Late Onset of Severe Demyelinating Peripheral Neuropathy in a 62-Year-Old African American Woman.

ABSTRACT: Hereditary neuropathies are typically associated with an early onset of symptoms, but same types of neuropathies may also manifest late, after the age 50 years. A 62-year-old African American woman presented with a 6-year history of gait unsteadiness and has been using a walker since the age 57 years after an unwitnessed fall. Gradual worsening of walking difficulties was later followed by decreased dexterity. The family history was negative for neuromuscular disorders, including neuropathy. On examination, the patient had both distal and proximal weakness with distal sensory loss to all modalities and hyporeflexia. Charcot Marie Tooth Examination Score was 12. Previous electrodiagnostic testing at the age 60 years showed severe sensorimotor demyelinating polyneuropathy with bilateral severe carpal tunnel syndrome. Genetic testing showed a homozygous pathogenic mutation in SH3TC2 gene (c.2860C>T; p.Arg954*), associated with CMT4C. CMT4C is the most common recessive demyelinating sensorimotor polyneuropathy and overall comprises 0.4%-1.7% of all patients with Charcot-Marie-Tooth disease. It is more common in French Canadians and Spanish Roma and in recent natural history study; only 1 of 56 patients was African American. This report demonstrates sporadic occurrence of CMT4C in other ethnic groups as well.

Cochlear Implantation in Charcot-Marie-Tooth Patients: Speech Perception and Quality of Life.

OBJECTIVES: There is a limited understanding of the impact of cochlear implantation (CI) in patients with Charcot-Marie-Tooth disease (CMT), given the scarcity of reported cases. We aim to evaluate the audiological outcomes and quality of life (QoL) after CI in CMT. METHODS: Multi-institutional, university-affiliated, tertiary-referral centers, retrospective chart review.Our cohort includes 5 patients with CMT. Patients' charts were reviewed for demographic characteristics, operation notes, and pre- and post-implantation audiology evaluation. Patients completed the Cochlear Implant Quality of Life-10 (CIQOL-10) Global questionnaire. RESULTS: Pre-implantation, the mean pure tone average was 84.1 ± 7.2 dB, and the mean word recognition score was 2.4% in the implanted ear. AzBio sentence test was performed in quiet, revealing a mean of 4 ± 1.4% in the implanted ear. Post-implantation, PTA results were all within the mild hearing loss range (mean 33.0 ± 5.9 dB). Post-CI, AZ-Bio test results were 5%, 65%, and 74% (for 3 patients), and HINT scores were 55% and 58% (for 2 patients). The mean score of the CIQOL-10 questionnaire was 42.7 ± 10.47 (range 1-100). Patients were most satisfied with their ability to listen to the television or radio, have conversations in a quiet environment, and feel comfortable being themselves. CONCLUSION: To the best of our knowledge, this is the most extensive series of CI in CMT-associated sensorineural hearing loss and auditory neuropathy. Our cohort suggests that CI is a safe and reliable method for hearing rehabilitation that can achieve good speech performance and improve QoL in CMT patients.

An Elderly Woman with Complaints of Pain and Hearing Loss, Diagnosed with CMT1A with PMP22 Duplication.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous hereditary motor and sensory neuropathy of the peripheral nervous system, with CMT1A in particular being the most common form. We encountered a 76-year-old woman with CMT1A who had a history of pain attacks and hearing loss from a young age, with motor symptoms manifesting late in life. Her pain and hearing loss may have been related to CMT. Our case also raises the possibility that neuropathic pain and hearing loss may precede the classic motor symptoms of CMT1A.

Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts.

BACKGROUND AND PURPOSE: Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB. METHODS: Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features. RESULTS: The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination. DISCUSSION: In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy.

Nitrous-oxide-induced polyneuropathy and subacute combined degeneration of the spine: clinical and diagnostic characteristics in 70 patients, with focus on electrodiagnostic studies.

