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We describe the case of a 5-month-old girl who presented to the emergency department with left-sided periorbital edema and erythema. During the assessment, she was observed to suffer repeated hyper-acute episodes of screaming associated with left-sided hemifacial flushing, lacrimation and rhinorrhea. This child was diagnosed with probable short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), one of the trigeminal autonomic cephalalgias. We believe that this is the youngest probable case of SUNCT for which there is photographic and video evidence. Int J Clin Pediatr. 2021;10(2-3):49-52 doi: https://doi.org/10.14740/ijcp433

Background: Hip dysplasia is a lack of femoral head coverage and disruption of hip and acetabular alignment and congruency, with severity ranging from mild subluxation in nascent at-risk hips to complete dislocation. Presentation of hip dysplasia in neuromuscular conditions can be sub-clinical or associated with a limp with or without hip pain, abductor and flexor weakness and reduced hip range of motion. Untreated hip dysplasia leads to early onset osteoarthritis requiring hip arthroplasty in early adulthood. Hip dysplasia occurs in 6–20% of children with Charcot-Marie-Tooth disease, however little is known about the reliability and sensitivity of detection on plain film pelvic radiographs. Methods: 14 common measures of hip dysplasia on anteroposterior pelvis radiographs were independently assessed by 2 orthopaedic specialists in 30 ambulant children with Charcot-Marie-Tooth disease. Hip health was also categorised based on clinical impression to assess the sensitivity of radiographic measures to identify hip dysplasia status. Results: 8 measures (acetabular index, head width, lateral centre-edge angle, lateral uncoverage, medial joint width, migration percentage, neck shaft angle, triradiate status) exhibited ‘excellent’ reliability between clinical evaluators. 5 of the 30 patients (17%) were identified as having nascent hip dysplasia. Reliable radiographic measures that significantly distinguished between nascent hip dysplasia and healthy hips were acetabular index, lateral centre edge angle, medial joint width and migration percentage. Conclusions: We have identified a subset of reliable and sensitive radiographic hip measures in children with Charcot-Marie-Tooth disease to prioritise during hip screening to mitigate the deleterious effects of hip dysplasia, pain and disability in adulthood.

ObjectiveTo describe the clinical, genetic, and disability profile of pediatric distal hereditary motor neuropathy (dHMN) and to determine the utility of an outcome measure validated for children with Charcot-Marie-Tooth disease (CMT) in assessing disability in this cohort.MethodsWe reviewed the clinical, neurophysiologic, and disability data on individuals with dHMN, evaluated before the age of 20 years, at 2 tertiary neuromuscular clinics in Australia and Spain. Disability was assessed annually with the CMT Pediatric Scale (CMTPedS) in a subset of individuals.ResultsTwenty-two children (13 female) from 19 families were included. Fourteen individuals were symptomatic in the first year of life. Intellectual disability was present in 6 individuals; upper motor neuron signs were seen in 8. Pathogenic variants were found in 9 families, more frequently inBICD2(BICD2-4,DYNC1H1-2,MFN2-2,GARS-1). A novel pathogenic variant in theGARSgene was detected and characterized phenotypically. Disability was moderate on the CMTPedS (mean [SD] 18.2 [6.3], n = 16), with balance and long jump being the most affected and sensation items and grip strength the least affected. Over 1 year, the CMTPedS total score deteriorated, on average 1.5 points (SD 3.7) or 9% (n = 12), with significant variability in the rate of progression within the cohort.ConclusionsThe genetic profile of pediatric dHMN is different from that identified in adult cohorts. This study has identified distinct functional limitations for the CMTPedS in children and adolescents with dHMN.

usc Refereed/Peer-reviewed Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.

Background and ObjectivesThis study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT).MethodsWe conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI 2), underweight (BMI ≥17–2), healthy weight (BMI ≥18.5–2), overweight (BMI ≥25–2), and obese (BMI ≥30 kg/m2). Scores on the 0 to 44–point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI.ResultsThere was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) (p< 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) (p< 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled (p< 0.001), as was being obese (p= 0.015).DiscussionThe proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.

