ABSTRACT
BACKGROUND AND AIMS: Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised clinically by pontobulbar palsy, sensory ataxia, sensorineural deafness, muscle weakness, optic atrophy and respiratory failure. A robust and responsive functional outcome measure is essential for future clinical trials of disease-modifying therapies including genetic therapies. The Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS) is a well-validated outcome measure for CMT and related neuropathies, and might have utility for measuring disease progression in individuals with RTD. However, the CMTPedS requires modifications to account for phenotypic differences between children with CMT and RTD. The aim of this study was to develop a functional outcome measure based on the CMTPedS for specific use in individuals with RTD. METHODS: The CMTPedS data collected over the last 10 years in individuals with RTD attending the Peripheral Neuropathy Management Clinic at the Children's Hospital at Westmead (Sydney, Australia) were reviewed to evaluate each item within the CMTPedS. A literature review of articles published until September 2021 for functional outcome measures generated an item pool for pilot testing. The results of this pilot testing, alongside analysis of existing CMTPedS item scores in the RTD cohort, informed the modification of the CMTPedS. RESULTS: CMTPedS data were reviewed for eight individuals over the past 10 years. Two items were identified as requiring modification or removal and additional items of proximal strength and function needed to be considered. Six studies were identified in the literature review, and five items were selected for pilot testing. 'Shoulder internal rotation' and the '30-s sit to stand test' were added as proximal measures of strength and function. The composite balance item comprising nine tasks in the CMTPedS showed a ceiling effect and was replaced with the single 'Feet apart on a line eyes open' balance item. 'Pinprick sensation' was removed due to a floor effect. INTERPRETATION: This study provides preliminary evidence that the Riboflavin Transporter Deficiency Pediatric Scale (RTDPedS) is a functional outcome measure covering strength, upper and lower limb function, balance and mobility for individuals with RTD to assess disease severity and progression in clinical trials and cohort studies.
Subject(s)
Bulbar Palsy, Progressive , Hearing Loss, Sensorineural , Humans , Child , Hearing Loss, Sensorineural/physiopathology , Hearing Loss, Sensorineural/diagnosis , Bulbar Palsy, Progressive/physiopathology , Bulbar Palsy, Progressive/diagnosis , Male , Outcome Assessment, Health Care , Female , Adolescent , Child, Preschool , Charcot-Marie-Tooth Disease/physiopathology , Membrane Transport Proteins/genetics , Membrane Transport Proteins/deficiencyABSTRACT
Muscle strength is routinely measured in patients with neuromuscular disorders by hand-held dynamometry incorporating a wireless load cell to evaluate disease severity and therapeutic efficacy, with magnitude of effect often based on normative reference values. While several hand-held dynamometers exist, their interchangeability is unknown which limits the utility of normative data. We investigated the variability between six commercially available dynamometers for measuring the isometric muscle strength of four muscle groups in thirty healthy individuals. Following electro-mechanical sensor calibration against knowns loads, Citec, Nicholas, MicroFET2, and Commander dynamometers were used to assess the strength of ankle dorsiflexors, hip internal rotators, and shoulder external rotators. Citec, Jamar Plus, and Baseline Hydraulic dynamometers were used to capture hand grip strength. Variability between dynamometers was represented as percent differences and statistical significance was calculated with one-way repeated measures ANOVA. Percent differences between dynamometers ranged from 0.2% to 16%. No significant differences were recorded between the Citec, Nicholas, and MicroFET2 dynamometers (p > 0.05). Citec grip strength measures differed to the Jamar Plus and Baseline Hydraulic dynamometers (p < 0.01). However, when controlling for grip circumference, they were comparable (p > 0.05). Several hand-held dynamometers can be used interchangeably to measure upper and lower limb strength, thereby maximising the use of normative reference values.