BACKGROUND AND PURPOSE: Nitrous oxide (N2 O) induced neurological symptoms are increasingly encountered. Our aim is to provide clinical and diagnostic characteristics with a focus on electrodiagnostic studies. METHODS: Patients with neurological sequelae due to N2 O presenting in our hospital between November 2018 and December 2021 reporting clinical and diagnostic data were retrospectively reviewed. RESULTS: Seventy patients (median 22 years) were included. Median N2 O usage was 4 kg/week during 12 months. Patients' history revealed a higher rate of sensory symptoms compared to motor (97% vs. 57%) and 77% walking difficulties. Clinical diagnosis was polyneuropathy (PNP) in 44%, subacute combined degeneration (SCD) of the spine in 19%, both in 37%. Median vitamin B12 level was low (159 pmol/L), normal in 16%. The median methylmalonic acid was increased (2.66 µmol/L). Electrodiagnostic abnormalities were observed in 91%, with 72% fulfilling axonal PNP criteria, 20% showing mild to intermediate slowing. One patient fulfilled demyelinating PNP criteria not related to N2 O abuse (Charcot-Marie-Tooth type 1a). More prominent motor nerve conduction abnormalities were found; lower limbs were more affected. In 64% with normal conduction, myography showed signs of axonal loss. Magnetic resonance imaging showed cervical myelopathy in 58% involving generally five to six segments. CONCLUSIONS: Nitrous oxide (N2 O) leads to neurological symptoms by causing PNP and/or SCD primarily involving the legs. Distinguishing PNP and SCD clinically was shown to be insufficient. Electrodiagnostic studies showed axonal PNP. Demyelinating PNP due to N2 O abuse was not present in our cohort. Therefore, further diagnostic work-up is warranted if demyelinating features are present.

Anesthetic Management of Coronary Artery Bypass Grafting in a Patient with Charcot-Marie-Tooth Disease and Multivessel Coronary Artery Disease.

BACKGROUND The anesthetic management of patients with Charcot-Marie-Tooth disease (CMT) requires special deliberation. Previous literature has suggested that patients with CMT may have increased sensitivity to non-depolarizing neuromuscular blocking agents, and hyperkalemia associated with the administration of succinylcholine has been reported. The potential risk of malignant hyperthermia and underlying cardiopulmonary abnormalities, such as pre-existing arrhythmias, cardiomyopathy, or respiratory muscle weakness, must also be considered in patients with CMT. CASE REPORT We describe a case of a patient with a history of CMT and multivessel coronary artery disease who underwent coronary artery bypass grafting (CABG). Careful consideration was given to the anesthetic plan, which consisted of thorough pre- and perioperative evaluation of cardiac function, total intravenous anesthesia with propofol and remifentanil infusions, the use of a non-depolarizing neuromuscular blocking agent, and utilization of a malignant hyperthermia protocol with avoidance of volatile anesthetics to decrease the possible risk of malignant hyperthermia. Following a 3-vessel CABG, no anesthetic or surgical complications were noted and the patient was discharged on postoperative day 6 after an uneventful hospital course. CONCLUSIONS Exacerbation of underlying cardiac and pulmonary abnormalities associated with the pathophysiology of CMT, as well as patient response to neuromuscular blocking and volatile agents, should be of concern for the anesthesiologist when anesthetizing a patient with CMT. Therefore, CMT patients undergoing surgery require special consideration of their anesthetic management plan in order to ensure patient safety and optimize perioperative outcomes.

Severe Dry Eye Disease in Charcot-Marie-Tooth Disease: A Comprehensive Case Report.

BACKGROUND Charcot-Marie-Tooth disease (CMT) is a hereditary neurological disorder that primarily leads to peripheral neuropathy, characterized by progressive muscle weakness, atrophy, and loss of sensation in the extremities. It can also present with some ocular manifestations, such as glaucoma, nystagmus, and cranial nerve involvement. The purpose of this article was to report a case of severe dry eye disease (DED) possibly associated with Charcot-Marie-Tooth disease. CASE REPORT We report the clinical presentation, workup, and management of a woman diagnosed with CMT type 2EE based on genetic testing who suffered from severe DED sequelae. The patient had regularly followed up in the cornea service at our hospital due to DED for several years. A thorough workup to exclude causes associated with dry eye disease, including rheumatoid factor, erythrocyte sedimentation rate (ESR), anti-nuclear antibody (ANA), anti-Sjögren's-syndrome-related antigen A (anti-SSA), and anti-Sjögren's-syndrome-related antigen B (Anti-SSB), were performed, and all came out negative. She recently presented to the emergency room with redness, tearing, and a decline in visual acuity after minor ocular trauma 3 weeks before her presentation. The slit lamp examination showed central corneal perforation measuring 2×2 mm with a positive Seidel test. The case was managed first by multiple attempts to seal the defect with cyanoacrylate glue, and then a patch corneal graft was performed as the anterior chamber failed to deepen. CONCLUSIONS DED may be one of the many ocular manifestations associated with CMT. Hence, a thorough assessment and multidisciplinary approach, including supportive therapy, are warranted to prevent long-term ocular sequelae, including visual loss.

[A case of Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation].

