Search

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. Muscle Nerve 39: 158-166, 2009 [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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 lessor extent by leg cramps, suggesting clinical trials targeting weakness and cramps may improve HRQoL in patients with CMT. [Copyright &y& Elsevier]

Abstract: Introduction: The limitations of clinical methods for appraising foot posture are well documented. A new measure, the Foot Posture Index is proposed, and its development and validation described. Methods: A four-phase development process was used: (i) to derive a series of candidate measures, (ii) to define an appropriate scoring system, (iii) to evaluate the validity of components and modify the instrument as appropriate, and (iv) to investigate the predictive validity of the finalised instrument relative to static and dynamic kinematic models. Methods included initial concurrent validation using Rose’s Valgus Index, determination of inter-item reliability, factor analysis, and benchmarking against three dimensional kinematic models derived from electromagnetic motion tracking of the lower limb. Results: Thirty-six candidate components were reduced to six in the final instrument. The draft version of the instrument predicted 59% of the variance in concurrent Valgus Index scores and demonstrated good inter item reliability (Cronbach’s α =0.83). The relevant variables from the motion tracking lower limb model predicted 58–80% of the variance in the six components retained in the final instrument. The finalised instrument predicted 64% of the variance in static standing posture, and 41% of the variance in midstance posture during normal walking. Conclusion: The Foot Posture Index has been subjected to thorough evaluation in the course of its development and a final version is proposed comprising six component measures that performed satisfactorily during the validation process. The Foot Posture Index assessment is quick and simple to perform and allows a multiple segment, multiple plane evaluation that offers some advantages over existing clinical measures of foot posture. [Copyright &y& Elsevier]

Introduction Peripheral nerve involvement is common in mitochondrial disease but often unrecognised due to the prominent central nervous system features. Identification of the underlying neuropathy may assist syndrome classification, targeted genetic testing and rehabilitative interventions. Methods Clinical data and the results of nerve conduction studies were obtained retrospectively from the records of four tertiary children's hospital metabolic disease, neuromuscular or neurophysiology services. Nerve conductions studies were also performed prospectively on children attending a tertiary metabolic disease service. Results were classified and analysed according to the underlying genetic cause. Results Nerve conduction studies from 27 children with mitochondrial disease were included in the study (mitochondrial DNA (mtDNA) – 7, POLG – 7, SURF1 – 10, PDHc deficiency – 3). Four children with mtDNA mutations had a normal study while three had mild abnormalities in the form of an axonal sensorimotor neuropathy when not acutely unwell. One child with MELAS had a severe acute axonal motor neuropathy during an acute stroke-like episode that resolved over 12 months. Five children with POLG mutations and disease onset beyond infancy had a sensory ataxic neuropathy with an onset in the second decade of life, while the two infants with POLG mutations had a demyelinating neuropathy. Seven of the 10 children with SURF1 mutations had a demyelinating neuropathy. All three children with PDHc deficiency had an axonal sensorimotor neuropathy. Unlike CMT, the neuropathy associated with mitochondrial disease was not length-dependent. Conclusions This is the largest study to date of peripheral neuropathy in genetically- classified childhood mitochondrial disease. Characterising the underlying neuropathy may assist with the diagnosis of the mitochondrial syndrome and should be an integral part of the assessment of children with suspected mitochondrial disease. [ABSTRACT FROM AUTHOR]

Aim: The alpha-1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary children's hospital.Method: We reviewed retrospectively nine children with a proven CACNA1A mutation who presented to the Children's Hospital at Westmead between 2005-2015. The initial and subsequent clinical presentation, radiological features and molecular genetic profile of each child was reviewed.Results: Nine children presented to out institute over a 10 year period; six were female and three male. The median age of presentation was 1.2 years. Eye movement disorders were the presenting feature in eight children. Three of these children later presented with severe hemiplegic migraine episodes often requiring ICU care. Affected children also had developmental delay and developed classical hemiplegic migraine, episodic ataxia and seizures. Calcium channel blockers were used with some efficacy in preventing severe HM episodes.Interpretation: Eye movement disorders are an early manifestation of CACNA1A mutations in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling and appropriate emergency management. There is some early evidence that calcium channel blockers may be an effective prophylactic agent for the severe hemiplegic migraine episodes. [ABSTRACT FROM AUTHOR]