The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2‐year natural history data from 187 children aged 3–20 years with a range of CMT genetic subtypes. Subsets based on age (3–8 years), disability level (CMTPedS score 0–14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.

Charcot-Marie-Tooth disease (CMT) causes disabling cavovarus foot deformity. Orthopaedic surgery is performed in severe cases; however few studies have investigated whether surgery improves health outcomes during childhood. This study investigated the impact of cavovarus surgery on validated physical, functional, parent/self-reported and biomechanical measures in 21 consecutive patients (mean age at surgery 12.5 years, SD 2.7) evaluated before and after surgery (mean duration 15.7 months, SD 5.9), and compared to natural history data from 206 children with CMT. Measures from the CMT Pediatric Scale evaluated foot alignment (Foot Posture Index), ankle flexibility (lunge test), strength (foot dorsiflexion/plantarflexion by hand-held dynamometry), function (balance, long jump, 6-minute walk test) and self-reported symptoms. Quality of life (Child Health Questionnaire) and gait (pressure loading) were also assessed. Foot Posture Index and lunge improved with surgery by 6.0 points (SD 3.2) and 6.1° (SD 7.3) respectively (p 0.01), and differed to the natural course of the disease (p 0.005). Self-reported daily trips/falls reduced from 60% to 13% (p = 0.016). Pressure improved beneath the rearfoot and midfoot (p = 0.043). Surgery had no effect on strength, function or quality of life, which generally mirrored the natural course. Cavovarus surgery improved foot alignment, ankle flexibility and self-reported trips/falls in children with CMT.

INTRODUCTION: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents. METHODS: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system. RESULTS: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score. DISCUSSION: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019.

ObjectiveTo determine rates of psychiatric comorbidity in a clinical sample of childhood movement disorders (MDs).DesignCohort study.SettingTertiary children’s hospital MD clinics in Sydney, Australia and London, UK.PatientsCases were children with tic MDs (n=158) and non-tic MDs (n=102), including 66 children with dystonia. Comparison was made with emergency department controls (n=100), neurology controls with peripheral neuropathy or epilepsy (n=37), and community controls (n=10 438).InterventionsOn-line development and well-being assessment which was additionally clinically rated by experienced child psychiatrists.Main outcome measuresDiagnostic schedule and manual of mental disorders-5 criteria for psychiatric diagnoses.ResultsPsychiatric comorbidity in the non-tic MD cohort (39.2%) was comparable to the tic cohort (41.8%) (not significant). Psychiatric comorbidity in the non-tic MD cohort was greater than the emergency control group (18%, pConclusionsPsychiatric comorbidity is common in non-tic MDs such as dystonia. These psychiatric comorbidities appear to be under-recognised and undertreated.

Brown-Vialetto-van Laere syndrome is characterized by a progressive sensorimotor neuropathy, optic atrophy, hearing loss, bulbar dysfunction, and respiratory insufficiency. Mutations in SLC52A2 and SLC52A3, encoding riboflavin transporters RFVT2 and RFVT3, respectively, are the genetic basis of this disorder, often referred to as riboflavin transporter deficiency types 2 and 3, respectively. We present cases of both types of riboflavin transporter deficiency, highlighting the distinguishing clinical features of a rapidly progressive motor or sensorimotor axonal neuropathy, optic atrophy, sensorineural hearing loss, and bulbar dysfunction. One child presented with isolated central apnea and hypoventilation, not previously described in genetically confirmed Brown-Vialetto-van Laere, later complicated by diaphragmatic paralysis secondary to phrenic nerve palsy. Magnetic resonance imaging showed T2 hyperintensity in the dorsal spinal cord in 2 children, as well as previously unreported cervical nerve root enlargement and cauda equina ventral nerve root enhancement in 1 child. Novel homozygous mutations were identified in each gene-a NM_024531.4(SLC52A2):c.505C > T, NP_078807.1(SLC52A2):p.(Arg169Cys) variant in SLC52A2 and NM_033409.3(SLC52A3):c.1316G > A, NP_212134.3(SLC52A3):p.(Gly439Asp) variant in SLC52A3. Both treated children showed improvement on high-dose riboflavin supplementation, highlighting the importance of early recognition of this treatable clinical entity.

