Foot surgery for adults with Charcot-Marie-Tooth disease.

People with Charcot-Marie-Tooth (CMT) disease often undergo foot and ankle surgery, as foot deformities are common and cause a degree of functional limitations impairing quality of life. Surgical approaches are variable and there are no evidence-based guidelines. A multidisciplinary approach involving neurology, physical therapy and orthopaedic surgery is ideal to provide guidance on when to refer for surgical opinion and when to intervene. This review outlines the range of foot deformities associated with CMT, their clinical assessment, and their conservative and surgical and postoperative management.

Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009-2023. Genetic testing was performed using single gene testing, next-generation sequencing targeted panels, research whole exome and whole genome sequencing (WGS), and latterly WGS through the UK National Health Service. Variants were assessed using the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science criteria. Excluding patients with hereditary ATTR amyloidosis, 1515 patients with a clinical diagnosis of CMT and related disorders were recruited. 621 patients had CMT1 (41.0%), 294 CMT2 (19.4%), 205 intermediate CMT (CMTi, 13.5%), 139 hereditary motor neuropathy (HMN, 9.2%), 93 hereditary sensory neuropathy (HSN, 6.1%), 38 sensory ataxic neuropathy (2.5%), 72 hereditary neuropathy with liability to pressure palsies (HNPP, 4.8%) and 53 'complex' neuropathy (3.5%). Overall, a genetic diagnosis was reached in 76.9% (1165/1515). A diagnosis was most likely in CMT1 (96.8%, 601/621), followed by CMTi (81.0%, 166/205) and then HSN (69.9%, 65/93). Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies. The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%). We recruited 233 cases to the UK 100,000 Genomes Project (100KGP), of which 74 (31.8%) achieved a diagnosis; 28 had been otherwise diagnosed since recruitment leaving a true diagnostic rate of WGS through the 100KGP of 19.7% (46/233). However, almost half of the solved cases (35/74) received a negative report from the study, and the diagnosis was made through our research access to the WGS data. The overall diagnostic uplift of WGS for the entire cohort was 3.5%. Our diagnostic rate is the highest reported from a single centre, and has benefitted from the use of WGS, particularly access to the raw data. However, almost one quarter of all cases remain unsolved, and a new reference genome and novel technologies will be important to narrow the 'diagnostic gap'.

RFC1 expansions are a common cause of idiopathic sensory neuropathy.

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren's syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.

A prospective study on surgical management of foot deformities in Charcot Marie tooth disease.

Foot deformities are frequently observed in patients with Charcot Marie tooth disease (CMT) and orthopaedic surgery is often required. Currently there is no evidence-based guideline on surgical management and only a few studies which have evaluated long-term outcomes of surgical procedures. The aim of the study was to evaluate longitudinally the effect of foot surgery in a cohort of CMT patients. Twenty-five CMT adult patients were assessed using a comprehensive group of validated scales and questionnaires before and after surgery. A wide range of surgical procedures was performed by one team of dedicated foot ankle orthopaedic surgeons. Foot alignment as measured by the foot posture index, pain, quality of life and callosities significantly improved after one year and the improvement was maintained up to 4 years after surgery. There was a trend towards a reduction in the number of falls post-operatively. Surgery had no effect on fatigue, balance and CMT examination score. Our findings showed significant improvement of pain, foot alignment, callosities and quality of life after surgery and suggested that foot deformity correction in adults with CMT performed in a specialised foot and ankle unit is beneficial.

Charcot neuroarthropathy in patients with Charcot Marie Tooth Disease.

Charcot Marie Tooth disease (CMT) is the most common inherited neuropathy and is also called Hereditary Motor Sensory Neuropathy (HMSN). Whilst both motor and sensory deficits are present, motor deficits tend to predominate over sensory deficits. Charcot neuroarthropathic joints occur in conditions, most commonly diabetes nowadays, where joints are destroyed in association with reduced protective sensation, pain in particular. Three cases of development of Charcot joint disorders in patients with CMT are discussed and the literature is reviewed. Orthopaedic surgeons should be aware that Charcot joints can occur in CMT and surgery can be complicated by Charcot joints.

