Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of motor and sensory neuropathies associated with mutations in more than 30 genes. Charcot-Marie-Tooth disease type 4J (OMIM 611228) is a recessive, potentially severe form of the disease caused by mutations of the lipid phosphatase FIG4. We provide a more complete view of the features of this disorder by describing 11 previously unreported patients with Charcot-Marie-Tooth disease type 4J. Three patients were identified from a small cohort selected for screening because of their early onset disease and progressive proximal as well as distal weakness. Eight patients were identified by large-scale exon sequencing of an unselected group of 4000 patients with Charcot-Marie-Tooth disease. In addition, 34 new FIG4 variants were detected. Ten of the new CMT4J cases have the compound heterozygous genotype FIG4(I41T/null) described in the original four families, while one has the novel genotype FIG4(L17P/nul)(l). The population frequency of the I41T allele was found to be 0.001 by genotyping 5769 Northern European controls. Thirty four new variants of FIG4 were identified. The severity of Charcot-Marie-Tooth disease type 4J ranges from mild clinical signs to severe disability requiring the use of a wheelchair. Both mild and severe forms have been seen in patients with the same genotype. The results demonstrate that Charcot-Marie-Tooth disease type 4J is characterized by highly variable onset and severity, proximal as well as distal and asymmetric muscle weakness, electromyography demonstrating denervation in proximal and distal muscles, and frequent progression to severe amyotrophy. FIG4 mutations should be considered in Charcot-Marie-Tooth patients with these characteristics, especially if found in combination with sporadic or recessive inheritance, childhood onset and a phase of rapid progression.

Catapult splint: a foot dorsiflexion assist splint.

BACKGROUND: Loss of dorsiflexion is a common problem in cases where an external fixator or Ilizarov assembly is applied. It results in functional impairment of the foot by affecting the swing phase of gait cycle. We devised a simple dynamic dorsiflexion assist splint for prevention, correction of equinus/cavus deformity and maintenance of normal dorsiflexion of foot. METHODS: This prospective study used a rubber splint styled in the shape of a catapult, made of discarded car rubber tubes attached to the frame of fixator in 50 patients. RESULTS: In 17 patients there was varying amount of loss of dorsiflexion at the time of application of splint while in 22 patients it was applied soon after the application of the fixator. In the rest of patients it was applied for cavus deformity. Out of 17 patients 10 had complete recovery of dorsiflexion. 22 patients in whom it was applied at the outset had normal range of movement at ankle. Correction was achieved in all 6 cases of cavus deformity and prevented its occurrence in the rest of 5 cases. CONCLUSION: Catapult splint is a low cost foot dorsiflexion assist splint.

Pressure characteristics in painful pes cavus feet resulting from Charcot-Marie-Tooth disease.

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.

Charcot-Marie-Tooth disease and the cavovarus foot.

This article focuses on the cavovarus foot shape, with particular emphasis on those patients who have Charcot-Marie-Tooth disease. Recent greater understanding of this deformity has led to a better appreciation of how the underlying condition drives deformity progression and treatment of the problems associated with it. The basic science underpinning the development of Charcot-Marie-Tooth disease is reviewed and some elements of the importance of the genetic variability are emphasized. The mechanics of the development of the cavovarus foot deformity in patients who have this neuromuscular condition are reviewed and the evaluation of such patients is described. The surgical options for treatment are reviewed and the outcomes of studies relevant to surgical planning for this patient population are summarized.

Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease is a group of genetic peripheral neuropathies that is associated with a broad variety of clinical genetic features. Most CMT syndromes are characterized by a progressive muscle weakness and atrophy with a distally pronounced sensory dysfunction. Bone deformities as pes cavus or hammertoes are frequent. The severity of disability varies considerably between different subclasses. Physical examination, electrophysiological testing and family history are current methods to investigate a patient affected by CMT. We used these methods for clinical assessment of two cases. Whenever available molecular genetic testing establishes the certain diagnosis and defines the type of CMT.

