Search

Introduction: Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neuromuscular diseases--there is no effective treatment. Foot and ankle weakness is a major problem for children with CMT, thus interventions that focus on maintaining and increasing strength may provide a solution., Research Question: Is progressive resistance strength training an effective and safe intervention to improve strength, disability, gait and quality of life of children with CMT?, Participants and Setting: Sixty children (6 to 17 years) with confirmed CMT who reside in Sydney, Australia will be recruited via referral from a paediatric neurologist, advertisements or the Australasian Paediatric CMT Registry., Intervention: Participants will be randomised to undergo a 24-week, thrice weekly, high-intensity progressive resistance foot and ankle exercise programme (HIGH) or low-intensity foot and ankle exercise control programme (LOW)., Measurements: Out-come measures will be conducted at baseline, 6, 12 and 24 months.The primary outcome is isometric dorsiflexion strength measured by hand-held dynamometry. Secondary outcomes include disability, gait, quality of life, functional ankle instability and muscle volume and fatty infiltration of the anterior compartment of the lower leg (determined by MRI)., Procedure: Randomisation and allocation will be by a computer-generated algorithm, maintained and assigned by an external phone-based system, concealed to the investigators. Participants, parents and the outcome assessors will be blinded to group assignment., Analysis: Treatment effect between groups is by intention-to-treat with a linear regression approach to analysis of covariance using 95% CI and p < 0.05., Discussion: This study is the first randomised controlled trial to evaluate the risks and benefits of strengthening the affected muscles in children with CMT., Trial Registration: Australian New Zealand Clinical Trials Registry., Registration Number: ACTRN12613000552785.

Background: Charcot-Marie-Tooth disease is the most common inherited nerve disorder and typically presents with pes cavus foot deformity and ankle equinus during childhood. Level in the variation of symmetry of musculoskeletal lower limb involvement across the clinical population is unknown, despite early reports describing gross asymmetry., Methods: We measured foot alignment and ankle flexibility of the left and right limbs using accurate and reliable standardised paediatric outcome measures in 172 patients aged 3-20 years with a variety of disease subtypes recruited from the United States, United Kingdom, Italy and Australia., Findings: While a large range of differences existed between left and right feet for a small proportion of children, there was no overall significant difference between limbs., Interpretation: There are two important implications of these findings. Children with Charcot-Marie-Tooth disease generally exhibit symmetrical foot alignment and ankle flexibility between limbs. As such, analysing one limb only for biomechanical-related research is appropriate and satisfies the independence requirements for statistical analysis. However, because there are large differences between feet for a small proportion of children, an individualised limb-focused approach to clinical care is required., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Charcot-Marie-Tooth disease (CMT) is a common heritable peripheral neuropathy. There is no treatment for any form of CMT, although clinical trials are increasingly occurring. Patients usually develop symptoms during the first 2 decades of life, but there are no established outcome measures of disease severity or response to treatment. We identified a set of items that represent a range of impairment levels and conducted a series of validation studies to build a patient-centered multi-item rating scale of disability for children with CMT., Methods: As part of the Inherited Neuropathies Consortium, patients aged 3 to 20 years with a variety of CMT types were recruited from the USA, United Kingdom, Italy, and Australia. Initial development stages involved definition of the construct, item pool generation, peer review, and pilot testing. Based on data from 172 patients, a series of validation studies were conducted, including item and factor analysis, reliability testing, Rasch modeling, and sensitivity analysis., Results: Seven areas for measurement were identified (strength, dexterity, sensation, gait, balance, power, endurance), and a psychometrically robust 11-item scale was constructed (CMT Pediatric Scale [CMTPedS]). Rasch analysis supported the viability of the CMTPedS as a unidimensional measure of disability in children with CMT. It showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for children with CMT., Interpretation: The CMTPedS is a well-tolerated outcome measure that can be completed in 25 minutes. It is a reliable, valid, and sensitive global measure of disability for children with CMT from the age of 3 years., (Copyright © 2012 American Neurological Association.)

Objectives: To identify correlates of calf cramp in children with Charcot-Marie-Tooth disease type 1A (CMT1A)., Methods: Throughout Australia, 81 children aged 2-16 years with CMT1A were recruited. Measures of strength, ankle range, foot posture, balance, agility, endurance, gait, and neurophysiology were collected. Post hoc logistic regression analyses were performed to identify independent predictors of calf cramp., Results: Of the 81 children, 26 (32%) reported calf cramp, and 1 child each reported toe, quadriceps, or arm cramp. Calf cramp was associated (p < 0.05) with older age; the presence of hand tremor; stronger foot inversion, eversion, dorsiflexion, and plantarflexion; and better performance in long-jump and 9-hole peg tests. Logistic regression analysis revealed only increasing age (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.11-1.58; p = 0.002) and the presence of hand tremor (OR 3.81, 95% CI 1.18-12.56; p = 0.028) as independent predictors of calf cramp., Conclusion: Calf cramps are common in children with CMT1A and worsen with age. This study revealed a previously unrecognized link between cramp and hand tremor in children with CMT1A. Further investigation of proposed mechanisms and risk factors common to both cramp and tremor will contribute to our understanding of these common complications of CMT1A.

