Gita Ramdharry

Charcot–Marie–Tooth disease: frequency of genetic subtypes and guidelines for genetic testing

Background Charcot–Marie–Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice. Methods The genes known to cause CMT were sequenced in 1607 patients with CMT (425 patients attending an inherited neuropathy clinic and 1182 patients whose DNA was sent to the authors for genetic testing) to determine the proportion of different subtypes in a UK population. Results A molecular diagnosis was achieved in 62.6% of patients with CMT attending the inherited neuropathy clinic; in 80.4% of patients with CMT1 (demyelinating CMT) and in 25.2% of those with CMT2 (axonal CMT). Mutations or rearrangements in PMP22, GJB1, MPZ and MFN2 accounted for over 90% of the molecular diagnoses while mutations in all other genes tested were rare. Conclusion Four commonly available genes account for over 90% of all CMT molecular diagnoses; a diagnostic algorithm is proposed based on these results for use in clinical practice. Any patient with CMT without a mutation in these four genes or with an unusual phenotype should be considered for referral for an expert opinion to maximise the chance of reaching a molecular diagnosis.

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

De-stabilizing and training effects of foot orthoses in multiple sclerosis

This study evaluates the effects of dynamic foot orthoses (DFO) on walking and balance performance in people with multiple sclerosis (MS). Sixteen ambulant subjects with MS and ten age-matched healthy control subjects were studied on initial receipt of foot orthoses and after four weeks of daily wear. Walking speed, MS Walking Scale-12 (MSWS-12) and standing balance were assessed with and without orthoses at both these times. During standing, stance width and vision were varied, and performance was quantified using the velocity of the centre of pressure (COP), body sway velocity and the mean COP position relative to the shoe. People with MS walked slower (p<0.001) and showed increased sway when standing (p<0.001). At the first assessment, the foot orthoses caused an increase in sway and a medial and posterior shift of the COP position. At repeat measurement, the DFOs continued to increase sway compared to a shoe only condition. However, MS subjects reported an improvement in the MSWS-12 (p<0.05) and, compared to the initial session, showed decreased sway when eyes were closed both with and without DFOs. Dynamic foot orthoses may increase sway and change COP position by altering foot alignment and/or plantar afferent stimulation. Improvement in body sway over time may be an overall training effect of the DFOs, as MS subjects adapt to the initial de-stabilization.

Hip flexor fatigue limits walking in Charcot–Marie–Tooth disease

Charcot–Marie–Tooth (CMT) disease results in distal lower limb weakness that affects walking. In this study we assess the role of the hip flexors in compensating for distal weakness while walking and the effects of prolonged walking on these putative compensatory strategies. Eighteen subjects with CMT disease were compared with 14 matched controls while they walked on a treadmill to a predetermined point of perceived effort. A significant reduction was observed in peak hip flexor velocity during walking and hip flexor maximal voluntary contraction. In a second session following selective fatigue of the hip flexors, hip flexor velocity decreased immediately on walking, and walking duration was greatly reduced. This study suggests that hip flexors compensate for distal weakness and that fatigue in the hip flexors can limit walking duration. Treatments directed toward improving proximal muscle strength may therefore help to delay onset of hip flexor fatigue and thus prolong walking duration. Muscle Nerve, 2009

Foot drop splints improve proximal as well as distal leg control during gait in Charcot-Marie-Tooth Disease

Introduction: During walking, people with Charcot‐Marie‐Tooth (CMT) disease may compensate for distal weakness by using proximal muscles. We investigated the effect of different AFOs on distal leg control and proximal compensatory actions. Methods: Fourteen people with CMT were tested while wearing 3 types of ankle‐foot orthosis (AFO) bilaterally compared with shoes alone. Walking was assessed using three‐dimensional gait analysis. Stiffness of the splints was measured by applying controlled 5‐degree ankle stretches using a motor. Results: The results showed that each AFO significantly stiffened the ankle and increased ankle dorsiflexion at foot clearance compared with shoes alone. At push off, peak ankle power generation was reduced, but only with 1 type of AFO. A significant decrease in hip flexion amplitude during the swing phase was observed with all 3 AFOs. Conclusions: These results indicate that AFOs reduce foot drop and remove the need for some proximal compensatory action. Muscle Nerve 46: 512–519, 2012

Muscle paresis and passive stiffness: Key determinants in limiting function in Hereditary and Sporadic Spastic Paraparesis

Background People with Hereditary and Sporadic Spastic Parapresis (SP) walk with a stiff legged gait characterised by a lack of knee flexion. Objective We investigated the relationship between lower limb strength and stiffness and knee flexion during swing phase while walking in 20 people with SP and 18 matched controls. Methods Maximal isometric strength was measured using a dynamometer. Passive stiffness and spasticity was assessed during motor-driven slow (5°/s) and fast (60°/s) stretches at the ankle and knee while the subject was relaxed or preactivating the muscle. Walking was assessed using 3D motion analysis. Results Isometric muscle strength was decreased in people with SP with over a 50% reduction in strength being found in the ankle dorsiflexors. Passive stiffness, assessed during slow stretches, was 35% higher in the plantarflexors in people with SP (P < 0.05). Faster stretches induced large stretch evoked muscle activity and over a 110% increase in stiffness at the ankle and knee in people with SP reflecting the presence of spasticity (P < 0.05). However, stretch reflex size and stiffness was similar between the groups following identical stretches of the pre-activated muscle (P > 0.05). Lower knee flexion during swing phase was associated with reduced knee flexion velocity at the end of stance phase which in turn was associated with reduced plantarflexor strength and increased passive stiffness in the knee extensors. Conclusions The relative importance of muscle paresis and passive stiffness in limiting walking in SP suggests that these impairments should be the target of future therapies.