Subject(s)
Hand Strength , Muscle Strength , Humans , Hand Strength/physiology , Reproducibility of Results , Muscle Strength/physiology , Upper Extremity , ShoulderABSTRACT
Riboflavin transporter deficiency (RTD) is a progressive inherited neuropathy of childhood onset, characterised by pontobulbar palsy, sensorineural deafness, sensory ataxia, muscle weakness, optic atrophy and respiratory failure. Riboflavin supplementation is beneficial in short-term reports, but the quantum of benefit in various clinical domains is not well understood. A PubMed search was conducted, which identified 94 genetically confirmed cases of RTD who received riboflavin supplementation and had follow-up assessments. Information on the clinical and functional status before and after riboflavin supplementation was collected and analysed. Seventy-six of the 94 patients (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable, though some patients had deteriorations in individual domains with no reported deaths. The domains that had the highest rates of response to riboflavin supplementation were gross motor function (93.3% improved), bulbar palsy (91.3%) and ataxia (90.0%). Improvements were also seen in limb muscle weakness, audiology, facial nerve palsy and respiratory function. Despite treatment, many patients required assistance to ambulate and had severe or profound hearing loss and some remained gastrostomy or tracheostomy dependent. Riboflavin supplementation is a lifesaving intervention for patients with RTD and results in a profound improvement in several functional domains, with early diagnosis and treatment further improving outcomes. Despite treatment, patients are left with residual disability. There is a need to accurately measure functional outcomes in children with RTD and develop additional disease-modifying therapies.
Subject(s)
Bulbar Palsy, Progressive , Hearing Loss, Sensorineural , Child , Humans , Riboflavin/therapeutic use , Bulbar Palsy, Progressive/diagnosis , Bulbar Palsy, Progressive/drug therapy , ParalysisABSTRACT
INTRODUCTION: The 6-minute walk test (6MWT) is a well-established clinical assessment of functional endurance, validated as a measure of walking ability in spinal muscular atrophy (SMA). The current availability of disease-modifying therapies for SMA indicates a growing need for normative reference data to compare SMA patients with healthy controls. METHODS: The literature was searched in two scientific databases. Studies were evaluated and selected based on adherence to American Thoracic Society guidelines for administering the 6MWT. Reference equations from the selected studies were applied to 6MWT data collected from SMA patients to calculate and compare % predicted values. RESULTS: Three pediatric and six adult studies were selected for comparison. The % predicted values using the pediatric and adult equations ranged from 47.7 ± 18.2% to 67.6 ± 26.2% and 43.0 ± 17.9% to 59.5 ± 26.2%, respectively, and were significantly different (P < 0.001). DISCUSSION: Results suggest significant variability between % predicted values derived from published reference equations in children and adults, despite adherence to 6MWT standardization.
Subject(s)
Muscular Atrophy, Spinal/diagnosis , Walk Test/standards , Adolescent , Child , Child, Preschool , Female , Humans , Male , Muscular Atrophy, Spinal/physiopathology , Reference ValuesABSTRACT
The Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS) is a Rasch-built clinical outcome measure of disease severity. It is valid, reliable, and responsive to change for children and adolescents aged 3 to 20 years. The aim of this study was to translate and validate an Italian version of the CMTPedS using a validated framework of transcultural adaptation. The CMTPedS (Italian) was translated and culturally adapted from source into Italian by two experts in CMT with good English language proficiency. The two translations were reviewed by a panel of experts in CMT. The agreed provisional version was back translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the same panel. CMT patients were assessed with the final version of the outcome measure and a subset had a second assessment after 2 weeks to evaluate test-retest reliability. Seventeen patients with CMT aged 5 to 20 years (eight female) were evaluated with the CMTPedS (Italian), and test-retest was performed in three patients. The CMTPedS (Italian) showed a high test-retest reliability. No patient had difficulty in completing the scale. The instructions for the different items were clearly understood by clinicians and therefore the administration of the outcome measure was straight forward and easily understood by the children assessed. The CMTPedS (Italian) will be used for clinical follow-up and in clinical research studies in the Italian population. The data is fully comparable to that obtained from the English language version.
Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Outcome Assessment, Health Care/standards , Psychometrics/standards , Severity of Illness Index , Adolescent , Adult , Charcot-Marie-Tooth Disease/therapy , Child , Child, Preschool , Female , Humans , Italy , Male , Psychometrics/instrumentation , Psychometrics/methods , Reproducibility of Results , Translating , Young AdultABSTRACT
The CMT-FOM is a 13-item clinical outcome assessment (COA) that measures physical ability in adults with Charcot-Marie-Tooth disease (CMT). Test-retest reliability, internal consistency and convergent validity have been established for the CMT-FOM. This current study sought to establish inter-rater reliability. Following an in-person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18-74 years, 6 female). Participants were evaluated using the CMT-FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT-FOM exhibited excellent inter-rater reliability for raw scores (ICC1,1 0.825-0.989) and z-scores (ICC1,1 0.762-0.969). Reliability of the CMT-FOM total score was excellent (ICC1,1 0.983, 95% CI 0.958-0.995). The CMT-FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT-FOM in the Accelerate Clinical Trials in CMT (ACT-CMT) study.
Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/standards , Psychometrics/methods , Psychometrics/standards , Severity of Illness Index , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Reproducibility of Results , Young AdultABSTRACT
INTRODUCTION: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents. METHODS: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system. RESULTS: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score. DISCUSSION: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019.
Subject(s)
Charcot-Marie-Tooth Disease/complications , Charcot-Marie-Tooth Disease/diagnostic imaging , Disabled Persons , Gait Disorders, Neurologic/etiology , Leg/diagnostic imaging , Magnetic Resonance Imaging , Muscle Weakness/etiology , Adolescent , Child , Female , Gait Disorders, Neurologic/diagnostic imaging , Humans , Image Processing, Computer-Assisted , Male , Muscle Strength , Muscle Weakness/diagnostic imaging , Muscle, Skeletal/diagnostic imagingABSTRACT
INTRODUCTION: Balance impairment contributes to gait dysfunction, falls, and reduced quality of life in adults with Charcot-Marie-Tooth disease (CMT) but has been minimally examined in pediatric CMT. METHODS: The CMT Pediatric Scale (CMTPedS) was administered to 520 children with CMT. Associations between balance function (Bruininks-Oseretsky Test of Motor Proficiency [BOT-2]) and sensorimotor and gait impairments were investigated. RESULTS: Daily trips/falls were reported by 42.3% of participants. Balance (BOT-2) varied by CMT subtype, was impaired in 42% of 4-year-olds, and declined with age (P < 0.001). Vibration (P < 0.001), pinprick (P < 0.004), ankle dorsiflexion strength (P < 0.001), and foot alignment (P < 0.004) were associated with BOT-2 balance (adjusted R2 = 0.28). The visual dependence of balance increased with age. DISCUSSION: Balance impairment occurs from a young age in children with CMT. Balance intervention studies are required in pediatric CMT and should consider the degree of sensorimotor impairment, foot malalignment, and visual dependence. Muscle Nerve, 2019.
Subject(s)
Charcot-Marie-Tooth Disease/physiopathology , Gait Disorders, Neurologic/physiopathology , Movement Disorders/physiopathology , Muscle Strength/physiology , Adolescent , Age Factors , Child , Child, Preschool , Female , Gait/physiology , Humans , Male , Physical Therapy Modalities , Quality of Life , Young AdultABSTRACT
OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. METHODS: Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. RESULTS: On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p < 0.001). There was no difference between males and females (mean difference, 0.5; 95% confidence interval [CI], -0.9 to 1.9; p = 0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change, -0.3; 95% CI, -0.6 to -0.05; p = 0.02), balance (z-score change, -1.0; 95% CI, -1.9 to -0.09; p = 0.03), and long jump (z-score change, -0.4; 95% CI, -0.7 to -0.02; p = 0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8 ± 4.2 (12% change from baseline; p < 0.001), 9 participants with CMT1B/MPZ mutation progressed by 2.2 ± 5.1 (11% change), 6 participants with CMT2A/MFN2 mutation progressed by 6.2 ± 7.9 (23% change), and 7 participants with CMT4C/SH3TC2 mutations progressed by 3.0 ± 4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference, -4.4; 95% CI, -8.1 to -0.8; p = 0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years; mean difference, 1.1; 95% CI, -0.6 to 2.7; p = 0.19), whereas CMT2A appeared to progress faster during early childhood than adolescence (mean difference, 10.0; 95% CI, -2.2 to 22.2; p = 0.08). INTERPRETATION: Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2 years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. Ann Neurol 2017;82:353-359.