The patient is a 44-year-old man. His parents are consanguineous. He experienced muscle weakness in his toe and distal tingling sensation in his feet at 42 years of age, which gradually progressed. Additionally, a marked cyanotic discoloration of the feet appeared and worsened progressively. Neurological examination revealed loss of tendon reflexes and distal muscle weakness in the lower extremities. Findings from nerve conduction studies indicated axonal polyneuropathy. Upon detection of the MME gene mutation, the patient was diagnosed with autosomal-recessive Charcot-Marie-Tooth disease 2T (ARCMT2T). In this case, cyanosis of the lower extremities possibly was associated with ARCMT2T, and it was suggested to be due to neprilysin deletion linked with the MME mutation. This represents the first documented occurrence of cyanosis as a distinctive feature of CMT with MME mutation.

Perioperative Autonomic Dysfunction in a Patient With Charcot-Marie-Tooth Disease: A Case Report.

Autonomic dysfunction can lead to unexpected hemodynamic instability during surgery, and best practices for the perioperative care of patients with this condition are not well-defined. We report the case of a 63-year-old woman with Charcot-Marie-Tooth disease who experienced perioperative autonomic dysfunction characterized by severe fluctuations in blood pressure while under spinal anesthesia. However, <1 month later, a second hip surgery performed under general anesthesia with special precautions resulted in an uncomplicated perioperative course, with only mild fluctuations in blood pressure.

Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.

BACKGROUND: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series. METHODS: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. RESULTS: ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001). CONCLUSIONS: Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients' management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.

Association of Body Mass Index With Disease Progression in Children With Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the impact of body mass index (BMI) on disease progression over 2 years in children with Charcot-Marie-Tooth disease (CMT). METHODS: BMI was classified in 242 participants aged 3-20 years with CMT enrolled in the Inherited Neuropathy Consortium, using the International Obesity Task Force (based on adult BMI values, kg/m2) criteria. Groups were categorized as severely underweight (BMI <17 kg/m2), underweight (BMI ≥17 to <18.5 kg/m2), healthy weight (BMI ≥18.5 to <25 kg/m2), overweight (BMI ≥25 to <30 kg/m2), and obese (BMI ≥30 kg/m2). Disease severity was assessed using the CMT Pediatric Scale (CMTPedS), a clinical outcome assessment of disability (0-44 points, mild to severe). RESULTS: At baseline, compared with individuals being of a healthy weight (mean CMTPedS 15.48, SD 9.22), children who were severely underweight (mean CMTPedS difference 9.03, 95% CI 0.94-17.12; p = 0.02), underweight (mean CMTPedS difference 5.97, 95% CI 0.62-11.31; p = 0.02), or obese (mean CMTPedS difference 7.96, 95% CI 1.03-14.88; p = 0.015) exhibited greater disability. At 2 years, compared with individuals being of a healthy weight (mean CMTPedS 17.53, SD 9.41), children who were severely underweight exhibited greater disability (mean CMTPedS difference 9.27, 95% CI 0.90-17.64; p = 0.02). Over the 2-year periods, the mean CMTPedS for the whole sample deteriorated by 1.72 points (95% CI 1.09-2.38; p < 0.001), with severely underweight children progressing at the fastest rate (mean CMTPedS change of 2.3, 95% CI 1.53-6.13; p = 0.21). In children who did not have a change in BMI categories over 2 years (69% of sample), CMTPedS scores deteriorated faster in those who were severely underweight (mean CMTPedS change 6.40 points, 95% CI 2.42-10.38; p = 0.01) than those of healthy weight (mean CMTPedS change 1.79 points, 95% CI 0.93-2.69; p < 0.001). For children who changed BMI categories (31% of sample), CMTPedS scores deteriorated faster in children who became overweight/obese (mean CMTPedS change 2.76 points, 95% CI 0.11-5.41; p = 0.031). DISCUSSION: Children with CMT who were severely underweight, underweight, or obese exhibited greater disability at baseline. Over the 2-year period in those whose BMI remained stable, severely underweight children deteriorated at the fastest rate. For children who changed BMI categories over the 2 years, CMTPedS scores deteriorated faster in children who became overweight/obese. Interventions that maintain or improve BMI toward healthy weight may reduce disability in children with CMT.

Thoracic synovial cyst as cause of cord compression in a patient with Charcot-Marie-Tooth disease.

An 80-year-old male patient affected by Charcot-Marie-Tooth (CMT) disease came to our attention in July 2020, for the occurrence of low back pain and lower limb weakness, and also saddle anesthesia, urinary and faecal retention were referred. His diagnosis of CMT is dated back to 1955 and through the years, the clinical picture slowly worsened but never got particularly severe. The quick symptoms outbreak and the presence of urinary disturbances were red flags, which lead us to direct the diagnostic orientation elsewhere. A Magnetic Resonance Imaging of the thoraco-lumbar spinal cord was then performed and it was suggestive for synovial cyst at T10-T11. The patient underwent a decompression with laminectomy and then stabilized through arthrodesis. In the very next days after the surgery, the patient showed a sudden and significant improvement of his condition. At the last visit, he showed a remarkable relief of the symptoms, walking by himself.