Quantification of muscle strength and imbalance in neurogenic pes cavus, compared to health controls, using hand-held dynamometry.

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.

Botulinum toxin treatment of pes cavovarus in a child suffering from autosomal recessive axonal Charcot-Marie-Tooth neuropathy (AR-CMT2).

In a 12-year old girl suffering from autosomal recessive axonal Charcot-Marie-Tooth (CMT) neuropathy, pes cavovarus was treated with botulinum toxin injection in the tibialis posterior. The patient underwent a clinical evaluation, video analysis of spatiotemporal gait parameters and dynamic foot plantar pressure assessment before treatment and then two weeks, three months and six months thereafter. The video gait analysis revealed a decrease in varus during the swing phase of gait. The dynamic foot plantar pressure decreased by 50% in the excessive pressure at the side of the foot six months after the injection (maximal pressure=42.6N/cm2 before treatment and 18.9 N/cm2 after 6 month). Botulinum toxin injection appears to be an efficacious means of correcting pes cavovarus in CMT disease. A larger-scale clinical trial is now required to evaluate the putative longer-term preventive effect of this treatment on the pes cavus deformity.

Dynamic pedobarography (DPB) in operative management of cavovarus foot deformity.

Dynamic pedobarography (DPB) was performed in 21 patients, 9 male and 12 female with cavovarus foot deformity mostly of Charcot-Marie-Tooth origin. Age ranged from 14 to 52 years (mean 30 y). Twenty-six feet were examined pre- and postoperatively clinically, radiologically and by dynamic pedobarography with a follow-up time from 9 to 49 months (mean 22.5 mo). The EMED SF system was used for data collection during walking. Gait line, contact areas (CA), peak pressures (PP) and pressure time integral (PTI) were determined. According to the contact pattern the examined feet could be divided into three groups with antegrade, retrograde and inversion contact pattern. Data analysis showed postoperatively considerable increase in CA and decrease in PP and PTI. Clinical results such as plantar callosities and "roll over avoidance gait" did not always correlate with pedobarographic data. DPB adds a dynamic component in the diagnosis and management of cavovarus feet but certain limitations exist.

Treatment of the cavus foot. Deformity in the pediatric patient with Charcot-Marie-Tooth.

The orthopedic management of foot and ankle problems associated with Charcot-Marie-Tooth disease is becoming better understood but is still evolving. It is now known that Charcot-Marie-Tooth disease should be considered a spectrum of neurologic disorders with variable inheritance patterns, clinical course, and severity of deformities. Over half of the patients with Charcot-Marie-Tooth disease develop foot and ankle problems of which the cavovarus deformity is by far the commonest. Other clinical problems include weakness, parathesias, pain, and an unsteady gait. The cavovarus deformity seems to develop from a relative imbalance between the peroneus longus and tibialis anterior muscles and from an imbalance between the tibialis posterior and peroneus brevis muscles. Treatment of the cavovarus foot deformities should be individualized for each patient after careful preoperative evaluation. Surgery using a variety of soft tissue procedures and osteotomies seems to be the treatment of choice for the progressive cavovarus deformity in younger patients. For a patient who has severely rigid deformities a triple arthrodesis may be the only option but is considered by most to be a salvage procedure. It always should be kept in mind that Charcot-Marie-Tooth disease is a progressive neurologic disorder and the deformities can progress despite surgical intervention. Even though the results of treatment in this disease are difficult to evaluate because of the wide [figure: see text] spectrum of disease, it seems reasonable to believe that early surgical intervention in the flexible cavus foot can restore normal foot posture and help prevent or delay the need for more extensive bony procedures.

The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease.