Subject(s)
Charcot-Marie-Tooth Disease/pathology , Adolescent , Charcot-Marie-Tooth Disease/genetics , Child , Child, Preschool , Disease Progression , Female , Humans , Longitudinal Studies , Male , Mutation , Myelin Proteins/genetics , Young AdultABSTRACT
Hand function is a problem in patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and Riboflavin Transporter Deficiency type 2 (RTD2). However, a detailed understanding of upper limb involvement in these conditions is lacking. The aim of this pilot study was to compare hand and upper limb function between children with CMT1A, RTD2 and healthy controls using established and novel outcome measures. Three age-and sex-matched groups of four children (5-15 years, 1 male/group) with CMT1A, RTD2, and healthy controls were assessed for function, strength, and sensation. Fatigue and muscle activity of the FDI was also assessed using a submaximal contraction at 40% of the participants' maximal voluntary contraction. Functional measures were most affected in children with RTD2 followed by children with CMT1A, compared to healthy controls. Strength was similarly impaired in CMT1A and RTD2 compared to controls (p < 0.05). Sensation was significantly impaired in RTD2 compared to CMT1A and controls (p = 0.008). While time to fatigue did not differ between groups, a decline in muscle activity while force remained constant showed that controls compensated with other muscles during the fatigue task while children with CMT1A and RTD2 did not have this compensatory ability. Children with CMT1A and RTD2 exhibited marked hand/upper limb impairment. These results suggest the upper limb should be a focus of rehabilitative therapy in affected children using sensitive outcome measures of strength and sensation, as well as functional activities of daily living, which are most relevant to the patient.
Subject(s)
Charcot-Marie-Tooth Disease/complications , Membrane Transport Proteins/deficiency , Muscle Weakness/etiology , Neurodegenerative Diseases/complications , Sensation Disorders/etiology , Adolescent , Charcot-Marie-Tooth Disease/physiopathology , Child , Child, Preschool , Fatigue/diagnosis , Fatigue/etiology , Female , Humans , Male , Muscle Weakness/diagnosis , Neurodegenerative Diseases/physiopathology , Pilot Projects , Sensation Disorders/diagnosis , Upper Extremity/physiopathologyABSTRACT
AIM: To investigate if children with neurofibromatosis type 1 (NF1) have reduced muscle strength compared with children with typical development. METHOD: Maximal isometric strength of 15 upper and lower limb muscle groups was evaluated in 30 children with NF1 (16 males, 14 females; aged 4-16y) and 30 age-, sex-, height-, and weight-matched controls using hand-held dynamometry by a single evaluator. Both the left and right sides were assessed. RESULTS: Children with NF1 were significantly weaker than children with typical development across all 15 muscle groups assessed (p<0.05). Apart from elbow flexion, there were no differences between the left and right sides (p>0.05). Magnitude of differences between the children with NF1 compared with the controls ranged from 3% to 43%. Males and females were equally affected. INTERPRETATION: This study shows that children with NF1 have reduced muscle strength compared with children with typical development. This muscle weakness is present from the earliest stages of the disease assessed and persists throughout childhood with no sex difference. These results support recent evidence from mouse studies that NF1 is associated with a primary myopathy.
Subject(s)
Muscle Strength/physiology , Muscle Weakness/etiology , Muscle, Skeletal/physiopathology , Neurofibromatosis 1/complications , Adolescent , Child , Child, Preschool , Female , Humans , Isometric Contraction/physiology , Male , Muscle Weakness/diagnosis , Neurofibromatosis 1/physiopathologyABSTRACT
Objectives: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Methods: 82 participants (42 DM1 adults & 40 CDM children) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL] inferred in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL] inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics. Results: Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL] inferred in our cohort of all DM1 individuals and when assessing CDM children independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL] inferred from select clinical outcome assessments alone in all subjects (adjusted R 2 = 0.6723) or exclusively in CDM children (adjusted R 2 = 0.5875). Interpretation: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL] inferred, in DM1. The strength of these correlations and the development of the predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.
