerated and easy for children to understand and easy for clinicians to apply. None of the patients had any difficulty completing the scale. The Spanish version of the CMTPedS can be used for monitoring and conducting clinical trials in the Spanish population and in Spanish-speaking countries.

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases.

Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To better understand the consequences on the cellular phenotype and pathophysiology of neurogenetic diseases associated with defective mitochondrial dynamics, we have compared the fibroblasts phenotypes of (i) patients carrying pathogenic variants in genes involved in mitochondrial dynamics such as DRP1 (also known as DNM1L), GDAP1, OPA1, and MFN2, and (ii) patients carrying mutated genes that their dysfunction affects mitochondria or induces a mitochondrial phenotype, but that are not directly involved in mitochondrial dynamic network, such as FXN (encoding frataxin, located in the mitochondrial matrix), MED13 (hyperfission phenotype), and CHKB (enlarged mitochondria phenotype). We identified mitochondrial network alterations in all patients’ fibroblasts except for CHKBQ198*/Q198*. Functionally, all fibroblasts showed mitochondrial oxidative stress, without membrane potential abnormalities. The lysosomal area and distribution were abnormal in GDAP1W67L/W67L, DRP1K75E/+, OPA1F570L/+, and FXNR165C/GAA fibroblasts. These lysosomal alterations correlated with mitochondria-lysosome membrane contact sites (MCSs) defects in GDAP1W67L/W67L exclusively. The study of mitochondrial contacts in all samples further revealed a significant decrease in MFN2R104W/+ fibroblasts. GDAP1 and MFN2 are outer mitochondrial membrane (OMM) proteins and both are related to Charcot-Marie Tooth neuropathy. Here we identified their constitutive interaction as well as MFN2 interaction with LAMP-1. Therefore MFN2 is a new mitochondria-lysosome MCSs protein. Interestingly, GDAP1W67L/W67L and MFN2R104W/+ fibroblasts carry pathogenic changes that occur in their catalytic domains thus suggesting a functional role of GDAP1 and MFN2 in mitochondria–lysosome MCSs. Finally, we observed starvation-induced autophagy alterations in DRP1K75E/+, GDAP1W67L/W67L, OPA1F570L/+, MFN2R104W/+, and CHKBQ198*/Q198* fibroblasts. These genes are related to mitochondrial membrane structure or lipid composition, which would associate the OMM with starvation-induced autophagy. In conclusion, the study of mitochondrial dynamics and mitochondria-lysosome axis in a group of patients with different neurogenetic diseases has deciphered common and unique cellular phenotypes of degrading and non-degrading pathways that shed light on pathophysiological events, new biomarkers and pharmacological targets for these disorders.

An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families.

Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

Proximal nerve MR neurography with diffusion tensor imaging in differentiating subtypes of Charcot-Marie-Tooth disease.

To evaluate the feasibility of proximal nerve MR neurography with diffusion tensor imaging (DTI) for differentiating Charcot-Marie-Tooth (CMT) 1A, CMT2, and healthy controls. The diameters, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of L4-L5 nerve roots, femoral nerve (FN), and sciatic nerve (SN) were compared. Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the diagnostic performance. DeLong's tests were applied to compare multiple ROC curves. Intraclass correlation coefficients were calculated for interobserver agreement assessment. The diameters of the L4 nerve root, L5 nerve root, and SN of CMT1A patients were significantly larger than those of CMT2 patients and healthy controls. The FA values of all measured proximal nerves were significantly higher in controls (0.46 ± 0.09, 0.46 ± 0.08, 0.45 ± 0.07, and 0.48 ± 0.08) than in CMT1A patients (0.30 ± 0.09, 0.29 ± 0.06, 0.35 ± 0.08, and 0.29 ± 0.09). The FA values of the L5 nerve root, FN, and SN were significantly higher in controls (0.46 ± 0.08, 0.45 ± 0.07, and 0.48 ± 0.08) than in CMT2 patients (0.36 ± 0.06, 0.34 ± 0.07, and 0.34 ± 0.10). The MD and RD values of the L5 nerve root in CMT1A patients (1.59 ± 0.21 and 1.37 ± 0.21) were higher than those in CMT2 patients (1.31 ± 0.17 and 1.05 ± 0.14). The AUCs of the above parameters ranged from 0.780 to 1.000. For the measurements of nerve diameters, the ICC ranged from 0.91 to 0.97. For the measurements of DTI metrics, the ICC ranged from 0.87 to 0.97. MR neurography with DTI is able to differentiate CMT1A patients, CMT2 patients, and healthy controls. • MR neurography with diffusion tensor imaging of the L4-5 nerve roots, proximal femoral nerve, and proximal sciatic nerve is able to discriminate CMT1A, CMT2, and healthy controls. • This method provides an alternative for the diagnosis and discrimination of CMT1A and CMT2, which is crucial for clinical management.

