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. 2024 Aug 12;103(5):e209763. doi: 10.1212/WNL.0000000000209763

Clinical Characteristics of Charcot-Marie-Tooth Disease Type 4J

Reza Sadjadi 1,*,✉, Vincent Picher-Martel 1,*, Jasper M Morrow 1, Daniel Thedens 1, Paul A DiCamillo 1, Brett A McCray 1, Davide Pareyson 1, David N Herrmann 1, Mary M Reilly 1, Jun Li 1, Diana Castro 1, Michael E Shy 1; for the Inherited Neuropathy Consortium1
PMCID: PMC11760056  PMID: 39133880

Abstract

Background and Objectives

Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by autosomal recessive variants in the Factor-Induced Gene 4 (FIG4) gene. Recent preclinical work has demonstrated the feasibility of adeno-associated virus serotype 9-FIG4 gene therapy. This study aimed to further characterize the CMT4J phenotype and evaluate feasibility of validated CMT-related outcome measures for future clinical trials.

Methods

This cross-sectional study enrolled children and adults with genetically confirmed CMT4J, with 2 documented disease-causing variants in the FIG4 gene. Patients were recruited through the Inherited Neuropathy Consortium network. Disease severity was assessed using standardized CMT-specific outcome measures and exploratory biomarkers including muscle MRI fat fraction, electrophysiology, and neurofilament light chain levels. Descriptive statistics and correlation analyses were conducted to explore relationships between variables.

Results

We recruited a total of 19 patients, including 14 pediatric patients (mean age 10.9 ± 3.9 years) and 5 adults (mean age 40.0 ± 13.9 years). The most frequent symptoms were gross motor delay and distal more than proximal muscle weakness, which were observed in 14 of 19 patients. The most common non-neuromuscular symptoms were cognitive and respiratory deficits, each seen in 8 of 19 patients. We denoted asymmetric weakness in 2 patients and nonuniform slowing of conduction velocities in 6 patients. Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), Pediatric Quality of Life Inventory, and Vineland Adaptive Behavior Scale scores were affected in most patients. We observed a significant positive correlation between neurofilament light chain levels and CMTPedS, but the study was underpowered to observe a correlation between CMTPedS and MRI fat fraction.

Discussion

We obtained baseline clinical and biomarker data in a broad cohort with CMT4J in pediatric and adult patients. Motor delay, muscle weakness, and respiratory and cognitive difficulties were the most common clinical manifestations of CMT4J. Many patients had nerve conduction studies with nonuniform slowing, and 2 had an asymmetric pattern of muscle weakness. We observed that the neurofilament light chain levels correlated with the CMTPedS in the pediatric population. This study showed feasibility of clinical outcomes including CMTPedS in assessment of disease severity in the pediatric patient population and provided baseline characteristics of exploratory biomarkers, neurofilament light chain levels, and muscle MRI fat fraction. The coronavirus disease 2019 pandemic affected some of the visits, resulting in a reduced number of some of the assessments.

Introduction

Charcot-Marie-Tooth disease (CMT) is a group of hereditary motor and sensory neuropathies with high genetic heterogeneity. Autosomal recessive variants in the Factor-Induced Gene 4 (FIG4) gene, with a compound heterozygous variant combining the I41T missense variant in 1 allele with either a frameshift/truncation variant or a missense variant in the other allele, and various other compound variant and I41T homozygous cases are identified as a cause of demyelinating polyneuropathy, CMT type 4J.1-5 Pathogenic variants of FIG4 have also been identified with various disease presentations including the Yunis-Varon syndrome,6 polymicrogyria with epilepsy,7 pediatric neurodegeneration with hypomyelination,8 and amyotrophic lateral sclerosis type 11.9-11

FIG4 gene encodes the phosphatidylinositol 3,5-bisphosphate 5-phosphatase (FIG4/SAC3) protein. It is implicated in vesicle trafficking between the lysosome and plasma membrane by removing the 5-phosphate from the membrane-bound phospholipid PI(3,5)P2.12-14 Compound heterozygous variants lead to reduced FIG4 protein expression in animal models and humans.2,15-17 Although little is known about the pathogenesis of CMT4J, the downregulation of FIG4 limits the production of PI(3,5)P218 and causes the accumulation of greatly enlarged lysosomes19 and vacuoles1,13,20,21 due to impaired lysosomal fission.22 FIG4 variants also cause intracellular inclusions composed of P62, ubiquitinated proteins, and other autophagic components by impairing autophagy.23

