Long-Term Effective Thalamic Deep Brain Stimulation for Neuropathic Tremor in Two Patients with Charcot-Marie-Tooth Disease.

BACKGROUND: It has been described that many Charcot-Marie-Tooth syndrome type 2 patients are affected by a very disabling type of tremor syndrome, the pathophysiology of which remains unclear. Deep brain stimulation (DBS) has been successfully applied to treat most types of tremors by implanting electrodes in the ventral intermediate nucleus of the thalamus (Vim). METHODS: We used DBS applied to the Vim in 2 patients with severe axonal inherited polyneuropathies who developed a disabling tremor. RESULTS: Both patients responded positively to stimulation, with a marked reduction of the tremor and with an improvement of their quality of life. CONCLUSION: We report 2 cases of tremor associated with a hereditary neuropathy with a good response to DBS.

Coenzyme Q10 therapy in hereditary motor sensory neuropathy type VI with novel mitofusin 2 mutation.

Hereditary motor sensory neuropathy type VI (HMSN VI) is hereditary neuropathy accompanied by optic neuropathy. The feasibility of Coenzyme Q10 (CoQ10) as a treatment for subacute visual impairment of HMSN VI was examined. A 37-year-old patient with HMSN VI with a novel mitofusin 2 mutation was treated with high dose of CoQ10 (200 mg/day) for eight months. Visual impairment was partially resolved after CoQ10 therapy. High dose CoQ10 therapy may improve the prognosis of subacute visual impairment in HMSN VI. To confirm the effectiveness of CoQ10 on HMSN VI, further studies are needed.

Enfermedad de Charcot-Marie-Tooth: consideraciones ortopédicas / Charcot-Marie-Tooth syndrome: orthopaedic considerations

La enfermedad de Charcot-Marie-Tooth es una enfermedad heredodegenerativa del sistema nervioso periférico. La alteración es progresiva, y provoca deformidades en pies y manos. La musculatura de la pierna y el pie es la más afectada. La forma de presentación es muy diversa debido a que la afectación muscular es diferente en cada paciente. El pie cavo-varo es la forma de presentación habitual. El tratamiento conservador consiste en férulas correctoras, plantillas y rehabilitación. La indicación quirúrgica se plantea cuando fracasa el tratamiento conservador. La deformidad y el dolor son los problemas principales. En las deformidades flexibles se plantean cirugías para preservar las articulaciones. Los dedos en garra se tratarán con transferencias tendinosas o artroplastias. La deformidad en garra del dedo gordo se produce por el descenso del primer metatarsiano y la hiperactividad del músculo extensor hallucis longus. El tratamiento de esta deformidad del dedo gordo se realiza mediante la técnica de Jones. El descenso del primer metatarsiano necesitará una osteotomía dorsiflexora en la base del primer metatarsiano. Para el varo de retropié se utiliza la osteotomía valguizante de calcáneo. La retracción de la fascia plantar, gastrocnemio y Aquiles se trata con elongación de las estructuras retraídas. Cuando las deformidades son rígidas, será necesario realizar una artrodesis de las articulaciones afectadas. La artrodesis más utilizada es la triple artrodesis (AU)

Charcot-Marie-Tooth disease is a degenerative hereditary disease of the peripheral nervous system. The change is progressive and causes deformities in the feet and hands. The musculature of the leg and foot are most affected. The form of presentation is very diverse owing to the muscle involvement being different in each patient. The high-arched foot is the most common form of presentation. Conservative treatment consists of correction splints, insoles and rehabilitation. Surgery may be indicated when conservative treatment fails. The deformity and pain are the main problems. In flexion deformities surgery is indicated to conserve the joints. Claw hammer toes should be treated with tendon transfers and arthroplasty. The claw deformity in the big toe is caused by the descent of the first metatarsal and hyperactivity of the hallucis longus extensor muscle. The Jones technique is performed as treatment for this deformity of the big toe. The descent of the first metatarsal requires a dorsiflexion osteotomy in the base of the first metatarsal. For the hind foot varus a calcaneal vagus osteotomy is used. The tightening of the plantar fascia, gastrocnemius and Achilles is treated with an extension of the muscle contractures. When the deformities are rigid, it will be necessary to perform an arthrodesis of the affected joints. The arthrodesis most used is the triple arthrodesis (AU)

Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A.