Pes cavus in Charcot-Marie-Tooth disease type 1A (CMT1A) is thought to be due to muscle imbalance of the lower leg. Botulinum toxin type A (BoNT-A) can modify foot deformity in other conditions of muscle imbalance. We tested the safety and effectiveness of BoNT-A on pes cavus progression in pediatric CMT1A. A 24-month, randomized, single-blind trial of BoNT-A was undertaken in 10 affected children (20 legs), aged 3-14 years. The treated leg received intramuscular BoNT-A injections at 6-month intervals in the tibialis posterior and peroneus longus. The control leg received no injections. Primary outcome was radiographic alignment at 24 months. Secondary outcomes were foot posture, ankle flexibility, and strength, assessed every 6 months. Radiographically, BoNT-A produced a small non-significant reduction in cavus progression. There was no effect of BoNT-A on secondary outcomes. There were no serious adverse events. At 24 months, the intramuscular BoNT-A injections proved safe and well-tolerated but did not affect the progression of pes cavus in CMT1A.

Mitofusin 2, a large transmembrane GTPase located in the outer mitochondrial membrane, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Mutations of the gene encoding mitofusin 2 (MFN2) have recently been identified as the cause of approximately one-third of dominantly inherited cases of the axonal degenerative forms of Charcot-Marie-Tooth disease (CMT type 2A) and of rarer variants. The latter include a severe, early-onset axonal neuropathy, which may occur in autosomal dominant or recessive forms, as well as some instances associated with pyramidal tract involvement (CMT type 5), with optic atrophy (CMT type 6), and, occasionally, with alterations of cerebral white matter. All individuals with a dominantly or recessively inherited or otherwise unexplained, chronic progressive axonal degenerative polyneuropathy should be tested for mutations of MFN2.

The authors studied the health-related quality of life of children aged 5 to 18 years with Charcot-Marie-Tooth disease of varying types and severity and compared it with the general pediatric population. To capture and compare the quality-of-life data across a broad range of ages, the Child Health Questionnaire was completed by parents of 127 children with Charcot-Marie-Tooth disease. Affected children exhibited lower physical, psychological, and social well-being than the general pediatric population, with subsequent worsening of many domains with age. The type of Charcot-Marie-Tooth disease influenced some physical and behavioral quality-of-life domains, while gender, body size, and ethnicity did not. Parent characteristics had generally little impact on the reporting of their child's quality of life, although parents with Charcot-Marie-Tooth disease reported higher bodily pain in their children than those without. Overall, quality of life is negatively affected by the presence and severity of Charcot-Marie-Tooth disease in childhood.

Background: Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features., Objective: To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN)., Design: Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations., Setting: Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies., Patients: One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero., Main Outcome Measures: Results of genetic analyses and phenotypic observations., Results: Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections., Conclusions: MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.

Weakness of ankle dorsiflexion is the cardinal manifestation of CMT. We investigated if a 12-week progressive resistance dorsiflexion strengthening program was feasible, safe and beneficial in a 15-year-old girl with an axonal form of CMT. Training load was based on a dose-escalating percentage of one-repetition maximum, completed on three non-consecutive days each week. Outcomes included dynamometric foot strength, motor function and instrumented walking ability. At 12-weeks, dorsiflexion strength improved 56-72% and plantarflexion strength by 15-20%. Standing long jump increased by 16%, while balance and endurance did not. Walking ability improved for speed, cadence, step time and stride length. Compliance was high and there were no adverse events. This case suggests progressive strength training might be a feasible intervention to help foot weakness and disability in childhood CMT.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor function and is caused by the duplication of PMP22, the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A., Methods: This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2-16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, Number 12606000481572., Findings: 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1.7 m/s, 95% CI -0.1 to 3.4; p=0.06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events., Interpretation: 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached.

We studied the timing and progression of foot and ankle changes in 81 children with genetically confirmed Charcot-Marie-Tooth disease type 1A (CMT1A) and determined their impact on motor function and walking ability. Foot deformity, weakness, pain, cramps, and instability were a common feature of CMT1A. Foot structure evolved toward pes cavus from early childhood to adolescence, although a subgroup with normal and planus feet remained. Foot strength increased with age, although compared to age-equivalent norms it declined from 4 years. Factors associated with evolving foot deformity included muscle weakness/imbalance, restricted ankle flexibility, and joint hypermobility. Regression modeling identified dorsiflexion weakness, global foot weakness, and difficulty toe-walking as independent predictors of motor dysfunction, while pes cavus and difficulty heel-walking were predictors of poor walking ability. Foot problems are present from the earliest stages of the disease and can have a negative impact on function. Early foot and ankle intervention may prevent long-term disability and morbidity in CMT1A.