Foot orthoses for treating paediatric flat feet.

Foot orthoses for treating paediatric flat feet.

Clinical and Genetic Survey for Charcot-Marie-Tooth Neuropathy Based on the Findings in Turkey, a Country with a High Rate of Consanguineous Marriages

Inherited peripheral neuropathies (IPNs) are a heterogeneous group of disorders of the peripheral nervous system. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease, which constitutes an interesting research focus for neurologists and human geneticists alike. Most cases with CMT manifest with a slowly progressive symmetric distal weakness in the lower limbs that usually begin in the first to the third decade that causes atrophy and foot drop. Deep tendon reflexes are usually absent or reduced. A proven and efficient CMT therapy is yet available and may require different molecules and approaches due to its high clinical and genetic heterogeneity. Several ongoing clinical trials are promising and are mostly focused on the most frequent form, namely CMT Type 1A (CMT1A). Approximately, 60% of patients with CMT can be genetically diagnosed using the most advanced mutation screening techniques that cover approximately 100 IPN genes. Turkey has a 25% consanguineous marriage rate, and nearly 60% genetic diagnosis rate can still be reached when SH3 Domain and Tetratricopeptide Repeat Domain 2, Ganglioside-induced Differentiation-Associated Protein 1, and Histidine Triad Nucleotide Binding Protein 1 genes are also screened along with Myelin Protein Zero and Gap Junction Protein Beta-1 after exclusion of CMT1A duplication in families with probable recessive inheritance. The genetic diagnosis rates in different regions worldwide implicate that the most recent sequencing techniques should be more commonly used for both diagnosis and identification of further CMT genes. Herein, presented our 30 years of experience on genetic diagnosis and management strategies in CMT neuropathy in Turkey and review clinical and genetic features of this group of disorders.

Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.

Charcot–Marie–Tooth disease (CMT) is the most common hereditary peripheral neuropathy. Mutations in the neurofilament light polypeptide (NEFL) gene produce diverse clinical phenotypes, including demyelinating (CMT1F), axonal (CMT2E), and intermediate (CMTDIG) neuropathies. From 2005 to 2020, 1,143 Korean CMT families underwent gene sequencing, and we investigated the clinical, genetic, and neuroimaging spectra of NEFL‐related CMT patients. Ten NEFL mutations in 17 families (1.49%) were identified, of which three (p.L312P, p.Y443N, and p.K467N) were novel. Eight de novo cases were identified at a rate of 0.47 based on a cosegregation analysis. The age of onset was ≤3 years in five cases (13.5%). The patients revealed additional features including delayed walking, ataxia, dysphagia, dysarthria, dementia, ptosis, waddling gait, tremor, hearing loss, and abnormal visual evoked potential. Signs of ataxia were found in 26 patients (70.3%). In leg MRI analyses, various degrees of intramuscular fat infiltration were found. All compartments were evenly affected in CMT1F patients. The anterior and anterolateral compartments were affected in CMT2E, and the posterior compartment was affected in CMTDIG. Thus, NEFL‐related CMT patients showed phenotypic heterogeneities. This study's clinical, genetic, and neuroimaging results could be helpful in the evaluation of novel NEFL variants and differential diagnosis against other CMT subtypes.

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

Cavovarus With a Twist: Midfoot Coronal and Axial Plane Rotational Deformity in Charcot-Marie-Tooth Disease

The cavovarus deformity of Charcot-Marie-Tooth (CMT) disease is often characterized by a paradoxical relationship of hindfoot varus and forefoot valgus. The configuration of the midfoot, which links these deformities, is poorly understood. Accurate assessment of 3-dimensional alignment under physiologic loadbearing conditions is possible using weightbearing computed tomography (WBCT). This is the first study to examine the rotational deformity in the midfoot of CMT patients and, thus, provide key insights to successful correction of CMT cavovarus foot. A total of 27 WBCT scans from 21 CMT patients were compared to control WBCTs from 20 healthy unmatched adults. CMT patients with a history of bony surgery, severe degenerative joint disease, or open physes in the foot were excluded. Scans were analyzed using 3-dimensional software. Anatomic alignment of the tarsal bones was calculated relative to the anterior-posterior axis of the tibial plafond in the axial plane, and weightbearing surface in the coronal plane. Maximal rotational deformity in CMT patients occurred at the transverse tarsal joints, averaging 61 degrees of external rotation (supination), compared to 34 degrees among controls (P < .01). The talonavicular joint was also the site of peak adduction deformity in the midfoot, with an average talonavicular coverage angle measuring 12 degrees compared with -11 degrees in controls (P < .01). This 3-dimensional WBCT analysis is the first to isolate and quantify the multiplanar rotational deformity in the midfoot of CMT patients. Compared with healthy unmatched control cases, CMT patients demonstrated increased axial plane adduction and coronal plane rotation at the talonavicular (TN) joint. These findings support performing soft tissue release at the TN joint to abduct and derotate the midfoot as a first step for targeted deformity correction. Level III, retrospective case-control study.

MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in a CMT2A-linked MFN2 mutant.

Mutations in mitofusin 2 (MFN2) that are associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. One such abundant MFN2 mutation, R364W, results in the generation of elongated, interconnected mitochondria. However, the mechanism leading to this mitochondrial aberration remains poorly understood. Here, we show that mitochondrial hyperfusion in the presence of R364W-MFN2 is due to increased degradation of DRP1 (also known as DNM1L). The E3 ubiquitin ligase MITOL (also known as MARCHF5) is known to ubiquitylate both MFN2 and DRP1. Interaction with and subsequent ubiquitylation by MITOL is stronger in the presence of wild-type MFN2 than with R364W-MFN2. This differential interaction of MITOL with MFN2 in the presence of R364W-MFN2 renders the ligase more available for DRP1 ubiquitylation. Multi-monoubiquitylation and proteasomal degradation of DRP1 in R364W-MFN2 cells in the presence of MITOL eventually leads to mitochondrial hyperfusion. Here, we provide a mechanistic insight into mitochondrial hyperfusion, while also reporting that MFN2 can indirectly modulate DRP1 - an effect not shown previously. This article has an associated First Person interview with the first author of the paper.

Foot orthoses for treating paediatric flat feet.

Foot orthoses for treating paediatric flat feet.

Conformational sampling of CMT-2D associated GlyRS mutations

During protein synthesis, aminoacyl-tRNA synthetases covalently link amino acids with their cognate tRNAs. Amino acid mutations in glycyl-tRNA synthetase can disrupt protein synthesis and lead to a neurological disorder known as Charcot-Marie-Tooth disease type 2D (CMT-2D). Several studies employing diverse techniques have identified potential disease mechanisms at the molecular level. The majority of CMT-2D mutations in glycyl-tRNA are found within its dimer interface. However, no atomic structures bearing these mutations have been solved. Consequently, the specific disease-causing structural changes that occur in glycyl-tRNA synthetase have not been definitively established. Here we use molecular dynamics simulations to probe conformational changes in glycyl-tRNA synthetase caused by one mutation within the dimer interface: G240R. Our results show that the mutation alters the number of native interactions at the dimer interface and also leads to altered dynamics of two regions of glycyl-tRNA synthetase associated with tRNA binding. Additionally, we use our simulations to make predictions about the effects of other clinically reported CMT-2D mutations. Our results identify a region of the glycyl-tRNA synthetase structure that may be disrupted in a large number of CMT-2D mutations. Structural changes in this region may be a common molecular mechanism in glycyl-tRNA synthetase CMT-2D pathologies. Statement of significanceIn this study, we use molecular dynamics simulations to elucidate structural conformations accessible to glycyl-tRNA synthetase (GlyRS), an enzyme that ligates cytosolic glycine with tRNA-Gly. This protein contains multiple flexible regions with dynamics that elude in vitro structural characterization. Our computational approach provides unparalleled atomistic details of structural changes in GlyRS that contribute to its role in protein synthesis. A number of mutations in GlyRS are associated with a peripheral nerve disorder, Charcot-Marie-Tooth disease type 2D (CMT-2D). Mutation-induced structural and dynamic changes in GlyRS have similarity that elude in vitro structural characterization. Our simulations provide insights into disease mechanisms for one such mutation: G240R. Additionally, we leverage our computational data to identify regions of GlyRS critical to its function and to predict the effects of other disease-associated mutations. These results open up new directions for research into the molecular characterization of GlyRS and into hypothesis-driven studies of CMT-2D disease mechanisms.