Clasificación del tubérculo suprameatal y análisis morfométrico con enfoque quirúrgico del hueso temporal / Classification of the suprameatal tubercle and morphometric analysis with a surgical approach to the temporal bone

Introducción: El hueso temporal es una estructura valiosa en el abordaje de patologías intracraneales a la fosa media y posterior, requiriendo en ocasiones la realización de petrosectomías anteriores, posteriores o abordajes combinados para la resección de tumores en dichas regiones. El propósito del presente estudio es realizar análisis morfométrico con enfoque quirúrgico del hueso temporal, en cráneos adultos, con énfasis en el tubérculo suprameatal (TSM) teniendo en consideración sus relaciones anatómicas. Material y métodos: El presente estudio se realizó en las instalaciones de la Facultad de Medicina de la Universidad Nacional Autónoma de México (UNAM). Se analizaron 200 huesos temporales de 100 cráneos humanos adultos. Se dio énfasis al TSM de acuerdo a su ubicación y tamaño, clasificándolo en: anterior medio o posterior y en tipo I (0-1 mm), tipo II (2-3 mm) y tipo III (>3 mm). Además, se realizaron mediciones con enfoque quirúrgico de la porción petrosa del hueso temporal y de la cresta supramastoidea. Resultados: El TSM se observó en 171 especímenes estudiados (85.5%). Entre ellos, la posición posterior fue la más frecuente 85 de 171 (49.70%), seguida de la posición media 43 (25.14%) y por último la posición anterior 43 (25.14%). En cuanto al tamaño, se encontró con mayor frecuencia el tipo II en 99 de los especímenes (49.5%), el tipo I en 82 especímenes (41%) y tipo III en 19 (9.5%). El asterion se reflejó dentro de la impresión de los senos en la mayoría 48.5%, la unión de la cresta supramastoidea con sutura escamosa se reflejaba en 98.5% de los casos a la fosa media. Discusión: En nuestra búsqueda de información no se cuenta con datos para realizar comparación con la obtenida en este estudio del tubérculo suprameatal, el hallazgo encontrado parece indicar que se encuentra una relación directa con la presencia de la impresión del surco del seno petroso superior. La distribución de acuerdo a su posición reviste importancia cuando se encuentra en grado III puesto que plantea una dificultad técnica, en abordajes como en petrosectomías, o bien, al cavum de Meckel desde un abordaje retrosigmoideo. Conclusión: La observación anatómica y clasificación que realizamos del tubérculo suprameatal, una estructura muy poco evaluada, nos da una consideración preoperatoria y transoperatoria cuando realizamos abordaje que involucra la cara posterior de la porción petrosa del hueso temporal

Introduction: The temporal bone is a valuable structure in the approach of intracranial pathologies to the middle and posterior fossa. Sometimes requiring the performance of petrosectomies or combined approaches for the resection of tumors in these regions. The purpose of this study is to perform morphometric analysis in adult skulls with a surgical approach to the temporal bone, with emphasis on the suprameatal tubercle (SMT) taking into account their anatomical relationships. Material and methods: The present study was carried out in the facilities of the Faculty of Medicine of the National Autonomous University of Mexico (UNAM). 200 temporal bones from 100 adult human skulls were analyzed. The SMT was emphasized according to its location and size, classifying it as: anterior, middle, or posterior and type I (0-1 mm), type II (2-3 mm) and type III (> 3mm). In addition, measurements were made with a surgical approach of the petrosal portion of the temporal bone and the supramastoid crest. Results: The SMT was observed in 171 specimens studied (85.5%). Among them, the posterior position was the most frequent 85 of 171 (49.70%), followed by the middle position in 43 (25.14%) and finally the anterior position in 43 (25.14%). In terms of size, type II was more frequently found in 99 of the specimens (49.5%), type I in 82 specimens (41%) and type III were found in 19 (9.5%). The asterion was reflected within the impression of the sinuses in the majority 48.5%, the union of the supramastoid crest with squamous suture was reflected in 98.5% of the cases to the middle fossa.Discussion: In our search for information, there is no data to make a comparison with that obtained in this study of the suprameatal tubercle. The findings seems to indicate that there is a direct relationship with the presence of the impression of the groove of the upper petrosal sinus. The distribution according to its position is important when it is in grade III since it poses a technical difficulty, in approaches such as petrosectomies, or approach to Meckel's cave from a retrosigmoid approach. Conclusion: The anatomical observation and classification that we perform of the suprameatal tubercle, a very poorly evaluated structure, gives us a preoperative and transoperative consideration when we perform an approach that involves the posterior aspect of the petrosal portion of the temporal bone

Clinical Presentation, Diagnosis and Treatment of TTR Amyloidosis.

Systemic amyloidosis can be hereditary or acquired with autosomal dominant mutations in the transthyretin gene (TTR) being the most common cause of hereditary amyloidosis. ATTRm amyloidosis is a multi-system disorder with cardiovascular, peripheral and autonomic nerve involvement that can be difficult to diagnose due to phenotypic heterogeneity. This review will focus on the neuropathic manifestations of ATTRm, the genotype-phenotype variability, the diagnostic approach and the recent therapeutic advances in this disabling condition.

