Charcot-Marie-Tooth Disease Type 1A Patients Research Articles

PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 megabase tandem duplication of chromosome 17 harboring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To get better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication on cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was dose-dependently downregulated throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signaling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity, and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane due to an alteration in the lipid composition, which ultimately may lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of CMT1A patients.

Comparative Analysis on Methylation Levels of Nerve and Stress Related Genes in Charcot-Marie-Tooth Disease Type 1A Patients

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of the 17p12 region including <i>PMP22</i> gene. In CMT1A patients, anticipation showing increased severity by generations has been reported in the CMT1A patients. It has also been reported that severity increases in the non-<i>de novo</i> cases than in the <i>de novo</i> cases. This study was performed to examine epigenetic differences between CMT1A cases and controls as well as between de novo cases and non-<i>de novo</i> cases.Methods: This study examined 40 Korean CMT1A patients and 11 controls. Methylation level was determined using the SureSelect XT Methyl-Seq reagent kit and bisulfite sequence mapping program.Results: Many differentially methylated CpG sites (DMCs) were identified in the comparisonbetween cases and controls and between <i>de novo</i> cases and non-<i>de novo</i> cases. Most DMCs were located within or nearby genes related to the nervous system, mental stress, and motor ability.Conclusions: This study is the first epigenetic study to uncover the mechanism of clinical heterogeneity among CMT1A patients. We suggest that weak severity in the <i>de novo</i> cases than the non-<i>de novo</i> cases may be related to the epigenomic differences in the nerve and stress-related genes.

Quantitative Foot Muscle Magnetic Resonance Imaging Reliably Measures Disease Progression in Children and Adolescents with Charcot-Marie-Tooth Disease Type 1A.

Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.9 ± 20.3% in CMT1A patients, and the 365-day FF (n = 15) increased by 2.0 ± 2.4% (p < 0.001 vs controls). Intrinsic foot-level FF demonstrated large responsiveness (12-month standardized response mean (SRM) of 0.86) and correlated with the CMT examination score (ρ = 0.58, P = 0.01). Intrinsic foot-level FF has the potential to be used as a biomarker in future clinical trials involving younger CMT1A patients. ANN NEUROL 2024;96:170-174.

A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A.

Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects. We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics. We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies. Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.

Testing SIPA1L2 as a modifier of CMT1A using mouse models.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), leading to muscle weakness and loss of sensation in the hands and feet. A recent case-only genome-wide association study of CMT1A patients conducted by the Inherited Neuropathy Consortium identified a strong association between strength of foot dorsiflexion and variants in signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be a genetic modifier of disease. To validate SIPA1L2 as a candidate modifier and to assess its potential as a therapeutic target, we engineered mice with deletion of exon 1 (including the start codon) of the Sipa1l2 gene and crossed them to the C3-PMP22 mouse model of CMT1A. Neuromuscular phenotyping showed that Sipa1l2 deletion in C3-PMP22 mice preserved muscular endurance assayed by inverted wire hang duration and changed femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggest involvement of Sipa1l2 in cholesterol biosynthesis, a pathway that is also implicated in C3-PMP22 mice. Although Sipa1l2 deletion did impact CMT1A-associated phenotypes, thereby validating a genetic interaction, the overall effect on neuropathy was mild.

Gait Pattern in Charcot-Marie-Tooth Disease Type 1A According to Disease Severity.

The aim of this study was to evaluate the characteristics of gait patterns in Charcot-Marie-Tooth disease type 1A (CMT1A) patients according to disease severity. Twenty-two CMT1A patients were enrolled and classified into two groups, according to the disease severity. The healthy control group consisted of 22 subjects with no gait impairment. Full barefoot three-dimensional gait analysis with temporospatial, kinematic, and kinetic data was performed among the mild and moderate CMT1A group and the control group. Minimal hip abduction, maximal hip extension generation, peak knee flexion moment at stance, ankle dorsiflexion at initial contact, maximal ankle plantarflexion at push-off and maximal ankle rotation moment at stance in the CMT1A group showed a significant difference compared to the control group (p < 0.05). In the moderate group, there were greater maximal hip flexion angles in swing, and smaller dorsiflexion angles at initial contact compared to the control group and mild group. CMT patients had typical gait characteristics and their gait patterns were different according to severity. The analysis of gait patterns in patients with CMT1A will help to understand gait function and provide important information for the treatment of patients with CMT in the future.