We present neuropathological findings based on sural nerve biopsy in six children with mutations of the mitofusin 2 gene (MFN2). All six children had severe axonal neuropathies (mild or severe hereditary motor and sensory neuropathy, HMSN), with onset in early childhood. All had a marked decrease in the density of mainly large myelinated fibers. Although neurophysiological findings were suggestive of axonal degeneration, some onion bulbs were present in each case. Unequivocal mitochondrial changes were apparent only on longitudinal sections. Many axonal mitochondria appeared smaller than normal and round or spherical instead of tubular. These mitochondria were abnormally aggregated, accumulating primarily at the axon periphery. This peripheral distribution was clearest in residual large myelinated fibers. The inner and outer mitochondrial membranes were irregular, and the cristae were quite often disrupted. These changes were observed in both myelinated and unmyelinated fibers. Mitofusin 2 is a large mitochondrial transmembrane GTPase, with two coiled coil domains and two transmembrane spans. It is targeted to the outer mitochondrial membrane, where it interacts with mitofusin 1 to regulate the mitochondrial network architecture by stimulating mitochondrialfusion. The mitochondrial changes we observed could thus result from abnormal mitochondrial fusion and fission. Neuropathologic abnormalities can be sufficiently characteristic to suggest the genetic basis of some hereditary neuropathies such as those associated with mutations in MPZ, GJB1, GDAP1, MTMR2, SH3TC2, PRX, FGD4 and LMNA. This may also be true of MFN2-related neuropathies.

Charcot-Marie-Tooth disease type 1A (CMT1A), a demyelinating neuropathy characterised by progressive length-dependent muscle weakness and atrophy, is thought to affect the foot and leg first followed some time later by hand weakness and dysfunction. We aimed to characterise hand strength, function and disease-related symptoms in children with CMT1A. Intrinsic and extrinsic hand strength was measured by hand-held dynamometry, function by nine-hole peg test, and disease-related symptoms by interview and examination in 84 affected children aged 2-16 years. Hand weakness and dysfunction was present from the earliest stages of the disease. While hand strength and function measures tended to increase with age throughout childhood, at no point did they reach normal values. Day-to-day hand problems such as poor handwriting, weakness, pain and sensory symptoms also worsened with age. The hand is affected at all ages in children with CMT1A, but may be under-recognised in its early stages, potentially delaying therapy.

Charcot-Marie-Tooth (CMT) disease often presents with peripheral muscle imbalance associated with a painful cavus (medial high-arched) foot deformity which becomes increasingly severe and rigid as the disease progresses. The purpose of this study was to investigate the effect of pes cavus on foot pain and dynamic plantar pressure in CMT, and to explore the relationships between plantar pressure and pain. Sixteen participants diagnosed with CMT and painful pes cavus were assessed for foot posture, ankle dorsiflexion range of motion, levels of foot pain, functional impairment, health-related quality of life and plantar pressure distribution while walking. Plantar pressure parameters (mean pressure, peak pressure, pressure-time integral) and contact duration were measured using the Novel Pedar in-shoe capacitance transducer system and the foot was divided into rearfoot, midfoot and forefoot regions for analysis. Increasing cavus foot deformity was associated with more widespread foot pain and increased pressure under the forefoot and midfoot regions. In contrast, peak pressure decreased under the rearfoot. Neither relationship was found between foot pain intensity and any of the pressure variables, nor was ankle dorsiflexion range of motion correlated with pain location, intensity or degree of pes cavus. Although pes cavus in CMT is associated with substantial pain and dysfunction, there is no clear link between foot pain and plantar pressure. The more severe the degree of pes cavus, however, the more pressure develops under the lateral margin of the foot; probably as a result of the changed foot-ground contact seen during gait.

Although Charcot-Marie-Tooth disease type 1A (CMT1A) initially manifests in the first decade, there are no large studies describing its neurophysiologic features in childhood. We report neurophysiologic findings in 80 children aged 2-16 years with CMT1A who underwent median motor and sensory nerve conduction studies. Neurophysiologic abnormalities were present in all children. Median motor nerve conduction velocity was invariably less than 33 m/s (mean 18.7 m/s, range 9.0-32.9 m/s), with conduction velocities significantly slower in children aged 7-16 years compared with children aged 6 years and below. All children had prolonged distal motor latencies (mean 7.3 ms, range 4.0-12.3 ms). The compound muscle action potential (CMAP) amplitude was reduced from an early age (mean 7.1 mV, range 2.1-13.5 mV), and its normal increase with age was attenuated. Median sensory responses were present in only seven children, all aged less than 9 years and with slowed sensory conduction. Neurophysiologic abnormalities are present in all children with CMT1A from the age of 2 years. Motor conduction slowing progresses through the first 6 years of life and thereafter remains stable. CMAP amplitude is reduced from an early age, and the normal physiologic increase with age is attenuated. Median sensory responses may be recorded in younger children, and their presence does not exclude the diagnosis of CMT1A.