Effects of Withania Somnifera on Charcot-Marie-Tooth Disease Type 1A in the model organism Eisenia Fetida

Charcot-Marie-Tooth disease type 1A (CMT1A) affects 250,000 people in the United States alone. CMT1A causes abnormalities in the myelin sheath due to the duplication of PMP22 on chromosome 17. This duplication causes the breakdown of the myelin sheath that wraps the sensory and spinal cord motor neurons. CMT1A is commonly associated with symptoms that include bone deformities, pes cavus (a deformity in the plantar arch), and muscle weakness. This study focused on finding a correlation between Withania somnifera ingestion and the speed of the nerve signal. W. somnifera is a plant in the Solanaceae family, which grows in the Middle East, India, and parts of Africa, and it has been reported to be protective against demyelination. Our model organism, Eisenia Fetida, is a species of earthworm. Our hypothesis was that if W. somnifera is added to E. fetida’s diet, there would be a decrease in demyelination leading to a faster nerve conduction rate. From the experiment, we found that W. somnifera significantly increased the speed of the nerve conduction in E. fetida, making W. somnifera a potential option to investigate as a treatment for CMT1A.

Torin1 restores proliferation rate in Charcot-Marie-Tooth disease type 2A cells harbouring MFN2 (mitofusin 2) mutation.

Mitofusin 2 (MFN2) is a mitochondrial outer membrane protein that serves primarily as a mitochondrial fusion protein but has additional functions including the tethering of mitochondrial-endoplasmic reticulum membranes, movement of mitochondria along axons, and control of the quality of mitochondria. Intriguingly, MFN2 has been referred to play a role in regulating cell proliferation in several cell types such that it acts as a tumour suppressor role in some forms of cancer. Previously, we found that fibroblasts derived from a Charcot-Marie-Tooth disease type 2A (CMT2A) patient with a mutation in the GTPase domain of MFN2 exhibit increased proliferation and decreased autophagy. Primary fibroblasts from a young patient affected by CMT2A harbouring c.650G > T/p.Cys217Phe mutation in the MFN2 gene were evaluated versus a healthy control to measure the proliferation rate by growth curves analysis and to assess the phosphorylation of protein kinase B (AKT) at Ser473 in response to different doses of torin1, a selective catalytic ATP-competitive mammalian target of rapamycin complex (mTOR) inhibitor, by immunoblot analysis. Herein, we demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) is highly activated in the CMT2AMFN2 fibroblasts to promote cell growth via the AKT(Ser473) phosphorylation-mediated signalling. We report that torin1 restores CMT2AMFN2 fibroblasts' growth rate in a dose-dependent manner by decreasing AKT(Ser473) phosphorylation. Overall, our study provides evidence for mTORC2, as a novel molecular target that lies upstream of AKT to restore the cell proliferation rate in CMT2A fibroblasts.

Genetic approaches and pathogenic pathways in the clinical management of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting at least 1 in 2500 individuals. CMT refers to a heterogeneous group of inherited neuropathies from both phenotypic and genetic points of view. Over the last decades, there have been important advances not only in the identification of causative genes but also in understanding the molecular basis for many forms of CMT. In fact, to date, around 100 genes have been related to CMT disease, thanks to next generation sequencing techniques, and they have been proven to affect either the myelin or axon of peripheral nerves. Moreover, its genetic diagnosis has remarkedly improved, although there are still difficulties when it comes to treatment. In this review, we explore in depth the eight most prevalent genes associated with CMT: GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, SH3TC2, and SORD. We also address the disrupted cellular processes and pathophysiological mechanisms involved in the disease. A better understanding of the pathogenic mechanisms responsible for each type of CMT would be essential to identifying molecular targets and therapeutic strategies.

Cavovarus with A Twist: Coronal and Axial Plane Rotational Deformity in the Midfoot of Charcot- Marie-Tooth Patients