Patients with CMT4J often present with distal lower and upper extremity muscle weakness associated with hammer toes and pes cavus during childhood or adolescence. Compared with other demyelinating hereditary neuropathies such as CMT type 1A, electrophysiologic features in CMT4J may be similar to those in an acquired demyelinating neuropathy, including nonuniform slowing of conduction velocities, conduction block, and temporal dispersion.16,17 Several preclinical therapeutic approaches have been explored.24-26 A recent study showed increased lifespan of Fig4-pale tremor mice (null for fig4) from 5 weeks to 1 year of age using a single-stranded adeno-associated virus serotype 9 containing a codon-optimized human FIG4 sequence.24 In addition, another preclinical study in the same mouse model suggested that chloroquine could increase the lifespan of mice from 4 to 8 weeks.25 These studies highlight the importance of having more robust clinical and natural history data to help with future clinical trial design.

The aim of this study was to further characterize the CMT4J disease phenotype using validated CMT-related outcome measures for future clinical trials. A cross-sectional severity study was conducted on 19 pediatric and adult patients.

Methods

Standard Protocol Approvals, Registrations, and Patient Consents

Patients were recruited at University of Texas Southwestern and University of Iowa, to participate in a natural history study of CMT4J. The study received institutional review board/ethics board approval from both sites before recruitment. All patients or their guardian signed consent forms.

The study was advertised, and patients were recruited through the Inherited Neuropathy Consortium network referral system, ClinicalTrials.gov, and CMT Association websites.

The study enrolled children or adults with 2 documented disease-causing variants in different alleles of the FIG4 gene between July 2019 and January 2022. Patients with a variant of uncertain significance were also included if they carried 1 known disease-causing variant and the other variant was listed as disease causing by the Inherited Peripheral Neuropathies Mutation Database; if the 2 variants were listed in the database; or if they carried a homozygous variant with or without consanguineous parents. Patients were assessed by trained evaluators for all outcome assessments. This study was registered at ClinicalTrials.gov (NCT01193075).

CMT Clinical Outcome Measures

Disease severity was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNSv2R) and the Charcot-Marie-Tooth Functional Outcome Measure (CMT-FOM) in adults and the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS) in the pediatric population at every visit. CMTNSv2R is a validated 9-item disease severity scale evaluating sensory symptoms; motor symptoms; neurologic examination; and ulnar, motor, and radial sensory electrophysiologic responses with a score ranging from 0 to 36.27 CMTPedS is a rigorously validated 11-item disability scale, consisting of standardized measurements of strength, dexterity, sensation, gait, balance, power, and endurance. It generates a normally distributed score ranging from 0 to 44.28 The preliminary CMT-FOM is a performance-based 13-item scale assessing functional ability in adult patients with CMT with a score ranging from 0 to 52.29,30 The CMT-FOM is a psychometrically robust 11-item, unidimensional, disease-specific outcome measure covering strength, upper and lower limb function, balance, and mobility to capture how patients with CMT function identify therapeutic efficacy. In all 3 scales, a higher score represents more disability. Development milestones were assessed using a standardized 10-point questionnaire.

Neurophysiology

Patients underwent electrodiagnostic evaluation. The radial sensory and median abductor policis brevis (APB) motor responses were recorded, using the right upper limb where possible. Peroneal motor responses from extensor digitorum brevis (EDB) and tibialis anterior (TA) muscles were recorded from the right lower extremity. Amplitude was entered as 0, but no data for latency and conduction velocity were entered when a response was absent.