A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth (CMT) disease is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT-specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited "good" face, discriminant, convergent and concurrent validity, and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine-motor skills. Scoring of items ranged from 2- to 7-point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions.

Objective To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. Methods Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. Results On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p

Item does not contain fulltext Gait abnormalities reported in childhood Charcot-Marie-Tooth disease (CMT) include foot-drop, reduced ankle power at push-off and increased knee and hip flexion for swing clearance ('steppage-gait'). The purpose of this study was to describe the gait patterns of 60 children aged 6-17 years with CMT (CMTall) and distinguish differences based on functional weakness using the CMT Pediatric Scale (CMTPedS). Data were captured using Vicon Nexus system and compared to 50 healthy norms. Data were subdivided into three groups denoting increasing severity of dorsiflexion and plantarflexion weakness from the CMTPedS: no difficulty heel or toe walking (CMTND), difficulty heel walking (CMTDH), difficulty toe and heel walking (CMTDTH). Compared to healthy norms, CMTall demonstrated significantly worse gait profile score, reduced ankle dorsiflexion during swing (foot-drop), reduced ankle dorsiflexor moment in loading response and reduced external thigh-foot angle. Contrary to previous studies there were no signs of reduced ankle power or compensation through 'steppage gait' in this mild-moderately affected population. Instead, CMTall demonstrated reduced internal hip rotation and reduced hip abductor moment. When data were sub-grouped and compared to healthy norms, three different gait patterns at the ankle emerged: CMTND had a near-normal gait pattern, CMTDH presented with foot-drop, and CMTDTH had increased peak dorsiflexion and reduced ankle power generation. Several distinct and abnormal gait patterns were identified in children with CMT, with increasing gait abnormalities in more functionally severe cases. Classifying gait patterns based on disease severity might be a valuable tool in clinical decision making, assessing disease progression and phenotype-genotype correlation studies. 01 juli 2017

ObjectiveTo quantify the economic and health-related quality of life (HRQoL) burden incurred by households with a child affected by spinal muscular atrophy (SMA).MethodsHospital records, insurance claims, and detailed resource use questionnaires completed by caregivers were used to capture the direct and indirect costs to households of 40 children affected by SMA I, II, and III in Australia between 2016 and 2017. Prevalence costing methods were used and reported in 2017 US dollar (USD) purchasing power parity (PPP). The HRQoL for patients and primary caregivers was quantified with the youth version of the EQ-5D and CareQoL multiattribute utility instruments and Australian utility weights.ResultsThe average total annual cost of SMA per household was $143,705 USD PPP for all SMA types (SMA I $229,346, SMA II $150,909, SMA III $94,948). Direct costs accounted for 56% of total costs. The average total indirect health care costs for all SMA types were $63,145 per annum and were highest in families affected by SMA II. Loss of income and unpaid informal care made up 24.2% and 19.8% respectively, of annual SMA costs. Three of 4 (78%) caregivers stated that they experienced financial problems because of care tasks. The loss in HRQoL of children affected by SMA and caregivers was substantial, with average caregiver and patient scores of 0.708 and 0.115, respectively (reference range 0 = death and 1 = full health).ConclusionOur results demonstrate the substantial and far-ranging economic and quality of life burden on households and society of SMA and are essential to fully understanding the health benefits and cost-effectiveness associated with emerging disease-modifying therapies for SMA.

Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0–4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven ‘at risk’ cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3–4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)(3,1) 0.999, 95% confidence interval 0.996–1.000) and inter-rater reliability (ICC(2,1) 0.997, 95% confidence interval 0.992–0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.

CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes remains uncertain. We identified a de novo missense variant in CHD7 in a family presenting with musculoskeletal abnormalities as the main manifestation of CHD7-related disease, representing a new phenotype. The proband presented with prominent scapulae, mild shoulder girdle weakness and only subtle dysmorphic features. Investigation revealed hypoplasia of the trapezius and sternocleidomastoid muscles and semicircular canal defects, but he did not fulfill diagnostic criteria for CHARGE syndrome. Although the shoulders are often sloping and anteverted in CHARGE syndrome, the underlying neuromuscular cause has never been investigated. This report expands the phenotypes associated with CHD7 mutations to include a musculoskeletal presentation, with hypoplasia of the shoulder and neck muscles. CHD7 should be considered in patients presenting in childhood with stable scapular winging, particularly if accompanied by dysmorphic features and balance difficulties.

Free to read at publisher 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.

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 10–21years) at baseline and after 12months of riboflavin (1000mg 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. Significance This study reveals a novel pathophysiological process for motor nerve dysfunction in BVVL. It also indicates that nerve excitability studies may be further developed in larger cohorts as a potential biomarker to identify treatment response for BVVL patients.

Charcot-Marie-Tooth disease (CMT) is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders. Exercise may be beneficial to maintain strength and function for people with CMT, however, no comprehensive evaluation of the benefits and risks of exercise have been conducted. A systematic review was completed searching numerous electronic databases from earliest records to February 2015. Studies of any design including participants of any age with confirmed diagnosis of CMT that investigated the effects of exercise were eligible for inclusion. Of 13,301 articles identified following removal of duplicates, 11 articles including 9 unique studies met the criteria. Methodological quality of studies was moderate, sample sizes were small, and interventions and outcome measures used varied widely. Although the majority of the studies identified changes in one or more outcome measurements across exercise modalities, the majority were non-significant, possibly due to Type II errors. Significant effects described included improvements in strength, functional activities, and physiological adaptations following exercise. Despite many studies showing changes in strength and function following exercise, findings of this review should be met with caution due to the few studies available and moderate quality of evidence. Well-powered studies, harmonisation of outcome measures, and clearly described interventions across studies would improve the quality and comparability of the evidence base. The optimal exercise modality and intensity for people with CMT as well as the long-term safety of exercise remain unclear.

Background Ankle-foot orthoses (AFO) are prescribed to manage difficulty walking due to foot drop, bony foot deformities and poor balance. Traditional AFOs are handmade using thermoplastic vacuum forming which provides limited design options, is labour-intensive and associated with long wait times. 3D printing has the potential to transform AFO production and health service delivery. The aim of this systematic review was to determine the feasibility of designing, manufacturing and delivering customised 3D printed AFOs by evaluating the biomechanical outcomes, mechanical properties and fit of 3D printed compared to traditionally manufactured AFOs. Method Electronic databases were searched from January 1985 to June 2018 according to terms related to 3D printing and AFOs. Studies of any design from healthy or pathological populations of any age were eligible for inclusion. Studies must have investigated the effect of customised 3D printed AFOs using any 3D printing technique on outcomes related to walking ability, biomechanical function, mechanical properties, patient comfort, pain and disability. Any other orthotic type or AFOs without a 3D printed calf and foot section were excluded. The quality of evidence was assessed using the GRADE process. Results Eleven studies met the eligibility criteria evaluating 3D printed AFOs in healthy adults, and adults and children with unilateral foot drop from a variety of conditions. 3D printing was used to replicate traditional AFOs and develop novel designs to optimise the stiffness properties or reduce the weight and improve the ease of use of the AFO. 3D printed custom AFOs were found to be comparable to traditional custom AFOs and prefabricated AFOs in terms of temporal-spatial parameters. The mechanical stiffness and energy dissipation of 3D printed AFOs were found to be similar to prefabricated carbon-fibre AFOs. However, the sample sizes were small (n = 1 to 8) and study quality was generally low. Conclusion The biomechanical effects and mechanical properties of 3D printed AFOs were comparable to traditionally manufactured AFOs. Developing novel AFO designs using 3D printing has many potential benefits including stiffness and weight optimisation to improve biomechanical function and comfort. Electronic supplementary material The online version of this article (10.1186/s13047-019-0321-6) contains supplementary material, which is available to authorized users.