Síndrome de jet lag o cambio de zonas de tiempo / The jet lag syndrome or time-zone changes

Resumen Nuestro planeta, así como la vida que en él se desarrolla, se encuentra en constante movimiento. Los ritmos geofísicos influyen en la actividad de los organismos, de tal manera que los seres vivos han desarrollado mecanismos adaptativos para poder responder a las variaciones diarias del medio ambiente. El sistema circadiano es el responsable de responder a estas variaciones cíclicas ambientales. Cuando se modifican las señales ambientales, como en un viaje que implica atravesar varias zonas horarias, se ocasionan cambios fisiológicos que han llevado a buscar estrategias para contrarrestar los síntomas que se presentan; estas estrategias incluyen el ejercicio programado, la exposición a la luz brillante, la melatonina y la alimentación programada.

Abstract Our planet and the life that develops in it are in constant movement, therefore, the geophysical rhythms influence the activity of organisms, in such a way that living beings have developed adaptative mechanims in order to respond to the daily variations of the environment. The circadian system is responsible for responding to these cyclical environmental variations. When the environmental signals are modified, like for instance, on a trip that involves crossing several time zones, physiological changes occur. This results in searching for possible strategies to counteract the symptomatology. These strategies include scheduled exercise, exposure to a bright light, melatonin and scheduled meals.

Prevalence and orthopedic management of foot and ankle deformities in Charcot-Marie-Tooth disease.

INTRODUCTION: Foot deformities are frequent complications in Charcot-Marie-Tooth disease (CMT) patients, often requiring orthopedic surgery. However, there are no prospective, randomized studies on surgical management, and there is variation in the approaches among centers both within and between countries. METHODS: In this study we assessed the frequency of foot deformities and surgery among patients recruited into the Inherited Neuropathies Consortium (INC). We also designed a survey addressed to orthopedic surgeons at INC centers to determine whether surgical approaches to orthopedic complications in CMT are variable. RESULTS: Foot deformities were reported in 71% of CMT patients; 30% of the patients had surgery. Survey questions were answered by 16 surgeons working in different specialized centers. Most of the respondents were foot and ankle surgeons. There was marked variation in surgical management. DISCUSSION: Our findings confirm that the approaches to orthopedic management of CMT are varied. We identify areas that require further research. Muscle Nerve 57: 255-259, 2018.

Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.

OBJECTIVES: To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL). METHODS: Combined analysis of newly identified patients with NEFL-related CMT and all previously reported cases from the literature. RESULTS: Five new unrelated patients with CMT carrying the NEFL mutations P8R and N98S and the novel variant L311P were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 37 (55%) and 50 (75%) kindreds, respectively. Eight patients had de novo mutations. Loss of large-myelinated fibres was a uniform feature in a total of 21 sural nerve biopsies and 'onion bulb' formations and/or thin myelin sheaths were observed in 14 (67%) of them. The neurophysiological phenotype was broad but most patients with E90K and N98S had upper limb motor conduction velocities <38 m/s. Age of onset was ≤3 years in 25 cases. Pyramidal tract signs were described in 13 patients and 7 patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia and/or cerebellar atrophy on brain MRI. CONCLUSIONS: NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT.

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial.

INTRODUCTION: Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. METHODS: We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. RESULTS: The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. CONCLUSIONS: Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.

Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy.

Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3' UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants.

c-Jun expression in human neuropathies: a pilot study.

Schwann cell dedifferentiation following nerve injury is important to permit neural survival and axonal regrowth. Animal studies have shown that the transcription factor c-Jun is upregulated in Schwann cells of injured and pathological nerves where it acts as an important regulator of Schwann cell plasticity, promoting dedifferentiation and demyelination. This pilot immunohistochemical study investigates whether c-Jun is also upregulated in human neuropathies. We examined c-Jun expression in normal and diseased human nerves, as well as in dermal myelinated nerve fibres. Our findings show that although as predicted c-Jun is rarely expressed in normal nerves, it is expressed in Schwann cell nuclei of pathological nerves as predicted by animal studies. Pathological dermal myelinated nerve fibres also show clear nuclear c-Jun expression. Further studies of c-Jun expression will help clarify its role in human neuropathies.

Immunological reactivity against neuronal and non-neuronal antigens in sporadic adult-onset cerebellar ataxia.

In recent years, the involvement of the immune system in acquired forms of cerebellar ataxia has been frequently demonstrated. In this study, we describe 6 out of 49 patients with subacute or chronic progressive cerebellar ataxia in whom antibodies against neuronal and non-neuronal antigens were identified. Two women had anti-Yo antibodies; two patients had anti-gliadin antibodies in the presence of celiac disease; one patient had a complex autoimmune disorder associated with anti-Ro-52/SS-A and anti-muscle-specific kinase antibodies, and a patient developed subacute cerebellar syndrome associated with the presence of a prostatic adenocarcinoma and atypical antibodies reacting both with cerebellar tissue and with the prostatic tumor. Our study confirms previous findings in paraneoplastic syndromes, and indicates that at least 10% of sporadic cerebellar ataxia may be related to immune-mediated mechanisms.