CMT Imaging Biomarkers

Patients were scanned at 3 Tesla (Siemens TIM Trio, Erlangen, Germany) in a supine position with surface array coils to cover the bilateral thigh and calf. T1-weighted and short tau inversion recovery axial images were obtained. A 3-point Dixon technique was used for water/fat decomposition assessment, as previously reported.31 All muscle MRI scans were assessed by an independent evaluator who defined regions of interest bilaterally for rectus femoris, vastus intermedius, vastus lateralis, vastus medialis, semimembranosus, semitendinosus, biceps femoris, adductor magnus, gracilis, and sartorius in the thigh and tibialis anterior, peroneus longus, medial gastrocnemius, lateral gastrocnemius, soleus, and tibialis posterior in the calf. Segmentations were performed on a single slice at mid-thigh and mid-calf. The mean intramuscular fat fraction in both the calf and thigh was calculated.31

Other Outcome Measures

Patients and family members, when appropriate, completed the Pediatric Evaluation of Disability Inventory–Computer Adaptive Test (PEDI-CAT), Pediatric Quality of Life (PedsQOL) Family Impact Module, and Vineland Adaptive Behavior Scale. The PEDI-CAT assesses functional capabilities and performance in children ages 6 months to 7 years old, as well as older children when the expected functional ability is less than that of a 7-year-old.32 The PEDI-CAT is a parent-reported outcome measure that assesses (1) functional skill level, (2) caregiver assistance, and (3) modifications or adaptive equipment used. The PedsQOL Family Impact Module is a parent self-reported outcome measuring the impact of chronic health conditions on patients and their family. It measures physical, emotional, social, and cognitive functioning; communication; worry; and daily activities and family relationships.33 Each item is reported on a 0–4 scale (0 = never, 1 = almost never, 2 = sometimes, 3 = often, and 4 = almost always) and transformed to 0–100 scale, with 100 being a better health-related quality of life. The Vineland Adaptive Behavior Scale is a comprehensive psychological tool used in assessment of adaptive behavior in children.34 Vision impairment, hearing impairment, gross motor issues, fine motor issues, cognitive difficulties, behavioral difficulties, seizures, eating difficulties, sleep disturbances, gastrointestinal problems, speech delay, and respiratory symptoms were assessed by history. Cognitive impairment was measured using qualitative assessment, the Pediatric QoL (cognitive functioning), and the PEDI-CAT (Computer Adaptive Test cognitive domains).

The total manual muscle testing score consisted of 2 unilateral (neck flexion and neck extension) and 12 bilateral muscle groups (shoulder abduction, elbow flexion, elbow extension, wrist flexion, wrist extension, finger abduction, finger flexion, hip flexion, hip extension, knee flexion, knee extension, and ankle dorsiflexion) for a total score of 130. The scale for each muscle was scored as follows: 5 (5), 4.75 (5−), 4.5 (4+), 4 (4), 3.75 (4−), 3.5 (3+), 3 (3), 2.75 (3−), 2.5 (2+), 2 (2), 1 (1), and 0 (0). Total score was not calculated when 1 or more muscle groups were missing.

Neurofilaments

Plasma neurofilament light chain (NfL) level was measured in patients who attended in-person visits using electrochemiluminescence immunoassay at LabCorp (Burlington, NC).

Statistical Analysis

The demographics, clinical characteristics, CMTPedS, Vineland Adaptive Behavior Scale, Pediatric Quality of Life Inventory (PedQOL), PEDI-CAT, fat fraction, and neurofilaments were analyzed using descriptive methods with GraphPad Prism software. Correlations were assessed with Spearman correlation coefficients. A 2-tailed p-value <0.05 was considered significant. Patients with missing values on specific features were not included for analysis.

Data Availability

Data not provided in the article because of space limitations may be shared (anonymized) at the request of any qualified investigator for purposes of replicating procedures and results.

Results

Patients' Demographics and Clinical Characteristics

We recruited a total of 19 patients (13 men, 6 women) with genetically confirmed autosomal recessive FIG4 variants. The average age was 18.5 ± 15.1 years (median 13, interquartile range [IQR] 10.5–21). 4 patients (21%) harbored the p.I41T biallelic variant, 13 patients (68%) had p.I41T in 1 allele and another variant in the other allele, and 2 (11%) had heterozygous non-p.I41T variants (Table 1). Patients were from the United States (14), Canada (2), India (1), Brazil (1), and the United Kingdom (1). Most (14/19 patients, 74%) were younger than 18 years at the time of recruitment (mean age of 10.9 ± 3.9 years, median age of 12; IQR 9.3–13.0 years), and 26% of patients were adults (mean age of 40.0 ± 13.9 years, median age of 36; IQR 30–52 years).