Evaluation of the median nerve by shear wave elastography in patients with Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is characterized by enlargement and stiffness of peripheral nerves due to edema with large numbers of "onion bulbs" in the endoneurium. Ultrasound elastography seems to be an ideal method to detect this condition. The aim of this study was to analyze the shear wave elastography (SWE) features of peripheral nerves in patients with CMT1A. We included 24 CMT1A patients with a mean age of 28 years, along with 24 age- and gender-matched controls. All patients presented with mutations of the PMP22 gene and showed length-dependent polyneuropathy. The motor nerve conduction velocity (MNCV) of the median nerve ranged from 5.2 to 37.4 m/s. SWE and cross-sectional area (CSA) were used to evaluate the bilateral median nerves at predefined sites in both patients and con-trols. The average elastography value (EV) of the median nerve was 73.5±11.7 kPa in patients with CMT1A and 37.5±6.1 kPa in control subjects. The difference between the two groups was statistically significant (P<0.05). In CMT1A pa-tients, the average EV at the proximal and distal parts of the median nerve were 81.4±9.4 kPa and 65.2±8.1 kPa, respectively. The average CSAs at the proximal and distal parts of the median nerve were 0.29±0.06 cm2 and 0.20±0.05 cm2, respectively. The EV on SWE was positively correlated with CSA (p< 0.01) and negatively correlated with MNCV in the median nerve (p< 0.01). Peripheral nerve stiffness dramatically increases in CMT1A and is correlated with the severity of nerve involvement.

Surgical Release of Ulnar and Median Nerves in CMT1A: Prevention and Treatment of a Second Hit (P14-8.013)

<h3>Objective:</h3> To evaluate outcomes of carpal tunnel (CT, CTS), cubital tunnel (CuT, CuTS), and Guyon’s Canal (GC, GCS) release in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). <h3>Background:</h3> Peripheral nerves in patients with CMT1A are diffusely enlarged and areas of potential compression at the CT, CuT, and GC can be released to reduce the risk of a “second hit” (nerve injury due to compression) in the setting of their genetic, progressive neuropathy, however there is little data on the efficacy and timing of surgical nerve decompression. <h3>Design/Methods:</h3> Genetically diagnosed and suspected CMT1A patients that reported hand symptoms seen in clinic in 2021–2022 with electrophysiologic data who were evaluated by neurosurgery for surgical decompression for CTS, CuTS, and GCS were reviewed. <h3>Results:</h3> All patients had severe slowing of motor nerve conduction velocities and absent sensory responses on NCS consistent with CMT1A. Electrographic CTS occurred bilaterally in 83%(5/6). Electrographic bilateral GCS and unilateral CuTS were observed in 33%(2/6) of patients. Three patients with sonographic data all demonstrated diffuse enlargement of the ulnar and median nerves at the forearm (mean cross-sectional area, CSA=20 mm2 and 26 mm2). Focal narrowing occurred at the CT in two patients (mean CSA=11.2 mm2 vs 37 mm2 at the forearm). One patient underwent unilateral and one patient underwent bilateral decompression at the CT, CuT, and GC with a follow-up time of 8 months and 2 months. Both patients endorsed significant improvement of gross grip strength in at least one hand and resolution of median sensory abnormalities in territories of released nerves. <h3>Conclusions:</h3> Although altered due to the nature of CMT1A, electrophysiologic and sonographic data provided focal findings in our patients with hand symptoms. Patients who underwent surgical decompression had symptomatic benefits. These releases can reduce the risk of a “second hit” of neurologic injury due to compression. <b>Disclosure:</b> Dr. McKeen has nothing to disclose. Dr. Katyal has nothing to disclose. Dr. Sakamuri has received personal compensation in the range of $0-$499 for serving as a Conference Faculty with AANEM. Dr. Wilson has nothing to disclose. Dr. Greene has received personal compensation in the range of $500-$4,999 for serving as a Advisory Board Member with Dysimmune Diseases Foundation .