X inactivation in females with X-linked Charcot-Marie-Tooth disease

X-linked Charcot–Marie–Tooth disease (CMT1X) is the second most common inherited neuropathy, caused by mutations in gap junction beta-1 (GJB1). Males have a uniformly moderately severe phenotype while females have a variable phenotype, suggested to be due to X inactivation. We aimed to assess X inactivation pattern in females with CMT1X and correlate this with phenotype using the CMT examination score to determine whether the X inactivation pattern accounted for the variable phenotype in females with CMT1X. We determined X inactivation pattern in 67 females with CMT1X and 24 controls using the androgen receptor assay. We were able to determine which X chromosome carried the GJB1 mutation in 30 females. There was no difference in X inactivation pattern between patients and controls. In addition, there was no correlation between X inactivation pattern in blood and phenotype. A possible explanation for these findings is that the X inactivation pattern in Schwann cells rather than in blood may explain the variable phenotype in females with CMT1X.

Comparing Gait Performance of People with Charcot-Marie-Tooth Disease Who Do and Do Not Wear Ankle Foot Orthoses

BACKGROUND AND PURPOSE Ankle foot orthoses (AFOs) are commonly prescribed for people with Charcot-Marie-Tooth (CMT) disease. Scant evidence exists to guide the type and timing of orthotic prescription. This study explores the latter issue by investigating the differences in presentation and gait function of people with CMT disease who wore AFOs for daily mobility (n = 11) and a group who did not (n = 21). The aim was to see if there was a difference in the characteristics in people who regularly wear AFOs. METHODS Primary measures of gait function were a 10-m timed walk (comfortable and maximum speed) and a 6-minute walk test. Means of the variables were compared using independent t-tests. Secondary measures included disease severity, lower limb muscle strength, sensory impairment, walking effort, fatigue severity and perceived walking ability. RESULTS AFO wearers walked slower with higher effort. They also had greater disease severity, weaker leg muscles and perceived greater walking difficulty. Subjects not wearing AFOs showed significant relationships between gait variables and muscle strength, whereas AFO wearers showed significant relationships between gait variables and perceived walking ability, fatigue severity and effort. CONCLUSIONS People who regularly wore AFOs were more severely affected, had a slower maximum walking speed, higher energy cost of walking and worse perceived walking ability. Walking ability in this group was related to fatigue, perceived exertion during walking and perceived walking ability. Gait function of people not using AFOs was determined by lower limb muscle function. People prescribed AFOs, those who do not wear them and those not prescribed AFOs were similar in presentation, suggesting that people choose to wear orthoses when their condition becomes sufficiently severe.

Frequency and circumstances of falls in people with Inclusion Body Myositis: a questionnaire survey to explore falls management and physiotherapy provision

OBJECTIVES To survey the incidence and circumstances of falls for people with inclusion body myositis (IBM) in the UK, and to investigate the provision of physiotherapy and falls management. DESIGN Postal questionnaire survey. SETTING Participants completed questionnaires at home. PARTICIPANTS Ninety-four people diagnosed with IBM were screened against the inclusion criteria. Seventy-two potential participants were sent a questionnaire, and 62 were completed and returned. Invited participants were sent an adapted Falls Event Questionnaire pertaining to falls, perceived causes of falls and the provision of physiotherapy. Questionnaires were returned anonymously. MAIN OUTCOME MEASURES The proportions of respondents who reported a fall or a near fall, along with the frequencies of falls and near falls were calculated. Descriptive data of falls were collected pertaining to location and cause. Data analysis was performed to investigate provision of physiotherapy services. RESULTS The response rate was 86% [62/72, mean (standard deviation) age 68 (8) years]. Falls were reported by 98% (61/62) of respondents, with 60% (37/62) falling frequently. In this study, age was not found to be an indicator of falls risk or frequency. Twenty-one percent (13/62) of respondents had not seen a physiotherapist in relation to their IBM symptoms, and of those that had, 31% (15/49) had not seen a physiotherapist until more than 12 months after IBM was diagnosed. Only 18% (11/61) of fallers reported that they had received falls management input. CONCLUSIONS Falls are a common occurrence for people with IBM, independent of age and years since symptoms first presented, and are poorly addressed by appropriate physiotherapy management. National falls guidelines are not being followed, and referral rates to physiotherapy need to improve.

A pilot study of proximal strength training in Charcot Marie Tooth disease.

Gait analysis of people with Charcot‐Marie‐Tooth (CMT) disease revealed proximal adaptive gait strategies to compensate for foot drop. We previously demonstrated that hip flexor muscle fatigue can limit walking endurance. This pilot study used a single‐blinded cross over design to investigate the effect of a 16‐week home‐based programme of resistance training on hip flexor muscle strength. Measures of walking endurance, gait speed, exertion, fatigue, and general activity were also recorded. The exercise protocol was based on American College of Sports Medicine recommendations. A mixed effects model was used for analysis. Twenty‐six people finished the study, with average reported exercise participation of 93%. No negative effects of exercise were observed. Significant increase in hip flexor muscle strength was observed on the left, but not the right. No changes were observed in walking speed and endurance measures. This pilot study of home‐based resistance training showed a modest improvement in hip strength but only on one side. The lack of a more significant improvement and no improvement in walking measures suggests that this training protocol may not be optimal for people with CMT and that patients may need to stratified differently for training studies in CMT.