Table.

Patients' Demographics, Variants, and Clinical Characteristics

Patient ID Age group Variant UE weakness LE weakness MMT (total/130) Scoliosis (degrees) Feet abnormalities Other features
001-001 Pediatric p.I41Ta, c.1373_137, 4dupT, 458 fs Distal Proximal/distal 124.5 Y (10) Pes cavus ADHD, tight Achilles
001-002 Pediatric p.I41Tc, c.1373dupT, p.Leu458PhefsX5 Proximal/distal Proximal/distal 78.5 Y (90) None Hyperlaxity, high-arched palate
001-003 Pediatric p.I41T, c.2212 C>T, p.Gln738Ter (Q738X) Distal Distal 126.5 Y (22–28) Pes cavus Pectus carinatum, hyperlaxity, ADHD, sleep apnea, high-arched palate
001-004 Pediatric p.I41T, c.2212 C>T, p.GlN738Ter (Q738X)c Distal Proximal/distal 125.5 Y (12) Pes cavus, hammertoes Short stature, high-arched palate
001-005 Pediatric p.I41T, partial deletion exons 8-10 Proximal/distal Proximal/distal 29 Y (NA) None Hyperkeratosis, ADHD, high-arched palate, contractures, hyperlaxity
001-006 Pediatric c.2459+1G>A, IVS21+1G>A, c.831_838delTAAATTTG, p.K278WfsX6 NA NA NA Y (10–13) Pes planus
Toe deformities		 Dysmorphic features, elbow hyperlaxity, chest wall deformity, high-arched palate
001-007 Pediatric p.I41Tb None Proximal/distal 120.8 N None Flexion contraction right ankle, hyperlaxity in elbow
001-008 Pediatric p.I41T, c.831_838delTAAATTTG, p.Lys278TrpfsX6 (K278WfsX6), c.606 T>A, p.Scr202Arg (S202R) Distal Proximal/distal 125.8 N Pes cavus, hammertoes Tight Achilles
001-009 Pediatric c.2421_2424delAGAT, p.Asp808AlafsTer39, c.1471 G>A, p.Asp491ASN NA NA NA N None Prominent orbital cavity, with small nasal bridge, flexion contraction in knee, high-arched palate, tongue atrophy
001-011 Pediatric p.I41T, partial deletion exons 2-23 Proximal/distal Proximal/distal NA Y (25) None Occipital plagiocephaly
002-001 Pediatric p.I41T, FRAMESHIFT Distal Distal 127 Y (NA) None None
002-002 Adult p.I41T, c.1294delC, p.Arg432AspfsX2 (R432DfsX2) None None 130 NA None None
002-004 Adult p.I41T, c.531T>G, p.Tyr177Ter NA NA NA NA Not reported Not reported
002-005 Pediatric p.I41Tb Distal Distal 121 Y (NA) None Autism
002-006 Pediatric p.I41T, c.718C>T, D348fsX NA NA NA NA Not reported Not reported
002-007 Adult p.I41T, c.1149_1150del, p.Lys383AsnfsX NA NA NA NA Not reported Not reported
002-008 Adult p.I41Tb NA NA NA NA Not reported Not reported
002-009 Adult p.I41T, c.759del, p.Phe254Serfs*8 NA NA NA NA Not reported Not reported
002-010 Pediatric p.I41Tb None Proximal/distal 127.8 Y None Knee contractures
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Abbreviations: ADHD = attention-deficit hyperactivity disorder; LE = lower extremity; MMT = manual muscle testing; NA = not available; UE = upper extremity.

a

p.I41T; c.122T>C, p.Ile41Thr (I41T).

b

Biallelic.

c

Also affected by trisomy 21.