The systemic inhibition of the terminal complement system reduces neuroinflammation but does not improve motor function in mouse models of CMT1A with overexpressed PMP22.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary demyelinating neuropathy. This autosomal, dominantly inherited disease is caused by a duplication on chromosome 17p which includes the peripheral myelin protein 22 (PMP22) gene. There is clinical evidence that the disability in CMT1A is to a large extend due to axonal damage rather than demyelination. Over-expression of PMP22 is recently thought to impede cholesterol trafficking causing a total shutdown of local cholesterol and lipid synthesis in the Schwann cells, thus disturbing their ability to remyelinate. But there is a large variety in disease burden between CMT1A patients with the same genetic defect, indicating the presence of modifying factors that affect disease severity. One of these potential factors is the immune system. Several reports have described patients with co-occurrence of CMT1A with chronic inflammatory demyelinating disease or Guillain-Barré syndrome. We have previously shown in multiple animal models that the innate immune system and specifically the terminal complement system is a driver of inflammatory demyelination. To test the contribution of the terminal complement system to neuroinflammation and disease progression in CMT1A, we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3-PMP22 and C3-PMP22 c-JunP0Cre models. Both models over-express human PMP22, and one (C3-PMP22 c-JunP0Cre) also has a Schwann cell-specific knockout of c-Jun, a crucial regulator of myelination controlling autophagy. We found that systemic inhibition of C6 using antisense oligonucleotides affects the neuroinflammation, Rho GTPase and ERK/MAPK signalling pathways in the CMT1A mouse models. The cholesterol synthesis pathway remained unaffected. Analysis of motor function during treatment with C6 antisense oligonucleotides did not reveal any significant improvement in the CMT1A mouse models. This study shows that the contribution of the terminal complement system to progressive loss of motor function in the CMT1A mouse models tested is limited.

Young infants with PMP22 duplication can have minor nerve conduction study abnormalities

Charcot-Marie-Tooth disease type 1A (CMT1A) is related to PMP22 gene duplication. It is characterized at electrodiagnostic testing (EDX) by diffuse homogeneous signs of demyelination, such as velocity slowing and prolonged distal latencies. These abnormalities are less pronounced in infants under two years old, and the possibility of normal nerve conduction studies (NCS) in infants with CMT1A under one year of age has been questioned. We report three infants who displayed normal or almost normal NCS. EDX abnormalities in CMT1A patients may therefore appear late during development. This may affect early EDX diagnosis in infants and should be considered for upcoming clinical trials.

Magnetic resonance imaging-based lower limb muscle evaluation in Charcot-Marie-Tooth disease type 1A patients and its correlation with clinical data

We aimed to derive comprehensive MRI parameters that reflect intramuscular fat infiltration severity for designated lower extremity levels, based on semiquantitative analyses in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. We reviewed lower extremity MRIs of 116 CMT1A patients. Intramuscular fat infiltration grading using the Mercuri scale was performed for the non-dominant lower extremity at three levels (proximal, mid, and distal) for the thigh and at two levels (proximal and distal) for the lower leg. Based on MRI results, the following parameters were calculated for each level and for entire muscles: fat infiltration proportion (FIP), significant fat infiltration proportion (SigFIP), and severe fat infiltration proportion (SevFIP). The relationships between the MRI parameters and clinical data were evaluated using Spearman’s correlation analysis. FIP, SigFIP, and SevFIP measured for entire muscles significantly correlated with Charcot-Marie-Tooth Neuropathy Score (p < 0.001), functional disability scale (p < 0.001), 10-m walk test time (p = 0.0003, 0.0010, and 0.0011), and disease duration (p < 0.001). Similar correlations were demonstrated for FIP, SigFIP, and SevFIP acquired from the lower leg. Our MRI parameters obtained through semiquantitative analyses of muscles significantly correlated with clinical parameters in CMT1A patients, suggesting their potential applicability as imaging markers for clinical severity.