INTRODUCTION Balance impairment contributes to gait dysfunction, falls, and reduced quality of life in adults with Charcot-Marie-Tooth disease (CMT) but has been minimally examined in pediatric CMT. METHODS The CMT Pediatric Scale (CMTPedS) was administered to 520 children with CMT. Associations between balance function (Bruininks-Oseretsky Test of Motor Proficiency [BOT-2]) and sensorimotor and gait impairments were investigated. RESULTS Daily trips/falls were reported by 42.3% of participants. Balance (BOT-2) varied by CMT subtype, was impaired in 42% of 4-year-olds, and declined with age (P < 0.001). Vibration (P < 0.001), pinprick (P < 0.004), ankle dorsiflexion strength (P < 0.001), and foot alignment (P < 0.004) were associated with BOT-2 balance (adjusted R2 = 0.28). The visual dependence of balance increased with age. DISCUSSION Balance impairment occurs from a young age in children with CMT. Balance intervention studies are required in pediatric CMT and should consider the degree of sensorimotor impairment, foot malalignment, and visual dependence. Muscle Nerve, 2019.

This report describes the first case of a child with genetically confirmed Brown-Vialetto-van Laere syndrome in sub-Saharan Africa. This is an extremely rare clinical condition that presents with an auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise that manifests with diaphragmatic and vocal cord paralysis. It is an autosomal recessive condition for which the genetic mutation has only recently been linked to a riboflavin transporter deficiency. We describe an 11-month-old affected male infant. He has required long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he had limited recovery of motor function. His respiratory chain enzyme studies were abnormal suggestive of mitochondrial (mt) dysfunction. In the setting of limited resources, recognition of this striking clinical phenotype is important to highlight, specifically regarding the genetic implications of the condition and the potentially remedial response to vitamin supplementation.

Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.

BACKGROUND AND OBJECTIVES: Pediatric encephalitis has a wide range of etiologies, clinical presentations, and outcomes. This study seeks to classify and characterize infectious, immune-mediated/autoantibody-associated and unknown forms of encephalitis, including relative frequencies, clinical and radiologic phenotypes, and long-term outcome. METHODS: By using consensus definitions and a retrospective single-center cohort of 164 Australian children, we performed clinical and radiologic phenotyping blinded to etiology and outcomes, and we tested archived acute sera for autoantibodies to N-methyl-D-aspartate receptor, voltage-gated potassium channel complex, and other neuronal antigens. Through telephone interviews, we defined outcomes by using the Liverpool Outcome Score (for encephalitis). RESULTS: An infectious encephalitis occurred in 30%, infection-associated encephalopathy in 8%, immune-mediated/autoantibody-associated encephalitis in 34%, and unknown encephalitis in 28%. In descending order of frequency, the larger subgroups were acute disseminated encephalomyelitis (21%), enterovirus (12%), Mycoplasma pneumoniae (7%), N-methyl-D-aspartate receptor antibody (6%), herpes simplex virus (5%), and voltage-gated potassium channel complex antibody (4%). Movement disorders, psychiatric symptoms, agitation, speech dysfunction, cerebrospinal fluid oligoclonal bands, MRI limbic encephalitis, and clinical relapse were more common in patients with autoantibodies. An abnormal outcome occurred in 49% of patients after a median follow-up of 5.8 years. Herpes simplex virus and unknown forms had the worst outcomes. According to our multivariate analysis, an abnormal outcome was more common in patients with status epilepticus, magnetic resonance diffusion restriction, and ICU admission. CONCLUSIONS: We have defined clinical and radiologic phenotypes of infectious and immune-mediated/autoantibody-associated encephalitis. In this resource-rich cohort, immune-mediated/autoantibody-associated etiologies are common, and the recognition and treatment of these entities should be a clinical priority.