The most frequent symptoms and signs observed in both pediatric and adult patients were gross motor delay and muscle weakness, each noted in 14 of 19 patients. Other symptoms included fine motor issues (13/19), respiratory symptoms (8/19), cognitive difficulties (8/19), speech delay (6/19), GI concerns (6/19), behavioral issues (5/19), vision issues (4/19), hearing loss (4/19), sleep disturbances (4/19), and weight loss (4/19). Other issues were reported to include attention-deficit hyperactivity disorder, constipation, sleep apnea, restless leg syndrome, shortness of breath, need for a feeding tube, insomnia, optic neuropathy, tinnitus, bowel and bladder incontinence, strabismus, autism, dysphagia, and strabismus (Table 1). None of the patients had acute decline or received IV immunoglobulin/immunotherapy. Motor milestones were only delayed for walking (mean 18.7 ± 8.7 and median 13 [12–26.8] months) (eTable 1).

A total of 12 patients underwent MMT. 3 patients (3/12, 25%) had distal upper extremity weakness and proximal and distal lower extremity weakness; 3 patients (3/12, 25%) had distal upper and distal lower extremity weakness; and 2 patients (2/12, 17%) had proximal and distal lower extremity weakness, but no upper extremity involvement. Therefore, 11 (11/12, 92%) had distal lower extremity weakness, 9 (9/12, 75%) had distal upper extremity weakness, 8 (8/12, 67%) had proximal lower extremity weakness, and only 3 (3/12, 25%) had proximal upper extremity weakness. Of more severely affected patients, 1 (001-002) had Medical Research Council (MRC) grade 2/5 proximal strength and relatively strong ankle dorsiflexion (MRC grade 4/5). 1 patient (001-011) had proximal (MRC grade 2/5) greater than distal (MRC grade 3/5) weakness, and 1 patient (001-005) was severely affected with only MRC grade 1/5 documented strength throughout, except MRC grade 2/5 in neck extension. Two patients (2/12, 17%) had asymmetric weakness in the lower extremities with normal upper extremities strength; patient 001-007 had more weakness in the left hip flexion, left hip extension, left knee flexion, and left ankle dorsiflexion; and patient 002-010 was weaker in the right hip flexion and right ankle dorsiflexion compared with the contralateral side. Deep tendon reflexes were absent in all patients except 2 (001-001 and 001-007 had normal or mildly reduced reflexes), and muscle tone was decreased in 5 patients (5/14, 35.7%). There was no sign of upper motor involvement in any patients. Vibration, position, and/or pinprick sensation were reduced in 8 patients (80% of tested patients). Patients were screened for scoliosis using a spine X-ray scoliosis survey. A total of 10 of 19 patients had scoliosis ranging from mild to severe (Table 1).

Pulmonary Function Testing

In total, 10 patients (10/19, 53%) completed pulmonary function testing (eTable 2). Average forced vital capacity (FVC), average forced expiratory volume (FEV), and mean ratio were within normal values. Two patients (2/10, 20%) had abnormal respiratory measures (001-005 with 19% FVC predicted value and 37% FEV1 predicted value and 002-005 with 75% FVC predicted value and 70% FEV1 predicted value). Patient 001-005 had severe weakness (MRC grade 1/5 documented strength throughout, except MRC grade 2/5 in neck extension), and patient 002-005 had moderate interosseous muscles weakness (MRC grade 3+/5) and severe ankle dorsiflexion weakness (MRC grade 1 + 5 on the right and MRC grade 2+/5 on the left).

Neurophysiology, Biofluids, and Imaging Biomarkers

A total of 14 patients (14/19, 74%) had nerve conduction studies throughout the study. Results are summarized in eTable 3. Average median-APB, peroneal-EDB, and peroneal-TA compound muscle action potential (CMAP) amplitudes were reduced. Average median-APB, peroneal-EDB, and peroneal-TA CMAP distal latencies were moderately prolonged, and conduction velocities were moderately reduced. Average radial sensory nerve action potential (SNAP) amplitude was mildly reduced, but average peak latency was within normal limits. Peroneal-EDB CMAP was absent in 5 patients (5/14, 35.7%), peroneal-TA CMAP was absent in 6 patients (6/14, 42.9%), radial SNAP was absent in 4 patients (4/14, 28.6%), and median-APB CMAP was present in all patients. There was nonuniform slowing of conduction velocities in 6 of 9 patients (67%) with more than one measurable conduction velocity. None of the patients had conduction block or temporal dispersion.