Characteristic 3D foot motion patterns during gait of patients with Charcot-Marie-Tooth identified by cluster analysis.

BACKGROUND: CMT is a clinically and genetically heterogenous disease with varying degrees of progression. Different foot deformities, gait and movement patterns are observed. In order to achieve an improved, targeted treatment strategy, the participants are divided into characteristic groups using a mathematical cluster analysis based on the data from the three-dimensional foot kinematics during walking. METHODS: Outpatients from age 5-64 years (N = 33 participants, 62 feet) with a proven CMT type 1 (N = 16, 31 feet) or CMT without any further type assignment (N = 17, 31 feet) were retrospectively analyzed. After a standard clinical examination, participants underwent 3D gait analysis using the Oxford Foot Model. To classify the movement patterns, a k-means cluster analysis was calculated based on the principal component analysis (PCA) of the foot kinematics data. Gait parameters, clinical parameters and X-ray data were statistically tested. RESULTS: The cluster analysis divided the gait data of the participants into two groups. Cluster 1 (N = 21 participants, 34 feet) showed increased dorsiflexion of the hindfoot and increased plantarflexion of the forefoot with cavus position in the sagittal plane, a hindfoot inversion and forefoot pronation with hindfoot varus in the frontal plane and in the transversal plane a forefoot adduction. Cluster 2 (N = 17 participants, 28 feet) deviated significantly from the norm mainly in the frontal plane and were characterized by a strong eversion of the hindfoot with a supination in the forefoot. DISCUSSION: Based on the findings, the resultant clusters can be interpreted as cavovarus feet (cluster 1) and pes valgus (cluster 2). The most reliable variables in the 3D gait analysis to classify CMT feet with regard to significance are the ones in the frontal plane. This subdivision of participants goes hand in hand with the various necessary guidelines for orthopedic treatment.

Natural history of ankle function during gait in youth with Charcot-Marie-Tooth disease types 1 and 2.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) can cause progressive muscle weakness and contracture, leading to gait abnormalities such as increased and delayed peak ankle dorsiflexion and reduced ankle power generation in terminal stance. Understanding strength loss on ankle function during gait is important for interpreting treatment outcomes and evaluating new therapies designed to improve gait. RESEARCH QUESTION: Do ankle kinematics and kinetics vary as a function of age, disease progression with associated loss of muscle strength and CMT type in youth with CMT types 1 and 2? METHODS: A prospective convenience sample of 45 participants with CMT1 and 2, ages 7-22 years, underwent comprehensive gait analysis. Seventeen patients underwent repeat analyses totaling 67 tests. Generalized mixed effects linear modeling was used to compare CMT1 versus CMT2 and to examine the effects of age on ankle strength, range of motion, kinematics, and kinetics within each CMT type. RESULTS: Plantarflexor and dorsiflexor strength were less in CMT2 compared with CMT1 (p ≤ 0.05), while peak dorsiflexion in terminal stance (TST) was greater (p = 0.02). Peak plantarflexion moment and power generation were also less in CMT2 (p ≤ 0.02). In CMT1, peak dorsiflexion in TST increased with age through 13 years (p = 0.004); then plateaued in the normal range (p = 0.73). Peak ankle angle in mid-swing was closely related to the angle in TST (p < 0.001) following a similar pattern with age. In CMT2, no significant associations were observed between age, peak dorsiflexion in TST, and peak ankle angle in mid-swing (p ≥ 0.19). There were no consistent trends with age for individual patients with repeat tests. SIGNIFICANCE: The heterogeneity of joint level impairments and gait kinematics and kinetics point to the importance of having an in-depth understanding of gait at the individual patient level using comprehensive gait analysis including valid and reliable strength measures.

Assessing the coronal plane deformity in Charcot Marie Tooth Cavovarus feet using automated 3D measurements.