ObjectiveTo describe in detail the clinical profile of Charcot-Marie-Tooth disease subtype 3 (CMTX3) to aid appropriate genetic testing and rehabilitative therapy.MethodsWe reviewed the clinical and neurophysiologic profile and CMT Pediatric Scale (CMTPedS) assessments of 11 children with CMTX3.ResultsCompared with the more common forms of CMT, CMT1A and CMTX, CMTX3 was characterized by early onset with early and progressive hand weakness. Most affected children were symptomatic within the first 2 years of life. The most common presentation was foot deformity in the first year of life. CMTPedS analysis in these children revealed that CMTX3 progressed more rapidly (4.3 ± 4.1 points over 2 years, n = 7) than CMT1A and CMTX1. Grip strength in affected boys was 2 SDs below age- and sex-matched normative reference values (z score −2.05 ± 1.32) in the second decade of life. The most severely affected individual was wheelchair bound at 14 years of age, and 2 individuals had no movement in the small muscles of the hand in the second decade of life. Nerve conduction studies showed a demyelinating sensorimotor neuropathy with motor conduction velocity ≤23 m/s.ConclusionsCMTX3 had an earlier onset, severe hand weakness, and more rapidly progressive disability compared to the more common forms of CMT. Understanding the unique phenotype of CMTX3 is essential for directing genetic testing because the CMTX3 insertion will not be seen on a routine microarray or neuromuscular gene panel. Early diagnosis will enable rehabilitation to be started early in this rapidly progressive neuropathy.

BackgroundSpinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1.MethodsAn Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017. Standard-of-care medical therapy and treatment with intrathecal nusinersen were provided to all patients. Clinical and diagnostic characteristics, molecular genetics, treatment administered, and functional motor outcomes were assessed.ResultsA total of 20 patients with SMA type 1 met the inclusion criteria, of whom 16 consented and received nusinersen treatment. Median time to diagnosis from symptom onset was 5.0 months and was correlated with age of onset (r=0.54, PSMN2 copies.ConclusionsThe nusinersen EAP highlights difficulties in achieving early diagnosis and/or prevention, the evolution of optimal clinical care in a time of uncertain prognostication, resource implications and ethical issues in clinical practice for SMA type 1. These challenges are broadly relevant to the realisation of all novel therapeutics in neurological disorders.

To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy.We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants.The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p 0.001, OR 0.6/year, P 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; p = 0.02) among the patients with identified pathogenic variants.Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing.

Summary Background Exercise is potentially therapeutic for neuromuscular disorders, but a risk of harm exists due to overwork weakness. We aimed to assess the safety and efficacy of progressive resistance exercise for foot dorsiflexion weakness in children with Charcot-Marie-Tooth disease. Methods We did this randomised, double-blind, sham-controlled trial across the Sydney Children's Hospitals Network (NSW, Australia). Children aged 6–17 years with Charcot-Marie-Tooth disease were eligible if they had foot dorsiflexion weakness (negative Z score based on age-matched and sex-matched normative reference values). We randomly allocated (1:1) children, with random block sizes of 4, 6, and 8 and stratification by age, to receive 6 months (three times per week on non-consecutive days; 72 sessions in total) of progressive resistance training (from 50% to 70% of the most recent one repetition maximum) or sham training (negligible non-progressed intensity), using an adjustable exercise cuff to exercise the dorsiflexors of each foot. The primary efficacy outcome was the between-group difference in dorsiflexion strength assessed by hand-held dynamometry (expressed as a Z score) from baseline to months 6, 12, and 24. The primary safety outcome was the between-group difference in muscle and intramuscular fat volume of the anterior compartment of the lower leg assessed by MRI (expressed as a scaled volume) from baseline to 6 months and 24 months. Participants, parents, outcome evaluators, and investigators other than the treatment team were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000552785. Findings From Sept 2, 2013, to Dec 11, 2014, we randomly assigned 60 children to receive progressive resistance exercise (n=30) or sham training (n=30), and 55 (92%) children completed the trial. ANCOVA-adjusted Z score differences in dorsiflexion strength between groups were 0 (95% CI −0·37 to 0·42; p=0·91) at 6 months, 0·3 (−0·23 to 0·81; p=0·27) at 12 months, and 0·6 (95% CI 0·03 to 1·12; p=0·041) at 24 months. Scaled muscle and fat volume was comparable between groups at 6 months (ANCOVA-adjusted muscle volume difference 0, 95% CI −0·03 to 0·10, p=0·24; and fat volume difference 0, 95% CI −0·01 to 0·05, p=0·25) and 24 months (0, −0·08 to 0·12, p=0·67; and 0, −0·05 to 0·03, p=0·58). No serious adverse events were reported. Interpretation 6 months of targeted progressive resistance exercise attenuated long-term progression of dorsiflexion weakness without detrimental effect on muscle morphology or other signs of overwork weakness in paediatric patients with Charcot-Marie-Tooth disease. Funding Muscular Dystrophy Association and Australian National Health and Medical Research Council.

Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.

Long-term studies of Charcot-Marie-Tooth (CMT) disease across the entire lifespan require stable endpoints that measure the same underlying construct (e.g., disability). The aim of this study was to assess the relationship between the CMT Pediatric Scale (CMTPedS) and the adult CMT Neuropathy Score (CMTNSv2) in 203 children, adolescents, and young adults with CMT. There was a moderate curvilinear correlation between the CMTPedS and the CMTNSv2 (Spearman's rho ρ = 0.716, p < 0.0001), although there appears to be a floor effect of the CMTNSv2 in patients with a milder CMT phenotype. Univariate analyses indicate that the relationship between the CMTPedS and CMTNSv2 scores improves with worsening disease severity and advancing age. Although one universal scale throughout life would be ideal, our data supports the transition from the CMTPedS in childhood to the CMTNSv2 in adulthood as a continuum of measuring lifelong disability in patients with CMT.

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.

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.

Aim Mutations in the genes encoding the riboflavin transporters RFVT2 and RFVT3 have been identified in Brown–Vialetto–Van Laere syndrome, a neurodegenerative disorder characterized by hearing loss and pontobulbar palsy. Treatment with riboflavin has been shown to benefit individuals with the phenotype of RFVT2 deficiency. Understanding the characteristics of hearing loss in riboflavin transporter deficiency would enable early diagnosis and therapy. Method We performed hearing assessments in seven children (from four families) with RFVT2 deficiency and reviewed results from previous assessments. Assessments were repeated after 12 months and 24 months of riboflavin therapy and after cochlear implantation in one individual. Results Hearing loss in these individuals was due to auditory neuropathy spectrum disorder (ANSD). Hearing loss was identified between 3 years and 8 years of age and progressed rapidly. Hearing aids were not beneficial. Riboflavin therapy resulted in improvement of hearing thresholds during the first year of treatment in those with recent-onset hearing loss. Cochlear implantation resulted in a significant improvement in speech perception in one individual. Interpretation Riboflavin transporter deficiency should be considered in all children presenting with an auditory neuropathy. Speech perception in children with ANSD due to RFVT2 deficiency may be significantly improved by cochlear implantation.

Muscle weakness in childhood can be caused by a lesion at any point extending from the motor cortex, brainstem and spinal cord to the anterior horn cell, peripheral nerve, neuromuscular junction and muscle. A comprehensive history and physical examination is essential to aid classification of the neuromuscular disorder and direct gene testing. The more common disorders such as spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy and facioscapulohumeral dystrophy may be diagnosed on direct gene testing based on the history and clinical examination. The congenital myopathies are classified based on structural abnormalities on muscle biopsy, while protein abnormalities on immunohistochemistry and immunoblotting aid classification of the muscular dystrophies. In this review, we provide an approach to diagnosis of a child with weakness, with a focus on the inherited neuromuscular disorders, and the features on history, examination and investigation that help to distinguish between them.