The foot deformities in CMT follow certain general patterns; however, like the underlying motor failures that cause them, the deformities present in each patient are unique, and care must be individualized. There is no simple algorithm that can be applied to all patients. The hindfoot, forefoot, and toe deformities in CMT all ultimately are interconnected. As a general rule, it makes sense to address the plantar fascia, then proceed from the hindfoot to the forefoot in analyzing the deformities and in surgery. Releasing the plantar fascia may alter the amount of bony correction required in any concomitant hindfoot procedure. Likewise, only after the heel is realigned can any residual forefoot valgus be assessed, and a hindfoot procedure may alter the resting tension of the digital flexors and extensors. Finally, if a patient has purely dynamic clawtoes preoperatively, the toes may appear perfectly normal in the operating room with the ankle plantar flexed. Tightness of the flexor digitorum longus should be elicited by bringing the ankle up to neutral as a final check. The variety of foot deformities in CMT present a unique challenge to the orthopedic foot and ankle surgeon. It is vital for the patient and physician to remember that CMT is an inexorably progressive disease, and an initially good result can deteriorate with changing motor function. With meticulous attention to the neurologic examination and the balance of supple and fixed deformities in the foot, very satisfying outcomes usually can be obtained.

Charcot-Marie-Tooth disease: genetic and clinical spectrum in a Spanish clinical series.

OBJECTIVES: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area. METHODS: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups. RESULTS: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically. CONCLUSIONS: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region.

Cavus foot, from neonates to adolescents.

Pes cavus, defined as a high arch in the sagittal plane, occurs in various clinical situations. A cavus foot may be a variant of normal, a simple morphological characteristic, seen in healthy individuals. Alternatively, cavus may occur as a component of a foot deformity. When it is the main abnormality, direct pes cavus should be distinguished from pes cavovarus. In direct pes cavus, the deformity occurs only in the sagittal plane (in the forefoot, hindfoot, or both). Direct pes cavus may be related to a variety of causes, although neurological diseases predominate in posterior pes cavus. Pes cavovarus is a three-dimensional deformity characterized by rotation of the calcaneopedal unit (the foot minus the talus). This deformity is caused by palsy of the intrinsic foot muscles, usually related to Charcot-Marie-Tooth disease. The risk of progression during childhood can be eliminated by appropriate conservative treatment (orthosis to realign the foot). Extra-articular surgery is indicated when the response to orthotic treatment is inadequate. Muscle transfers have not been proven effective. Triple arthrodesis (talocalcanear, talonavicular, and calcaneocuboid) accelerates the mid-term development of osteoarthritis in the adjacent joints and should be avoided.

Evolution of foot and ankle manifestations in children with CMT1A.

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.

The role of the dynamic pedobarograph in assessing treatment of cavovarus feet in children with Charcot-Marie-Tooth disease.

We used the dynamic pedobarographs to study pressure distribution patterns in the foot after surgical correction of cavovarus feet. We also assessed the influence of ankle power generation on pressure distribution in these feet. Nine children (14 feet) diagnosed with Charcot-Marie-Tooth disease who had undergone operative treatment with a combination of osteotomies and muscle transfers were the subjects of this study. Preoperative and postoperative pedobarographic measurements recorded included pressure over the medial forefoot, lateral forefoot, medial midfoot (MMF), lateral midfoot (LMF), and heel segments. In 6 patients (9 feet) who had a complete gait analysis, the power generation of the ankle was also obtained both preoperatively and postoperatively. Lateral radiographic measurements included the (1) talus-first metatarsal angle, (2) calcaneus-first metatarsal angle, and (3) calcaneal pitch. The radiographs showed significant improvements in all 3 angles. Increased LMF and decreased forefoot pressures were seen on preoperative pedobarographic measures. Postoperatively, improvement in pressure at the LMF was seen. When postoperative measurements were compared with the normal values, only the LMF was similar; the other 4 segments showed decreased forefoot and MMF pressures and increased heel pressures (P = 0.000 for the lateral forefoot and MMF; 0.040 for the heel and medial forefoot). The heel pressures displayed an inverse relationship to ankle power generation. The amount of correction achieved radiographically did not correlate with pedobarographic measurements. The increased heel pressure that was noted was not addressed by treatment. Normalization of pressure patterns should be the goal in treating children with symptomatic cavovarus feet. Although the foot deformity is corrected completely in neuromuscular disorders, pressure distribution was not normalized, and therefore, symptoms might persist. Both patients and parents should be informed about this possible problem before surgical intervention.