Objective: Brown-Vialetto-Van Laere (BVVL) syndrome is a progressive motor and sensory neuronopathy secondary to mutations in SLC52A2 encoding the riboflavin transporter type 2 (RFVT2). The phenotype is characterized by early childhood onset hearing loss and sensory ataxia followed by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure. To gain further insight into disease pathophysiology and response to riboflavin supplementation, the present study investigated whether axonal ion channel or membrane abnormalities were a feature of BVVL. Methods: Axonal excitability studies and clinical assessments were prospectively undertaken on six patients with BVVL secondary to riboflavin transporter deficiency type 2 (age range 10-21 years) at baseline and after 12 months of riboflavin (1000 mg daily) therapy. Results: At baseline, depolarizing and hyperpolarizing threshold electrotonus was 'fanned out' and superexcitability was increased, while the resting current-threshold gradient and refractoriness were significantly reduced in BVVL patients when compared to controls. Mathematical modeling suggested that functional alterations of myelin underlay these findings with an increase in myelin permeability. Riboflavin therapy resulted in partial normalization of the axonal excitability findings, paralleled by maintenance of muscle strength. Conclusions: The present study established that abnormalities in myelin permeability at the paranode was a feature of BVVL and were partially normalized with riboflavin therapy. [ABSTRACT FROM AUTHOR]

Abstract: Benign hereditary chorea caused by mutations in the NK2 homeobox 1 gene (NKX2-1), shares clinical features with ataxic and dyskinetic cerebral palsy (CP), resulting in the possibility of misdiagnosis. A father and his two children were considered to have ataxic CP until a possible diagnosis of benign familial chorea was made in the children in early teenage. The father's neurological condition had not been appreciated prior to examination of the affected son. Whole exome sequencing of blood derived DNA and bioinformatics analysis were performed. A 7 bp deletion in exon 1 of NKX2-1, resulting in a frame shift and creation of a premature termination codon, was identified in all affected individuals. Screening of 60 unrelated individuals with a diagnosis of dyskinetic or ataxic CP did not identify NKX2-1 mutations. BHC can be confused with ataxic and dyskinetic CP. Occasionally these children have a mutation in NKX2-1. [Copyright &y& Elsevier]

An abstract of the article "Correlates of calf cramp in children with Charcot-Marie-Tooth disease," by Fiona E Blyton, Monique M Ryan, Robert A Ouvrier, Joshua Burns is presented.

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. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Preschool-age children with neuromuscular disorders are often excluded from clinical trials due to the lack of reliable and objective strength measures. We evaluated the reliability of measuring foot and ankle muscle strength in 60 healthy children age 2-4 years. The strength of foot inversion and eversion, ankle plantarflexion, and dorsiflexion was measured using a hand-held dynamometer. Intrarater and interrater reliability of two assessors was determined for each muscle group using intraclass correlation coefficients (ICCs), 95% confidence intervals (CIs), and standard error of measurement (SEM). For all muscle groups intrarater (ICC2,2 = 0.85-0.94, 95% CI = 0.75-0.96, SEM = 1.5-4.7 N) and interrater (ICC2,1 = 0.88-0.96, 95% CI = 0.81-0.98, SEM = 1.2-4.6 N) reliability was high for all children. As expected, reliability was generally highest in 3- and 4-year-old children and lowest in 2-year-old children. Hand-held dynamometry can reliably measure foot and ankle strength in very young children and may help aid in diagnosis and in characterizing disease progression in disorders affecting the foot and ankle. Muscle Nerve, 2008 [ABSTRACT FROM AUTHOR]

Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T→C (p.L152P) in the Dutch family and c.398A→C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To describe the incidence and clinical features of children presenting to Australian child health specialists with conversion disorder.Method: Active, national surveillance of conversion disorder in children younger than 16 years of age during 2002 and 2003.Results: A total of 194 children were reported on. The average age was 11.8 years; 23% were younger than 10 years of age. Presentations were complex, with 55% presenting with multiple conversion symptoms. The most common presentations were disturbance of voluntary motor function (64%), sensory symptoms (24%), pseudoseizure (23%), and respiratory problems (14%). Hospital admission was required for 70%, with an average stay of 10.2 days. Antecedent stressors were also reported in 62% and a history of mental health concerns in 42%, with 14% of children taking psychotropic medications for comorbid anxiety or depression. The incidence of conversion disorder in Australian specialist child health practice is estimated to be between 2.3 and 4.2/100,000.Conclusions: Conversion disorder is associated with a significant burden for the child, family, and the health system. This study emphasizes the comorbidity with anxiety, depression, and symptoms of pain and fatigue. It also highlights the potential impact of "commonplace" stressors such as family conflict and children's loss of attachment figures. [ABSTRACT FROM AUTHOR]