Category:Hindfoot; Midfoot/ForefootIntroduction/Purpose:The cavovarus deformity of Charcot-Marie-Tooth (CMT) disease typically presents with hindfoot varus and forefoot valgus. This seemingly paradoxical relationship is poorly understood. Better insight into this complex three- dimensional alignment under physiologic load-bearing conditions is possible using weight-bearing computed tomography (WBCT). This is the first study to examine the extreme rotational deformity in the midfoot of CMT patients, and thereby provides a key to the successful operative correction of the CMT cavovarus foot.Methods:We retrospectively reviewed the WBCTs of patients with CMT who presented to a single surgeon. Those with history of bony surgical correction, severe degenerative joint disease, or open physes in the foot, were excluded. Scans were analyzed using three-dimensional analysis software (Disior Bonelogic) to generate axes of select bones and their relationship relative to the tibial plafond anterior-posterior axis in the axial plane. The coronal alignment of the foot involved angular measurements of the calcaneus, talar dome, midfoot and forefoot relative to the ground. We reported quantitative alignment parameters and compared the measurements to WBCT of 20 controls.Results:17 WBCT scans from 15 CMT patients (average age 24 years) met criteria for inclusion. In the axial plane, external rotation of the distal tibia accounted for the varus heel position rather than subtalar malalignment. The greatest change in axial alignment occurred between the talar neck and navicular (26 degrees). The average talonavicular (TN) medial uncoverage angle was -15 degrees for CMT patients, indicating medial overcoverage, compared to +11 degrees for controls, (p<0.01). Coronal plane analysis revealed varus rotational deformity at the calcaneus (23 degrees), a peak of 61 degrees varus across the navicular and cuboid, then compensatory rotation of the cuneiforms and metatarsals to achieve a plantigrade forefoot (11 degrees varus). In comparison, controls averaged 9 degrees coronal valgus at the calcaneus and 34 degrees varus at the naviculo-cuboid level, (p<0.01). Figure 1 shows the WBCT scans of a representative CMT patient and control case.Conclusion:This three-dimensional WBCT analysis is the first to characterize and quantify the axial and coronal rotational deformity in CMT. Axial plane deformity had a center of rotational angulation at the talonavicular joint, associated with medial ’overcoverage’ of the talar head, likely from chronic tibialis posterior over-pull. The peak coronal deformity was localized at the navicular and cuboid, which measured nearly twice as much as controls. These observations suggest dorsiflexion osteotomy of the 1st metatarsal would fail to address the coronal rotation; releases through the talonavicular joint may be necessary to abduct and de-rotate the midfoot to achieve a plantigrade foot.

CASE REPORT OF ADULT-ONSET CHARCOT MARIE TOOTH TYPE X

Charcot-Marie-Tooth (CMT) or Hereditary Motor and Sensory Neuropathy (HMSN) is the most common hereditary peripheral nerve disease with progressive chronic weakness, muscle atrophy, and sensory disturbances. There are several types and subtypes of CMT with their respective clinical manifestations. In this article, we reported a patient with of CMT type X. A 43-year-old male patient was referred to a neurology clinic with weakness in both limbs for 2 years, accompanied by tingling and sensory disturbance in both hands and feet. There are several of his family members who had similar complaints. Lumbosacral magnetic resonance imaging (MRI) examination revealed mild nucleus pulposus herniation. Electroneuromyography (ENMG) examination revealed demyelinating sensory motor polyneuropathy. Histopathological examination of nerve biopsy showed demyelination of the sural nerve. It is hard to make a diagnosis of CMT, because it requires high suspicion from clinicians once encounter a suspected case and also need to supported by sophisticated equipment such as electrophysiological examinations, nerve biopsy examinations, and genetic examinations. It is vital for clinicians for being able to diagnose CMT correctly and provide treatment as soon as possible in order to maintain the patients’ quality of life.

Genetic Spectrum of Inherited Neuropathies in India.

Background and Objectives:Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder and has heterogeneous manifestations. Data regarding genetic basis of CMT from India is limited. This study aims to report the variations by using high throughput sequencing in Indian CMT cohort.Methods:Fifty-five probands (M:F 29:26) with suspected inherited neuropathy underwent genetic testing (whole exome: 31, clinical exome: 17 and targeted panel: 7). Their clinical and genetic data were analysed.Results:Age at onset ranged from infancy to 54 years. Clinical features included early-onset neuropathy (n=23), skeletal deformities (n=45), impaired vision (n=8), impaired hearing (n=6), facial palsy (n=8), thickened nerves (n=4), impaired cognition (n=5), seizures (n=5), pyramidal signs (n=7), ataxia (n=8) and vocal cord palsy, slow tongue movements and psychosis in one patient each. Twenty-eight patients had demyelinating electrophysiology. Abnormal visual and auditory evoked potentials were noted in 60.60% and 37.5% respectively. Sixty two variants were identified in 37 genes including variants of uncertain significance (n=34) and novel variants (n=45). Eleven patients had additional variations in genes implicated in CMTs/ other neurological disorders. Ten patients did not have variations in neuropathy associated genes, but had variations in genes implicated in other neurological disorders. In seven patients, no variations were detected.Conclusion:In this single centre cohort study from India, genetic diagnosis could be established in 87% of patients with inherited neuropathy. The identified spectrum of genetic variations adds to the pool of existing data and provides a platform for validation studies in cell culture or animal model systems.