Overall, 11 patients (11/19, 58%) completed the MRI protocol. The mean calf muscle fat fraction was 6.8% ± 3.3%, and the mean thigh muscle fat fraction was 7.4% ± 4.2%. Neurofilament light chain levels were obtained in 10 patients. The NfL level was 9.1 ± 5.6 pg/mL and median 6.4 (4.8–13.5), excluding 1 outlier of 85 pg/mL. Although we observed a trend toward higher calf muscle fat fraction in patients with higher CMTPedS, there was no significant correlation between MRI muscle fat fraction and CMTPedS. Inversely, we observed a significant positive correlation between CMTPedS and NfL levels (r = 0.7385, p = 0.0364) (Figure).

Figure. Correlation of Muscle MRI Fat Fraction and NfL Levels With CMTPedS.

Figure

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Representative MRI T1-weighted and STIR axial images of the thigh muscles (A) (rectus femoris, vastus intermedius, vastus lateralis, vastus medialis, semimembranosus, semitendinosus, biceps femoris, adductor magnus, gracilis, and sartorius) and the calf muscles (B) (tibialis anterior, peroneus longus, medial gastrocnemius, lateral gastrocnemius, soleus, and tibialis posterior), used for calculation of mean fat fraction. (C and D) Simple linear regression of CMTPedS vs fat fraction (C) and CMTPedS vs NfL (D). CMTPedS = Charcot-Marie-Tooth Disease Pediatric Scale; NfL = neurofilament light chain; STIR = short tau inversion recovery.

CMT Scales and Other Clinical Outcomes

A total of 11 of 14 pediatric patients completed the CMTPedS evaluation with a mean of 26.6 ± 8.4 (median 28.0 [18.0–35]) indicating a moderate to severe disability. 4 parents (4/14, 29%) completed the PedQOL Family Impact Module. All domains of QoL were affected with a mean total score 54.9 ± 21.6 and median 54.1 (34.6–81.7) (on a 0–100 scale with 100 representing the highest). The category worry (mean 37.5 ± 15.5 and median 37.5 [22.5–52.5]) was the most affected category, and family relationship (mean 68.8 ± 26.9 and median 70 [42.5–100]) was affected less than other domains (eTable 4). All pediatric patients, except 002-006, had scoring on the Vineland Adaptive Behavior Scale and the PEDI-CAT test. All components of the Vineland Adaptive Behavior Scale were mildly affected in the cohort, with an average adaptive behavior composite score of 76 ± 25.0 (normal >85). The average PEDI-CAT scale scores were within the expected range (eTable 4). Unfortunately, CMTNSv2R was obtained in only 3 patients, and CMT-FOM was obtained in only 1 patient. Therefore, the 2 scales were excluded from analysis.

Discussion

We obtained baseline clinical characteristics and biomarker data in 19 pediatric and adult patients with CMT4J. While longitudinal data were severely affected by the coronavirus disease 2019 pandemic, which led to inability to travel for most follow-up visits, our cross-sectional baseline data provide important clinical characteristics of this rare disease and inform future natural history studies and clinical trial design and outcome measure selection.

Pediatric patients showed gross delays in motor milestones, and most pediatric and adult patients had distal lower extremity, distal upper extremity, and proximal lower extremity muscle weakness. Of interest and somewhat atypical for CMT, some patients had proportionate proximal and distal weakness and 1 patient had more severe proximal weakness. In comparison, sensory symptoms were generally milder in our cohort. Previous reports on CMT4J have also suggested that weakness may affect proximal and distal muscles2 and may sometimes be significantly asymmetric or affect only 1 limb and mimic motor neuron disease.35 In this study, significant asymmetric weakness was seen in 2 patients; both had 1 leg significantly more affected with normal upper extremities strength. Consistent with previous reports,16,17 6 patients had nonuniform slowing in nerve conduction studies, emphasizing the importance of considering CMT4J in the differential diagnosis of an acquired demyelinating neuropathy with asymmetric weakness and nonuniform slowing.

The most common non-neuromuscular comorbidity was cognitive difficulties, found in 42% of this cohort. Cognitive deficits were previously reported in 2 of 5 adult patients with CMT4J,36 2 Chinese siblings with severe neuropathy and global developmental delay,4 and 4 children with severe neuropathy and a combination of infantile dystonia, hypotonia, and swallowing difficulties37 and others.4 Although not found in this cohort, FIG4 variants can also be associated with parkinsonism and seizures.2,17,36,38,39 Thus, it is important for clinicians to consider CNS involvement in patients with CMT4J and include CMT4J in the differential diagnosis of demyelinating neuropathy with CNS involvement.