BACKGROUND: This study assesses the coronal-plane deformities in cavovarus feet secondary to Charcot-Marie-Tooth disease (CMT) using Weightbearing-CT (WBCT) and semi-automated 3D-segmentation software. METHODS: WBCTs from 30 CMT-cavovarus feet were matched to 30 controls and analysed using semi-automatic 3D-segmentation (Bonelogic, DISIOR). The software used automated cross-section sampling with subsequent straight-line representation of weighted centre points to calculate 3D axes of bones in the hindfoot, midfoot and forefoot. Coronal relationships of these axes were analysed. Supination/pronation of the bones in relation to the ground and within each joint were measured and reported. RESULTS: The most significant deformity in CMT-cavovarus feet occurred at the talonavicular joint (TNJ) with 23 degrees more supination than normal feet (6.4 ± 14.5 versus 29.4 ± 7.0 degrees, p < 0.001). This was countered by relative pronation at the naviculo-cuneiform joints (NCJ) of 7.0 degrees (-36.0 ± 6.6 versus -43.0 ± 5.3 degrees, p < 0.001). Combined hindfoot varus and TNJ supination resulted in an additive supination effect not compensated by NCJ pronation. The cuneiforms in CMT-cavovarus feet were therefore supinated by 19.8 degrees to the ground relative to normal feet (36.0 ± 12.1 versus 16.2 ± 6.8 degrees, p < 0.001). The forefoot-arch and 1st metatarsal-ground angles demonstrated similar supination to the cuneiforms suggesting no further significant rotation occurred distally. CONCLUSION: Our results demonstrate coronal plane deformity occurs at multiple levels in CMT-cavovarus feet. Majority of the supination arises at the TNJ, and this is partially countered by pronation distally, mainly at the NCJ. An understanding of the location of coronal deformities may help when planning surgical correction. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Patient Reported Outcomes Using Medical Cannabis for Managing Pain in Charcot-Marie-Tooth Disease.

Objective: Chronic pain is a major problem for patients with Charcot-Marie-Tooth (CMT) disease. This exploratory study examined patient reported efficacy of medical cannabis for pain management in this population. Methods: Participants (N = 56; 71.4% female; Age = 48.9, SD = 14.6; 48.5% CMT1) were recruited though the Hereditary Neuropathy Foundation. The online survey contained 52 multiple choice questions about demographics, medical cannabis use, symptomology, efficacy, and adverse effects. Results: Nearly all (90.9%) of respondents reported experiencing pain, including all (100%) females and 72.7% of males (chi-square P < .05) with 91.7% of respondents indicating cannabis provided at least 50% pain relief. The most frequent response was an 80% reduction in pain. Moreover, 80.0% of respondents reported using less opiates, 69% noted using less sleep medication, and 50.0% reported using less anxiety/antidepressant medications. Negative side effects were noted by 23.5% of respondents. However, almost all (91.7%) of that subgroup did not have plans to stop consuming cannabis. One-third (33.9%) possessed a medical cannabis certificate. Patient perceptions of their physicians' attitudes regarding patient medical cannabis use greatly impacted whether respondents informed their providers of their usage. Conclusion: The vast majority of patients with CMT reported that cannabis was effective to manage pain symptoms. These data support the need for prospective, randomized, controlled trials using standardized dosing protocols to further delineate and optimize the potential use of cannabis to treat pain related to CMT.

INF2 mutations in patients with a broad phenotypic spectrum of Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis.

Mutations in INF2 are associated with the complex symptoms of Charcot-Marie-Tooth disease (CMT) and focal segmental glomerulosclerosis (FSGS). To date, more than 100 and 30 genes have been reported to cause these disorders, respectively. This study aimed to identify INF2 mutations in Korean patients with CMT. This study was conducted with 743 Korean families with CMT who were negative for PMP22 duplication. In addition, a family with FSGS was included in this study. INF2 mutations were screened using whole exome sequencing (WES) and filtering processes. As the results, four pathogenic INF2 mutations were identified in families with different clinical phenotypes: p.L78P and p.L132P in families with symptoms of both CMT and FSGS; p.C104Y in a family with CMT; and p.R218Q in a family with FSGS. Moreover, different CMT types were observed in families with CMT symptoms: CMT1 in two families and Int-CMT in another family. Hearing loss was observed in two families with CMT1. Pathogenicity was predicted by in silico analyses, and considerable conformational changes were predicted in the mutant proteins. Two mutations (p.L78P and p.C104Y) were unreported, and three families showed de novo mutations that were putatively occurred from fathers. This study suggests that patients with INF2 mutations show a broad phenotypic spectrum: CMT1, CMT1 + FSGS, CMTDIE + FSGS, and FSGS. Therefore, the genotype-phenotype correlation may be more complex than previously recognized. We believe that this study expands the clinical spectrum of patients with INF2 mutations and will be helpful in the molecular diagnosis of CMT and FSGS.

Anxiety and depression in Charcot-Marie-Tooth disease: data from the Italian CMT national registry.

BACKGROUND: There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. METHODS: We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. RESULTS: We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. CONCLUSIONS: An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.