Prevalence of Charcot-Marie-Tooth disease in patients who have bilateral cavovarus feet.

It is not uncommon to see a patient with bilateral cavovarus feet in the outpatient setting. A large percentage of these patients are subsequently diagnosed with an associated condition, such as Charcot-Marie-Tooth disease. The purpose of the present report was to determine the prevalence of Charcot-Marie-Tooth disease in children who have bilateral cavovarus feet. A chart review of children with bilateral cavovarus feet was done. Patients were excluded if they had an existing medical problem known to be associated with bilateral cavovarus feet. Charcot-Marie-Tooth disease was diagnosed after a clinical assessment by an orthopaedic surgeon and a neurologist. The diagnosis was confirmed by either standard nerve conduction velocity studies and/or the CMT DNA Duplication Detection Test (Athena Diagnostics Inc, Worchester, MA). A positive family history was noted only if the diagnosis had been confirmed by a nerve conduction velocity study and/or CMT DNA Duplication Detection Test. One hundred forty-eight patients met the study criteria. The probability of a patient with bilateral cavovarus feet being diagnosed with Charcot-Marie-Tooth disease, regardless of family history, was 78% (116 patients). A family history of Charcot-Marie-Tooth disease increased the probability to 91%. It is recommended that all patients with bilateral cavovarus feet, especially with a known family history, be investigated for Charcot-Marie-Tooth disease.

Assessment and management of pes cavus in Charcot-Marie-tooth disease.

The sequential approach to evaluating the cavus foot is integrated with a description and assessment of the various treatment options. Decision making in the treatment of these cases is complicated by the progressive neurologic condition that underlies many of these deformities. An effort is made to recommend the most appropriate surgical intervention based on the nature of the deformity and its rigidity. Although these principles apply to all cavus feet, the deformity in Charcot-Marie-Tooth disease is the most difficult to treat and the most prone to recurrence because of the progressive nature of the muscular imbalance causing it.

A long-term study of triple arthrodesis for correction of pes cavovarus in Charcot-Marie-Tooth disease.

Twenty-two patients with severe pes cavovarus secondary to Charcot-Marie-Tooth disease who underwent triple arthrodesis were retrospectively reviewed with an average follow-up period of 12 years, 4 months. Although only 32% of the patients had good objective results, 88% had good or excellent function and 86% were satisfied with their result. Radiographic follow-up averaged 10 years, 4 months. Talonavicular pseudarthroses were present in 15% of the feet and were symptomatic in all but one foot. Twenty-four percent of the ankles and 62% of the feet demonstrated radiographic evidence of degenerative joint disease.

Investigation of muscle imbalance in the leg in symptomatic forefoot pes cavus: a multidisciplinary study.

The cross-sectional areas of the peroneal and anterior muscle compartments at the same level in the upper leg were measured using magnetic resonance imaging in 41 cases of forefoot pes cavus. The pes cavus group included idiopathic cases and pes cavus associated with Charcot-Marie-Tooth disease, Friedreich's ataxia, cerebral palsy, status postpoliomyelitis, nerve trauma, and spinal cord tethering. Thirty-nine of these cases were symptomatic. The results were compared with studies of 11 normal controls. It was found that in the majority of cases of forefoot cavus, the peroneal compartment was enlarged relative to the anterior compartment when compared with the normal controls. Biopsies of the tibialis anterior and peroneus longus muscles in 18 patients with forefoot pes cavus showed that any relative expansion of the peroneus longus was not due to pseudohypertrophy. Overaction of the peroneus longus in comparison to its antagonist the tibialis anterior is proposed as an important factor in the pathogenesis of the majority of symptomatic cases of forefoot pes cavus.