Abstract: Background. Clinical management of patients with painful pes cavus is challenging because the mechanism of foot pain is poorly understood. The purpose of this study was to explore the influence of various pes cavus aetiologies on foot pain and plantar pressure characteristics, and to identify the relationship between foot pain and plantar pressure. Methods. Seventy subjects were recruited for this study. They included 30 subjects with pes cavus of unknown aetiology (idiopathic), 10 subjects with pes cavus of neurological aetiology (neurogenic) and 30 subjects with a normal foot type. The presence and location of foot pain was recorded and barefoot plantar pressures were measured using the EMED-SF platform for the whole foot, rearfoot, midfoot and forefoot regions. Findings. Subjects with pes cavus of either idiopathic or neurogenic aetiology reported a higher proportion of foot pain (60%) compared to subjects with a normal foot type (23%) (P =0.009). Pressure–time integrals under the whole foot, rearfoot and forefoot regions in pes cavus, of both idiopathic and neurogenic origin, were higher than in the normal foot type (P <0.01). Pressure–time integrals in subjects reporting foot pain were higher than for pain free subjects (P <0.001). There was a significant correlation between pressure–time integral and foot pain (r =0.49, P <0.001). Interpretation. Foot pain is a common finding among individuals with pes cavus. Regardless of aetiology, pes cavus is characterized by abnormally high pressure–time integrals which are significantly related to foot pain. An understanding of the relationship between pes cavus pressure patterns and foot pain will improve the clinical management of these patients. [Copyright &y& Elsevier]

Examines a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Occurrence of severe muscle weakness; Linkage of the disorder to chromosome Xp22.3; Localization of the responsible gene to chromosome Xp22.3.

Abstract: 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. [Copyright &y& Elsevier]

This review is an overview of systemic conditions that can be associated with peripheral nervous system dysfunction. Children may present with neuropathic symptoms for which, unless considered, a causative systemic condition may not be recognized. Similarly, some systemic conditions may be complicated by comorbid peripheral neuropathies, surveillance for which is indicated. The systemic conditions addressed in this review are critical illness polyneuropathy, chronic renal failure, endocrine disorders such as insulin-dependent diabetes mellitus and multiple endocrine neoplasia type 2b, vitamin deficiency states, malignancies and reticuloses, sickle cell disease, neurofibromatosis, connective tissue disorders, bowel dysmotility and enteropathy, and sarcoidosis. In some disorders presymptomatic screening should be undertaken, while in others there is no benefit from early detection of neuropathy. In children with idiopathic peripheral neuropathies, systemic disorders such as celiac disease should be actively excluded. While management is predominantly focused on symptomatic care through pain control and rehabilitation, some neuropathies improve with effective control of the underlying etiology and in a small proportion a more targeted approach is possible. In conclusion, peripheral neuropathies can be associated with a diverse range of medical conditions and unless actively considered may not be recognized and inadequately managed., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Inflammatory disorders of the central nervous system have generally been separated into infectious or immune-mediated aetiologies. However, there are emerging examples of confirmed infectious viral infection of the brain followed by secondary inflammation or autoimmunity that is amenable to immune suppressive therapies., Methods: We report four children with confirmed enterovirus encephalitis (CSF enterovirus PCR positivity), who had MRI evidence of inflammatory demyelination compatible with ADEM., Results: Two patients had a monophasic course, whereas two had a biphasic course. Serum myelin oligodendrocyte glycoprotein antibodies were negative in two tested patients, although all patients had mirrored CSF and serum oligoclonal bands. All four patients only improved with introduction of immune therapy (corticosteroids in three, corticosteroid and intravenous immunoglobulin in one)., Conclusion: These cases provide a further example of the overlap between CNS infection and immune mediated CNS disease. Randomised controlled trials investigating immune therapies in encephalitis are required., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

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.

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.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of uncommon, inherited disorders affecting the neuromuscular junction. The defects interfere with presynaptic, synaptic, or postsynaptic function and compromise neuromuscular transmission. Most patients with CMS have similar clinical features regardless of the underlying defect, but attention to clinical and electrodiagnostic parameters can narrow the diagnostic spectrum. Recent advances in our understanding of the cellular mechanisms underlying specific syndromes allow DNA testing for some forms of CMS. Diagnosis of CMS enables a rationale for management to be developed. Two cases of genetically determined CMS as well as an undiagnosed infant are presented to highlight the clinical and electrophysiological difficulties associated with the diagnosis and management of such syndromes.