Rapid progression of late onset axonal Charcot-Marie-Tooth disease associated with a novel MPZ mutation in the extracellular domain.

Myelin protein zero (MPZ) is a major component of compact myelin in peripheral nerves where it plays an essential role in myelin formation and adhesion. MPZ gene mutations are usually responsible for demyelinating neuropathies, namely Charcot-Marie-Tooth (CMT) type 1B, Déjèrine-Sottas neuropathy and congenital hypomyelinating neuropathy. Less frequently, axonal CMT (CMT2) associated with MPZ mutations has been described. We report six patients (one sporadic case and five subjects from two apparently unrelated families) with a late onset, but rapidly progressive, axonal peripheral neuropathy. In all patients, molecular analysis demonstrated a novel heterozygous missense mutation (208C>T) in MPZ exon 2, causing the Pro70Ser substitution in the extracellular domain. The diagnosis of CMT2 associated with MPZ mutations should be considered in both sporadic and familial cases of late onset, progressive polyneuropathy. The mechanism whereby compact myelin protein mutations cause axonal neuropathy remains to be elucidated.

Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome.

OBJECTIVE: Distal hereditary motor neuropathy type V (dHMN-V) and Charcot-Marie-Tooth syndrome (CMT) type 2 presenting with predominant hand involvement, also known as CMT2D and Silver syndrome (SS) are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and in the glycyl-tRNA synthetase encoding (GARS) genes. Mutations in the heat-shock proteins HSPB1 and HSPB8 can cause related distal hereditary motor neuropathies (dHMN) and are considered candidates for dHMN-V, CMT2, and SS. DESIGN: To define the frequency and distribution of mutations in the GARS, BSCL2, HSPB1 and HSPB8 genes we screened 33 unrelated sporadic and familial patients diagnosed as either dHMN-V, CMT2D or SS. Exon 3 of the BSCL2 gene was screened in further 69 individuals with an unclassified dHMN phenotype or diagnosed as hereditary spastic paraplegia (HSP) complicated by pure motor neuropathy. RESULTS: Four patients diagnosed with dHMN-V or SS carried known heterozygous BSCL2 mutations (N88S and S90L). In one dHMN-V patient we detected a putative GARS mutation (A57V). No mutations were detected in HSPB1 and HSPB8. The diagnostic yield gained in the series of 33 probands was 12% for BSCL2 mutations and 3% for GARS mutations. In the series of unclassified dHMN and complicated HSP cases no mutations were found. CONCLUSIONS: Our data confirm that most likely only two mutations (N88S, S90L) in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. Mutations in GARS, HSPB1 and HSPB8. are not a common cause of dHMN-V, SS and CMT2D. We would therefore suggest that a genetic testing of dHMN-V and SS patients should begin with screening of exon 3 of the BSCL2 gene. Screening of the GARS gene is useful in patients with CMT2 with predominant hand involvement and dHMN-V. The rather low frequencies of BSCL2, GARS, HSPB1 and HSPB8 mutations in dHMN-V, CMT2D and SS patients strongly point to further genetic heterogeneity of these related disorders.

Multifocal motor neuropathy and asymptomatic Hashimoto's thyroiditis: first report of an association.

Motor neuropathy with multifocal conduction blocks represents a recently identified autoimmune disorder of the peripheral nerve myelin. Association of motor neuropathies or neuronopathies with thyroid disorders, such as hyperthyroidism, hypothyroidism or thyroid neoplasms has been rarely described. We studied a 61-year-old man with a 2-year-history of slowly progressive weakness of the left limbs with atrophy and fasciculations. Nerve conduction velocity studies revealed multifocal motor conduction blocks. Serum IgM titer of antibodies against GM1 was elevated (1:1280; n.v. up to 1:640). Thyroid studies were compatible with Hashimoto's thyroiditis. Therapy with high dose intravenous immunoglobulins was followed by a prompt clinical recovery. Then the disease assumed an intravenous immunoglobulins dependent course with a full clinical, but transient, recovery. This is the first observation of an association of multifocal motor neuropathy with high titers of GM1 and Hashimoto's thyroiditis and reinforces the multifocal motor neuropathy autoimmune origin as well as the repeated clinical recoveries after intravenous immunoglobulins. This case also suggests to deeply investigate the thyroid function in patients with multifocal motor neuropathy.