Intraepineurial fat quantification and cross-sectional area analysis of the sciatic nerve using MRI in Charcot-Marie-Tooth disease type 1A patients

The objectives of this study were to assess the fat fraction (FF) and cross-sectional area (CSA) of the sciatic nerve in Charcot-Marie-Tooth disease type 1A (CMT1A) patients using Dixon-based proton density fat quantification MRI and to elucidate its potential association with clinical parameters. Thigh MRIs of 18 CMT1A patients and 18 age- and sex-matched volunteers enrolled for a previous study were reviewed. Analyses for FF and CSA of the sciatic nerve were performed at three levels (proximal to distal). CSA and FF were compared between the two groups and among the different levels within each group. The relationship between the MRI parameters and clinical data were assessed in the CMT1A patients. The CMT1A patients showed significantly higher FF at level 3 (p = 0.0217) and significantly larger CSA at all three levels compared with the control participants (p < 0.0001). Comparisons among levels showed significantly higher FF for levels 2 and 3 than for level 1 and significantly larger CSA for level 2 compared with level 1 in CMT1A patients. CSA at level 3 correlated positively with the CMT neuropathy score version 2 (CMTNSv2). In conclusion, the sciatic nerve FF of CMT1A patients was significantly higher on level 3 compared with both the controls and the measurements taken on more proximal levels, suggesting the possibility of increased intraepineurial fat within the sciatic nerves of CMT1A patients, with a possible distal tendency. Sciatic nerve CSA at level 3 correlated significantly and positively with CMTNSv2, suggesting its potential value as an imaging marker for clinical severity.

Quantitative assessment of muscle echogenicity in Charcot-Marie-Tooth disease type 1A by automatic thresholding methods

ObjectiveTo investigate the utility of automatic thresholding methods for quantitative muscle echogenicity assessment as a marker of disease severity in Charcot-Marie-Tooth disease type 1A (CMT1A). MethodsMuscle ultrasound was performed in 15 CMT1A patients and 7 healthy controls. Muscle echogenicity of six limb muscles in each subject was assessed by 16 automatic thresholding methods and conventional grey-scale analysis. Echogenicity of each method in CMT1A patients was compared with that in controls. A correlation between the echogenicity and CMT neuropathy score (CMTNS) was also analysed in CMT1A patients. ResultsSignificant differences in mean echogenicity of the 6 muscles between CMT1A patients and controls were found both in grey-scale analysis (p < 0.01) and 11 of the 16 automatic thresholding methods (p < 0.05 in each method). In CMT1A patients, mean echogenicity of the 6 muscles was positively correlated with CMTNS in 8 of the 16 automatic thresholding methods, but not in grey-scale analysis. ConclusionAutomatic thresholding methods can be used to detect the difference in muscle echogenicity between CMT1A patients and controls. Echogenicity parameters correlate with the disease severity. SignificanceQuantitative muscle echogenicity assessment by automatic thresholding methods shows potential as a surrogate marker of disease progression in CMT1A.

Reference values for lower limb nerve ultrasound and its diagnostic sensitivity

We aimed to establish the cross-sectional area (CSA) reference values for peripheral nerves of lower extremities in a healthy Chinese population, and to determine their diagnostic values for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth disease type1A (CMT1A). One hundred eleven healthy subjects, 15–70 years of age, as well as 104 CIDP patients and 26 CMT1A patients were recruited. CSA at predetermined sites of the tibial, fibular, sciatic and sural nerves was measured. The CSA of the tibial nerve ranged from 10.2 ± 1.9 to 20.7 ± 3.6 mm2, and for fibular nerve from 8.4 ± 1.8 to 9.5 ± 1.9 mm2. 86% CIDP patients had upper limb nerve enlargement, while only 67% had lower limb nerve enlargement. In CIDP patients with normal upper limb ultrasound, 56% (5/9) would have lower limb nerve enlargement. All CMT1A patients had both upper and lower limb nerve enlargement. Addition of lower limb nerve ultrasound showed no added value in diagnosis of CMT1A, but could be supplementary for CIDP when upper limb ultrasound is normal.