Charcot-Marie-Tooth disease type 2A is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene. Mitofusin 2 encodes a mitochondrial outer membrane protein that participates in mitochondrial fusion in mammalian cells. How mutations in this protein lead to Charcot-Marie-Tooth disease type 2A pathophysiology remains unclear. We have generated a transgenic mouse expressing either a mutated (R94Q) or wild-type form of human mitofusin 2 in neurons to evaluate whether the R94Q mutation was sufficient for inducing a Charcot-Marie-Tooth disease type 2A phenotype. Only mice expressing mitofusin 2(R94Q) developed locomotor impairments and gait defects thus mimicking the Charcot-Marie-Tooth disease type 2A neuropathy. In these animals, the number of mitochondria per axon was significantly increased in the distal part of the sciatic nerve axons with a diameter smaller than 3.5 microm. Importantly, the analysis of R94Q transgenic animals also revealed an age-related shift in the size of myelinated axons leading to an over-representation of axons smaller than 3.5 microm. Together these data suggest a link between an increased number of mitochondria in axons and a shift in axonal size distribution in mitofusin 2(R94Q) transgenic animals that may contribute to their neurological phenotype.

Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial.

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.

Poor tolerability of high dose ascorbic acid in a population of genetically confirmed adult Charcot-Marie-Tooth 1A patients.

BACKGROUND: Preclinical studies have suggested that ascorbic acid (AA) treatment in a mouse model of Charcot-Marie-Tooth type 1A (CMT1A) improves motor function and prolongs lifespan. AIMS: I sought to determine the safety and tolerability of AA in adult patients with CMT1A. METHODS: An open-label cohort-controlled 2-year pilot study was used to evaluate the tolerability of 5 g of AA daily. Secondary measurements consisted of clinical and electrophysiological measurements at 0, 12, and 24 months in CMT1A patients. RESULTS: Twelve CMT1A patients received AA and 10 CMT1A patients formed a cohort group followed in identical manner. Five (42%) patients tolerated this dose of AA for the entire 2-year span, with six patients (50%) developing intolerable gastrointestinal side effects. No significant differences in clinical, disability, or electrophysiological measurements occurred between baseline and final follow-up in patients receiving AA when compared with cohorts. CONCLUSIONS: High dose AA was not well tolerated in all adult CMT1A patients who may be susceptible to gastrointestinal adverse effects of AA. Studies with greater powers to detect efficacy will be required to test the validity of AA as a therapy in CMT1A patients. Doses lower than 5 g of AA daily may be required for maintenance of tolerability in the CMT1A population.

Lower limb manual muscle testing in the early stages of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous disorder that affects approximately one in 2,500 individuals. CMT 1A, which is due to a duplication in the area containing the PMP-22 gene on chromosome 17, is the most frequent CMT subtype. To date, there is no consensus among authors about which muscles are weakened in the early stages of CMT, even though this knowledge would be crucial for deciding the most appropriate interventions to restore balance between muscles and prevent the development of deformities. The aim of this study was to evaluate the strength of several lower limb muscles in the early stages of CMT 1A. In a series of 45 patients (age 10-72 years; 21 males, 24 females) affected by CMT 1A, we evaluated 83 non-operated lower limbs that corresponded to the two milder stages of a five-level functional classification. The strength of two foot muscles, seven leg muscles, two thigh muscles, and three pelvic girdle muscles was graded using the manual muscle testing techniques of Daniels and Worthingham; the power of the triceps surae was graded, in the prone position, using a 4-level scale of ability to raise the heel from the floor. Muscle strength was determined on the basis of interobserver agreement estimated by kappa statistics between two observers. The flexor hallucis brevis and lumbricals were very weak in all the limbs; the leg muscles were strong in more than 90% of limbs, except the peronei (strong in 83.13%); all the triceps surae were strong in the prone test, but 16.87% were weak in the standing test; all the proximal muscles were strong. In the large majority of patients in the early stages of CMT 1A, the intrinsic foot muscles are very weak and the leg and proximal muscles are strong.

Effects of exercise and creatine on myosin heavy chain isoform composition in patients with Charcot-Marie-Tooth disease.