ABSTRACT
BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication of PMP22, is the most common hereditary peripheral neuropathy. For participants with CMT1A, few clinical trials have been performed; however, multiple therapies have reached an advanced stage of preclinical development. In preparation for imminent clinical trials in participants with CMT1A, we have produced a Clinical Outcome Assessment (COA), known as the CMT-Functional Outcome Measure (CMT-FOM), in accordance with the FDA Roadmap to Patient-Focused Outcome Measurement to capture the key clinical end point of function. METHODS: Participants were recruited through CMT clinics in the United States (n = 130), the United Kingdom (n = 52), and Italy (n = 32). To derive the most accurate signal with the fewest items to identify a therapeutic response, a series of validation studies were conducted including item and factor analysis, Rasch model analysis and testing of interrater reliability, discriminative ability, and convergent validity. RESULTS: A total of 214 participants aged 18-75 years with CMT1A (58% female) were included in this study. Item, factor, and Rasch analysis supported the viability of the 12-item CMT-FOM as a unidimensional interval scale of function in adults with CMT1A. The CMT-FOM covers strength, upper and lower limb function, balance, and mobility. The 0-100 point scoring system showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for adults with CMT1A exhibiting high inter-rater reliability across a range of clinical settings and evaluators. The CMT-FOM was significantly correlated with the CMT Examination Score (r = 0.643; p < 0.001) and the Overall Neuropathy Limitation Scale (r = 0.516; p < 0.001). Significantly higher CMT-FOM total scores were observed in participants self-reporting daily trips and falls, unsteady ankles, hand tremor, and hand weakness (p < 0.05). DISCUSSION: The CMT-FOM is a psychometrically robust multi-item, unidimensional, disease-specific COA covering strength, upper and lower limb function, balance, and mobility to capture how participants with CMT1A function to identify therapeutic efficacy.
Subject(s)
Charcot-Marie-Tooth Disease , Adult , Humans , Female , United States , Male , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/therapy , Reproducibility of Results , Outcome Assessment, Health Care , Factor Analysis, Statistical , ItalyABSTRACT
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.
Subject(s)
Charcot-Marie-Tooth Disease , Overweight , Adult , Humans , Child , Body Mass Index , Overweight/complications , Overweight/epidemiology , Thinness/epidemiology , Charcot-Marie-Tooth Disease/complications , Obesity/complications , Obesity/epidemiology , Disease ProgressionABSTRACT
Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2-10) and PREPL (deletion of exons 2-14). The molecular findings were consistent with the hypotonia-cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability.
Subject(s)
Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/physiopathology , Cystinuria/diagnosis , Cystinuria/genetics , Cystinuria/physiopathology , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/physiopathology , Muscle Hypotonia/diagnosis , Muscle Hypotonia/genetics , Muscle Hypotonia/physiopathology , Adult , Chromosome Deletion , Chromosomes, Human, Pair 21/genetics , Female , Humans , Male , Siblings , Young AdultABSTRACT
OBJECTIVE: To describe the clinical, genetic, and disability profile of pediatric distal hereditary motor neuropathy (dHMN) and to determine the utility of an outcome measure validated for children with Charcot-Marie-Tooth disease (CMT) in assessing disability in this cohort. METHODS: We reviewed the clinical, neurophysiologic, and disability data on individuals with dHMN, evaluated before the age of 20 years, at 2 tertiary neuromuscular clinics in Australia and Spain. Disability was assessed annually with the CMT Pediatric Scale (CMTPedS) in a subset of individuals. RESULTS: Twenty-two children (13 female) from 19 families were included. Fourteen individuals were symptomatic in the first year of life. Intellectual disability was present in 6 individuals; upper motor neuron signs were seen in 8. Pathogenic variants were found in 9 families, more frequently in BICD2 (BICD2-4, DYNC1H1-2, MFN2-2, GARS-1). A novel pathogenic variant in the GARS gene was detected and characterized phenotypically. Disability was moderate on the CMTPedS (mean [SD] 18.2 [6.3], n = 16), with balance and long jump being the most affected and sensation items and grip strength the least affected. Over 1 year, the CMTPedS total score deteriorated, on average 1.5 points (SD 3.7) or 9% (n = 12), with significant variability in the rate of progression within the cohort. CONCLUSIONS: The genetic profile of pediatric dHMN is different from that identified in adult cohorts. This study has identified distinct functional limitations for the CMTPedS in children and adolescents with dHMN.