High-density surface electromyography to assess motor unit firing rate in Charcot-Marie-Tooth disease type 1A patients

ObjectiveThe aim of this study was to elucidate the characteristics of the motor unit (MU) firing rate in Charcot-Marie-Tooth disease type 1A (CMT1A) patients and its longitudinal change using high-density surface-electromyography (surface-EMG) and MU decomposition analysis. MethodsNineteen patients with CMT1A and 21 force-matched healthy controls prospectively underwent surface-EMG recording of the vastus lateralis muscle during ramp-up and sustained contractions on performing isometric knee extension. After decomposition analysis, instantaneous firing rates (IFRs) of individually identified MUs were calculated. In CMT1A patients, follow-up measurements were performed one year after the baseline. Comparison of IFRs and clinical variables between CMT1A patients and controls at the baseline and between the baseline and after one year in CMT1A patients was performed. ResultsMean IFRs of MUs were lower in CMT1A patients than in controls. This was true at various force levels in ramp-up contractions (p < 0.01. e.g., 10.3 (CMT1A patients) vs. 12.2 (controls) pulses-per-second (pps) at 22.5–27.5% of maximal voluntary contraction (MVC) in MUs recruited at <7.5% of MVC) and at any time-point during sustained contractions (p < 0.001. e.g., 8.0 vs. 9.3 pps, respectively, at 10–20 seconds). In CMT1A patients, mean IFRs at 0–10 seconds of sustained contraction were significantly decreased over one year (from 8.06 to 7.52 pps; p = 0.027), whereas the disease severity score and MVC of knee extension did not change over time. ConclusionCMT1A patients had a lower individual MU firing rate. SignificanceThe MU firing rate is a potential short-term biomarker of axonal damage in CMT1A patients.

Diffuse brain connectivity changes in Charcot–Marie–Tooth type 1a patients: a resting‐state functional magnetic resonance imaging study

Changes of brain structure and function have been described in peripheral neuropathies. The aim of our study was to systematically investigate possible modifications of major large-scale brain networks using resting-state functional magnetic resonance imaging (RS-fMRI) in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. In this cross-sectional study, 3-T MRI brain scans were acquired of right-handed genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing neurological impairment. RS-fMRI data were analysed using a seed-based approach, with 32 different seeds sampling the main hubs of default mode, sensorimotor, visual, salience (SN), dorsal attention, frontoparietal, language and cerebellar networks. Between-group differences in terms of functional connectivity (FC) with the explored seeds were tested voxelwise, correcting for local grey matter density to account for possible structural abnormalities, whilst the relationship between FC modifications and neurological impairment was investigated using robust correlation analyses. Eighteen CMT1A patients (34.0±11.4years; M/F 11/7) were enrolled, along with 20 healthy controls (30.1±10.2years; M/F 11/9). In the CMT group compared to controls, clusters of increased FC with the visual cortex (P=0.001), SN (P<6 × 10-4 ), dorsal attention network (P<8 × 10-5 ) and language network (P<7 × 10-4 ) were found, along with a single cluster of reduced FC with the visual cortex in the left lentiform nucleus (P=10-6 ). A significant correlation emerged between neurophysiological impairment and increased FC with right temporal language areas (r=0.655, P=0.006), along with an association between walking ability and increased FC with the left supramarginal gyrus (SN) (r=0.620, P=0.006). Our data show evidence of diffuse functional reorganization involving multiple large-scale networks in the CMT1A brain, independent of structural modifications and partially correlating with peripheral nerve damage and functional impairment.

Rate of Changes in CMT Neuropathy and Examination Scores in Japanese Adult CMT1A Patients.

Introduction: We aimed to clarify when adult patients with Charcot-Marie-Tooth disease type 1A (CMT1A), especially those diagnosed at middle or advanced ages, first showed symptoms and whether the rate of disease progression is accelerated by aging.Methods: Medical records of CMT1A outpatients between 2012 and 2019 were reviewed. The age at diagnosis, age when symptoms first appeared, and rate of disease progression, assessed based on clinical outcome measures including the CMT Neuropathy Score (CMTNS), Rasch-modified CMTNS (CMTNS-R), CMT Examination Score (CMTES), and Rasch-modified CMTES (CMTES-R) were analyzed.Results: Among 45 adult CMT1A patients, 42% had been diagnosed after 50 years of age, whereas 91% of all patients had exhibited some CMT-related symptoms before 20 years of age. The annual increase of all clinical outcome measures did not differ between patients under and over 50 years. Even when limited to patients whose initial CMTES-R showed mild to moderate severity, the rate of change in CMTES-R did not differ between the two age groups (the annual mean ± standard deviation, under 50 years: 1.1 ± 1.0, and over 50 years: 0.9 ± 1.1, p = 0.68). To determine whether patients with disabilities at a young age have a higher deterioration rate, they were classified into three groups according to their current age and age at diagnosis: patients under 50 years of age, patients over 50 years of age but diagnosed before 50, and patients diagnosed after 50 years of age. The mean annual increase of all clinical outcome measures, however, did not differ among these groups (CMTES-R: 1.03 ± 1.01 vs. 0.94 ± 1.57 vs. 0.81 ± 0.88, respectively, p = 0.87).Discussion: CMT1A patients develop symptoms in childhood and adolescence even if such symptoms are not noticeable until reaching an advanced age. Deterioration rates of clinical outcome measures are constant irrespective of the age in their adulthood, although we cannot rule out the limitation that the difference did not reach significance because of the small number of patients. Being aware of the existence of a considerable number of undiagnosed CMT patients will help promote the avoidance of inadequate medication.