It is not known whether myosin heavy chain (MHC) content changes in response to exercise training or creatine supplementation in subjects with Charcot-Marie-Tooth disease (CMT). Based on previous data, we hypothesized that resistance exercise and creatine would increase the percentage of type I MHC composition in the vastus lateralis muscle and that myosin isoform changes would correlate with improved chair rise-time in CMT subjects. To test this hypothesis, 18 CMT subjects were randomly assigned to either a placebo or creatine group. All subjects performed a 12-week, home-based, moderate-intensity resistance training program. Chair rise-time was measured before and after the training program. Muscle biopsies were obtained from the vastus lateralis before and after the 12-week program. Gel electrophoresis showed a significant decrease (approximately 30%) in MHC type I in CMT subjects given creatine supplementation when compared with placebo. There was a nonsignificant increase in both MHC type IIa (approximately 23%) and MHC type IIx (approximately 7%) in CMT subjects given creatine. Reduced MHC type I content and increased MHC type IIa content correlated with faster chair rise-times (i.e., improved muscle performance). The training-induced change in MHC IIa content was inversely correlated with chair rise-time in CMT subjects given creatine. When the two subject groups were combined, there was a linear, negative relationship between the change in MHC type IIa content and chair rise-time after training and a positive relationship between the training-induced change in MHC type I content and chair rise-time. These data suggest that improved function (chair rise-time) was associated with a lower level of MHC type I and increased MHC type IIa composition. Furthermore, the data are consistent with the hypothesis that creatine supplementation alters MHC composition in CMT patients undergoing resistance training and that MHC changes associated with creatine supplementation can improve muscle function.

Auditory processing in patients with Charcot-Marie-Tooth disease type 1A.

HYPOTHESIS: It is unclear whether Charcot-Marie-Tooth (CMT) disease, type 1A, causes auditory processing disorders. Therefore, auditory processing abilities were investigated in five CMT1A patients with normal hearing. BACKGROUND: Previous studies have failed to separate peripheral from central auditory processing disorders. MATERIALS AND METHODS: Five genetically confirmed CMT1A cases in patients with normal hearing underwent behavioral and objective testing. Pure tone audiometry, speech audiometry, and OAE assessment were followed-up by an auditory processing test battery comprising sentences-in-noise test, pattern recognition tests, words-in-noise test, dichotic digit test, filtered speech test, binaural fusion test, and categorical speech perception test. Subsequently, ABR and ERP measurements were conducted. RESULTS: Either the behavioral or objective test scores of 4 out of the 5 CMT1A patients did not differ significantly from those of subjects with normal hearing. Significantly lower scores of one patient on auditory processing tests and ABR measurements could be ascribed to subnormal hearing. CONCLUSION: The authors conclude that CMT1A patients with normal peripheral hearing have auditory processing abilities that were not indicative for an auditory processing disorder. Furthermore, the presence of a peripheral hearing loss complicates the interpretation of auditory processing abilities.

Changes in sleep spindle activity of subject with chronic somatosensitive and sensorial deficits. Preliminary results.

We investigated the effects of the somatosensitive and sensory afferent inputs on the thalamic generators of sleep spindles (SS) in adult subjects affected by posterior funiculi lesions (five subjects), deafness (four subjects) or blindness (four subjects). The density, duration and frequency of SS, as well as the index of spindling, were analyzed during stage 2 NREM. The results show that the subjects with somatosensitive and sensorial lesions spent much more time on SS activity than the control group (eight subjects), and had a significantly increased density (< .0001), duration (< .0005) and index of spindling (< .0001). On the other hand, the frequency of spindling was little modified (< .05). Moreover, among the three groups of patients, those with somatosensitive deficits showed the greatest SS activity. In conclusion, our results suggest that the thalamic generators of SS are markedly modulated by peripheral inputs in man.

Charcot-Marie-Tooth disease.

OBJECTIVE: To discuss the similarities and differences in the clinical presentation of Charcot-Marie-Tooth Disease, an inherited peripheral neuropathy, and acquired lumbar spinal stenosis. CLINICAL FEATURES: Patients with lumbar spinal stenosis causing nerve root entrapment often have leg pain and weakness during such activities as walking or standing. Additional symptoms of poor balance, foot deformity and signs of cerebellar and sensory ataxia suggest a diagnosis of peripheral neuropathy rather than nerve root entrapment. INTERVENTION: Electrodiagnostic testing and nerve conduction studies reveal abnormal conduction velocities in cases of peripheral neuropathy such as Charcot-Marie-Tooth Disease. CONCLUSION: Sciatica and leg weakness may be due to a variety of causes, including nerve root entrapment and peripheral neuropathy. A diagnosis of Charcot-Marie-Tooth Disease should be considered in a case of progressive lower limb weakness associated with loss of balance and sensory ataxia. This diagnosis can be confirmed using nerve conduction studies.

Anaesthesia for Charcot-Marie-Tooth disease: a review of 86 cases.

Operative charts were reviewed in 86 patients with Charcot-Marie-Tooth disease, a condition characterized by chronic muscular denervation. A total of 161 surgical procedures was performed. Major complications were few, and only one operative death occurred, unrelated to anaesthesia. Succinylcholine and malignant hyperthermia triggering agents were used in 41 (48%) and 77 (90%) patients, respectively, without untoward effects. Contrary to previous reports, this survey supports the safe use of succinylcholine and MH triggering agents in this disease.