Health-related, quality of life (HRQoL) is an important outcome in clinical trials of patients with Charcot-Marie-Tooth disease (CMT). In a cross-sectional survey of 295 Australian adults with CMT, HRQoL was measured using the Short Form-36 (SF-36) and predictors of reduced HRQoL were identified with a CMT-specific health status questionnaire. People with CMT demonstrated lower HRQoL scores than the general Australian population in all SF-36 dimensions. The disparity between people with CMT and normative data was greater for physical dimensions than for mental health dimensions. SF-36 scores were generally lower in older vs younger people, but not between men and women, or between CMT types. HRQoL in CMT was predicted strongly by lower limb weakness and to a lesser extent by leg cramps, suggesting clinical trials targeting weakness and cramps may improve HRQoL in patients with CMT.

Nitrous oxide is routinely administered to children and adults with Charcot-Marie-Tooth disease (CMT) as an anaesthetic for procedures such as nerve conduction studies and maintenance for general anaesthesia. However it is listed as a 'moderate to significant' risk of potential toxicity and worsening neuropathy in people with CMT by the CMT Association (USA), CMT Association of Australia, CMT International (Canada) and CMT United Kingdom. We performed a systematic review focussing on the use of nitrous oxide in patients with CMT to help clarify its safety. This identified 11 studies reporting 41 exposures to therapeutically inhaled nitrous oxide as maintenance for general anaesthesia with no reports of adverse effects or worsening of CMT neuropathy. In the absence of a single case in the literature reporting worsening neuropathy in CMT patients receiving nitrous oxide, this review provides good evidence that nitrous oxide should be considered a safe agent for use in children and adults with CMT.

GTPases of the Rho subfamily are widely involved in the myelination of the vertebrate nervous system. Rho GTPase activity is temporally and spatially regulated by a set of specific guanine nucleotide exchange factors (GEFs). Here, we report that disruption of frabin/FGD4, a GEF for the Rho GTPase cell-division cycle 42 (Cdc42), causes peripheral nerve demyelination in patients with autosomal recessive Charcot-Marie-Tooth (CMT) neuropathy. These data, together with the ability of frabin to induce Cdc42-mediated cell-shape changes in transfected Schwann cells, suggest that Rho GTPase signaling is essential for proper myelination of the peripheral nervous system.

Background: Pes cavus foot deformity in neuromuscular disease is thought to be related to an imbalance of musculature around the foot and ankle. The most common cause of neurogenic pes cavus is Charcot-Marie-Tooth (CMT) disease. The aim of this investigation was to objectively quantify muscle strength and imbalance using hand-held dynamometry in patients diagnosed with CMT and pes cavus, compared to healthy controls., Methods: Muscles responsible for inversion, eversion, plantarflexion, and dorsiflexion of the foot and ankle were measured in 55 subjects (11 CMT patients with a frank pes cavus, and 44 healthy controls with normal feet) using the Nicholas hand-held dynamometer (HHD). Test-retest reliability of the HHD procedure also was determined for each of the four muscle groups in the healthy controls., Results: Test-retest reliability of the HHD procedure was excellent (ICC3,1 = 0.88 to 0.95) and the measurement error was low (SEM = 0.3 to 0.7 kg). Patients with CMT were significantly weaker than normal for all foot and ankle muscle groups tested (p < 0.001). Strength ratios of inversion-to-eversion and plantarflexion-to-dorsiflexion were significantly higher in the patients with CMT and pes cavus compared to individuals with normal foot types (p > 0.01)., Conclusions: Hand-held dynamometry is an objective and reliable instrument to measure muscle strength and imbalance in patients with CMT and a pes cavus foot deformity.

An abstract of the article "Calf cramp in children with Charcot-Marie-Tooth disease: searching for therapeutic targets," by Fiona Hawke and colleagues, to be presented at the Australasian Podiatry Council Conference 2011 in Melbourne, Victoria on April 26-29, is presented.

An abstract of the article "Development, reliability and validity of the Charcot-Marie Tooth disease Pediatric Scale (CMTPedS)," by Joshua Burns and colleagues, to be presented at the Australasian Podiatry Council Conference 2011 in Melbourne, Victoria on April 26-29, is presented.