High glucose level as a modifier factor in CMT1A patients.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common type of hereditary neuropathy worldwide and diabetes mellitus (DM) is the most frequent cause of peripheral neuropathy in the Western world. CMT1A typically manifest as a predominant motor neuropathy, while, DM-related neuropathy often manifests as a predominant sensory disorder. There are some evidences that CMT1A patients that also had DM had a more severe neuropathy. Although the real frequency and the underlying mechanisms related to this association has not yet been addressed in the literature. We sought to characterize the phenotypic variability of CMT1A patients with persistent high glucose levels (DM or impaired glucose tolerance [IGT]). Nineteen patients with CMT1A and DM (CMTdiab), seven with CMT1A and IGT (CMTintol) and 27 with CMT1A without comorbidities were analyzed. They were evaluated through clinical assessment, application of the following scales: visual analogue scale, McGill, CMTNS, SF-36 and COMPASS 31 and electrophysiological studies. Patients CMTdiab had a more severe motor and sensory neuropathy, more intense autonomic symptoms and worse quality of life. Surprisingly, proximal weakness and temporal dispersion on nerve conduction studies are frequently observed in this group. Patients CMTintol also had a more severe neuropathy. Curiously, we observed that the association of CMT1A and glucose metabolism disorders (CMTglic) clustered in some families. Patients CMTglic develop a more severe neuropathy. As there is yet no cure to CMT1A, a strict blood sugar control may be a useful measure.

P59-T The utility of sural NCS in differentiation of AIDP, CIDP and CMT1A

Objective Nerve conduction studies (NCS) are mainstay in diagnosis and classification of polyneuropathies as demyelinating or axonal. However, detection of demyelination and differentiation of hereditary and inflammatory polyneuropathies are mainly based on motor NCS. The aim of this study was to examine the utility of sural NCS in differentiation of the three most common demyelinating polyneuropathies; Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and Charcot-Marie-Tooth-Disease type 1A (CMT1A). Methods Fifty-eight patients (mean age: 50.90 ± 14.29) were included. Of these, 16 had AIDP, 19 CIDP and 23 CMT1A with PMP22 duplication. Sural nerve was examined with surface electrodes (13 patients) or near-nerve needle technique (45 patients). Results were compared to laboratory controls. The pathophysiological state of the sural nerve was classified as normal, axonal loss or demyelinating according to ESTEEM criteria (Tankisi et al., 2005). Results Of 16 AIDP patients, 10 had normal sural NCS, 2 demyelination and 4 axonal loss. CIDP patients had either axonal (14) or normal (5) sural NCS whereas all CMT1A patients showed demyelination. Sural sensory CV could distinguish all patients with CMT1A (CV 35 m/s). AIDP and CIDP patients had significantly higher CV (42.6m/s ± 5.6 and 46.5m/s ± 8.1, respectively) than CMT1A (22.5m/s ± 5.3)(p μ V ± 9.4) than CIDP (4.2 μ V ± 4.9) and CMT1A (3.0 μ V ± 4.5)(p Conclusion Sural NCS may contribute to differentiation of AIDP, CIDP and CMT1A. Demyelination is characteristic for CMT1A and axonal loss is mostly seen in CIDP whereas in AIDP sural nerve is often normal.

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

Background:Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5–Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.Objective:We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.Methods:We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.Results:The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10–7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10–7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10–7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10–7, beta = 3.014).Conclusions:While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.