Successful clinical trial readiness studies rely on resources, design, and validated outcome measures. A major challenge in clinical trials in rare and slowly progressive diseases such as CMT is reliable measurement of disease progression within short time frames. Using carefully curated clinical outcomes and imaging biomarkers is necessary to improve feasibility of clinical trials in shorter duration of time.40 We showed the feasibility of using the CMTPedS disease severity scale in patients with CMT4J. The CMTPedS has been thoroughly studied as a psychometrically sensitive outcome measure in pediatric patients with CMT1A and other common CMT, but not in CMT4J.28,41-43 The mean change in the CMTPedS has been reported to be 2.4 ± 4.9 over 2 years in a large cohort majorly composed of CMT1A.43 We were able to show an association between disease severity measured by CMTPedS and neurofilament light chain levels. Unfortunately, although we observed a trend toward higher muscle fat fraction in more affected patients, this study was underpowered to detect a significant correlation between CMTPedS and MRI muscle fat fraction. Calf muscle fat fraction has been studied as a more sensitive outcome measure to change in patients with other types of CMT,31,44,45 suggesting that it could also be used in CMT4J. Further longitudinal studies using these outcomes and biomarker assessments will provide natural history data that will enable future clinical trials for CMT4J.

Acknowledgment

The authors thank the CureCMT4J Foundation for their support, the patients for participation in this study, and the Inherited Neuropathy Consortium for their support in recruitment and review of the manuscript.

Glossary

APB

abductor policis brevis

CMAP

compound muscle action potential

CMT4J

Charcot-Marie-Tooth disease type 4J

CMT-FOM

Charcot-Marie-Tooth Functional Outcome Measure

CMTNSv2R

Charcot-Marie-Tooth Neuropathy Score

CMTPedS

Charcot-Marie-Tooth disease Pediatric scale

EDB

extensor digitorum brevis

FEV

forced expiratory volume

FIG4

Factor-Induced Gene 4

FVC

forced vital capacity

IQR

interquartile range

MRC

Medical Research Council

NfL

neurofilament light chain

PEDI-CAT

Pediatric Evaluation of Disability Inventory—Computer Adaptative Test

PedQOL

Pediatric Quality of Life Inventory

SNAP

sensory nerve action potential

TA

tibialis anterior

Appendix 1. Authors

Name Location Contribution
Reza Sadjadi, MD Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Vincent Picher-Martel, MD, PhD Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Jasper M. Morrow, MBChB, PhD Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom Drafting/revision of the manuscript for content, including medical writing for content; study concept or design
Daniel Thedens, PhD Department of Neurology, University of Iowa Health Care, Carver College of Medicine, Iowa City Major role in the acquisition of data; study concept or design
Paul A. DiCamillo, MD, PhD Department of Radiology, University of Iowa Health Care, Carver College of Medicine, Iowa City Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Brett A. McCray, MD, PhD Michigan Neuroscience Institute, University of Michigan, Ann Arbor Drafting/revision of the manuscript for content, including medical writing for content
Davide Pareyson, MD Unit of Medical Genetics and Neurogenetics, Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Drafting/revision of the manuscript for content, including medical writing for content; study concept or design
David N. Herrmann, MBChB, PhD Department of Neurology, University of Rochester, NY Drafting/revision of the manuscript for content, including medical writing for content; study concept or design
Mary M. Reilly, MD Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom Drafting/revision of the manuscript for content, including medical writing for content; study concept or design
Jun Li, MD, PhD Department of Neurology, Houston Methodist Research Institute, TX Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Diana Castro, MD Neurology & Neuromuscular Care Center/Neurology Rare Disease Center, Denton, TX Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design
Michael E. Shy, MD Department of Molecular Physiology and Biophysics, University of Iowa Health Care, Carver College of Medicine, Iowa City Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
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Appendix 2. Coinvestigators

Coinvestigators are listed at Neurology.org.
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Study Funding

This study was supported by the CureCMT4J Foundation and NeuroGene.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

References

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