Subject(s)
Muscle, Skeletal/diagnostic imaging , Muscular Atrophy, Spinal/diagnosis , Mutation , Neural Conduction/physiology , Adolescent , Child , Child, Preschool , Cytoplasmic Dyneins/genetics , Disability Evaluation , Female , GTP Phosphohydrolases/genetics , Humans , Magnetic Resonance Imaging , Male , Microtubule-Associated Proteins/genetics , Mitochondrial Proteins/genetics , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Muscular Atrophy, Spinal/physiopathology , Phenotype , Retrospective StudiesABSTRACT
OBJECTIVE: To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls. METHODS: Peak aerobic capacity (VO2peak ) and workload (Wpeak ) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% Wpeak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near-infrared spectroscopy, determined muscle oxygen uptake (ΔHHb) at rest and during CPET and SME. Dual energy X-ray absorptiometry assessed fat-free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (FatigueSME ) and six-minute walk test (Fatigue6MWT ), respectively. RESULTS: ΔHHb-PEAK, ΔHHb-SME, VO2peak , Wpeak , FFM%, and 6MWT distance were lower (P < 0.001), and Fatigue6MWT and FatigueSME were higher (P < 0.001) in SMA compared to controls. ΔHHb-PEAK correlated with FFM% (r = 0.50) and VO2peak (r = 0.41) only in controls. Only in SMA, Fatigue6MWT was inversely correlated with Wpeak (r = -0.69), and FatigueSME was inversely correlated with FFM% (r = -0.55) and VO2peak (r = -0.69). INTERPRETATION: This study provides further support for muscle mitochondrial dysfunction in SMA patients. During exercise, we observed diminished muscle oxygen uptake but no correlation with aerobic capacity or body composition. We also observed increased fatigue which correlated with decreased aerobic capacity, workload, and body composition. Understanding the mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may identify additional therapeutic targets that rescue symptomatic patients and mitigate their residual disease burden.
Subject(s)
Exercise/physiology , Fatigue/metabolism , Mitochondrial Myopathies/metabolism , Muscle, Skeletal/metabolism , Muscular Atrophy, Spinal/metabolism , Oxygen Consumption/physiology , Absorptiometry, Photon , Adolescent , Adult , Child , Exercise Test , Fatigue/etiology , Female , Humans , Male , Middle Aged , Mitochondrial Myopathies/complications , Muscle, Skeletal/diagnostic imaging , Muscular Atrophy, Spinal/complications , Spectroscopy, Near-Infrared , Young AdultABSTRACT
BACKGROUND AND OBJECTIVES: This study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT). METHODS: We conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI <17 kg/m2), underweight (BMI ≥17-<18.5 kg/m2), healthy weight (BMI ≥18.5-<25 kg/m2), overweight (BMI ≥25-<30 kg/m2), and obese (BMI ≥30 kg/m2). Scores on the 0 to 44-point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI. RESULTS: There was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) (p < 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) (p < 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled (p < 0.001), as was being obese (p = 0.015). DISCUSSION: The proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.
Subject(s)
Charcot-Marie-Tooth Disease/complications , Obesity/epidemiology , Thinness/epidemiology , Adolescent , Body Mass Index , Child , Child, Preschool , Cross-Sectional Studies , Disability Evaluation , Female , Humans , Male , Young AdultABSTRACT
The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2-year natural history data from 187 children aged 3-20 years with a range of CMT genetic subtypes. Subsets based on age (3-8 years), disability level (CMTPedS score 0-14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.
Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Clinical Trials as Topic/standards , Disabled Children , Outcome Assessment, Health Care/standards , Patient Selection , Severity of Illness Index , Adolescent , Adult , Child , Child, Preschool , Humans , Reference Standards , Young AdultABSTRACT
Charcot-Marie-Tooth disease (CMT) causes disabling cavovarus foot deformity. Orthopaedic surgery is performed in severe cases; however few studies have investigated whether surgery improves health outcomes during childhood. This study investigated the impact of cavovarus surgery on validated physical, functional, parent/self-reported and biomechanical measures in 21 consecutive patients (mean age at surgery 12.5 years, SD 2.7) evaluated before and after surgery (mean duration 15.7 months, SD 5.9), and compared to natural history data from 206 children with CMT. Measures from the CMT Pediatric Scale evaluated foot alignment (Foot Posture Index), ankle flexibility (lunge test), strength (foot dorsiflexion/plantarflexion by hand-held dynamometry), function (balance, long jump, 6-minute walk test) and self-reported symptoms. Quality of life (Child Health Questionnaire) and gait (pressure loading) were also assessed. Foot Posture Index and lunge improved with surgery by 6.0 points (SD 3.2) and 6.1° (SD 7.3) respectively (p< 0.01), and differed to the natural course of the disease (p< 0.005). Self-reported daily trips/falls reduced from 60% to 13% (pâ¯=â¯0.016). Pressure improved beneath the rearfoot and midfoot (pâ¯=â¯0.043). Surgery had no effect on strength, function or quality of life, which generally mirrored the natural course. Cavovarus surgery improved foot alignment, ankle flexibility and self-reported trips/falls in children with CMT.