Sir, Thank you for the opportunity to reply to the correspondence concerning our recent publication in Brain , ‘Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2’ (Rossor et al. , 2015). We read with great interest the letter from Bansagi et al. and thank the authors for providing further evidence that p.Ser107Leu in BICD2 is a mutation ‘hot spot’. Bansagi et al. (2015) describe two unrelated families with a typical Spinal Muscular Atrophy Lower Extremity Dominant (SMALED) phenotype. In both families, affected individuals presented at birth with either toe deformities …

Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible hot spot mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.

Clinical phenotypes of congenital myasthenic syndromes and primary mitochondrial disorders share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis. Next generation sequencing is transforming molecular diagnosis of inherited neuromuscular disorders by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were initially suspected to have a mitochondrial myopathy, but in whom a clear diagnosis of congenital myasthenic syndromes was made through whole exome sequencing. In patient 1, whole exome sequencing revealed compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase ( COLQ ). In patient 2, in whom a deletion of exon 52 in Dystrophin gene was previously detected by multiplex ligation-dependent probe amplification, Sanger sequencing revealed an additional homozygous mutation c.1511_1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7). These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like congenital myasthenic syndromes, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that whole exome sequencing is an effective diagnostic tool in providing molecular diagnosis in patients with complex phenotypes.

Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous and classification based on motor nerve conduction velocity and inheritance is used to direct genetic testing. With the less common genetic forms of CMT, identifying the causative genetic mutation by Sanger sequencing of individual genes can be time-consuming and costly. Next-generation sequencing technologies show promise for clinical testing in diseases where a similar phenotype is caused by different genes. We report the unusual occurrence of CMT4J, caused by mutations in FIG4, in a apparently dominant pedigree. The affected proband and her mother exhibit different disease severities associated with different combinations of compound heterozygous FIG4 mutations, identified by whole exome sequencing. The proband was also shown to carry a de novo nonsense mutation in the dystrophin gene, which may contribute to her more severe phenotype. This study is a cautionary reminder that in families with two generations affected, explanations other than dominant inheritance are possible, such as recessive inheritance due to three mutations segregating in the family. It also emphasises the advantages of next-generation sequencing approaches that screen multiple CMT genes at once for patients in whom the common genes have been excluded.

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, and of other patients with undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

BACKGROUND AND PURPOSE: The relationship between the MR imaging features and clinical outcomes in patients with hypoglycemic encephalopathy has always been evaluated retrospectively. The aim of this study was to prospectively evaluate whether MR imaging features of patients presenting with hypoglycemic coma are predictive of short-term (1-week) outcomes. MATERIALS AND METHODS: Subjects were 36 consecutive patients with hypoglycemia who were in a comatose state on arrival at our hospital from April 2006 to March 2010. MR imaging findings on arrival in relation to the patients' clinical course after glucose infusion were evaluated. RESULTS: Thirteen of the 36 patients showed no MR imaging abnormalities on arrival. DWI revealed focal lesions involving the internal capsule in 13 patients and lesions involving bilateral hemispheric white matter in 10 patients. After glucose administration, the patients without lesions and patients with focal internal capsule lesions recovered completely within 1 day. However, patients with diffuse white matter lesions did not recover even within 1 week despite glucose administration. There was no statistical difference in the initial blood glucose levels among patients with the various types of MR imaging findings. CONCLUSIONS: On early MR imaging, hypoglycemic brain injury may first appear in the internal capsule and then spread into the hemispheric white matter. The absence of a lesion or the presence of a focal internal capsule lesion may suggest a good outcome. However, diffuse hemispheric white matter lesions may indicate a poor 1-week outcome.

Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date.To assess the variability of disease severity in a large cohort of children and adolescents with CMT.A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015.Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected).Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P .05). Participants with CMT2A had the weakest grip strength (P .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P .001) as independent predictors of disease severity.These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials.

Microtubules are essential components of axon guidance machinery. Among β-tubulin mutations, only those in TUBB3 have been shown to cause primary errors in axon guidance. All identified mutations in TUBB2B result in polymicrogyria, but it remains unclear whether TUBB2B mutations can cause axon dysinnervation as a primary phenotype. We have identified a novel inherited heterozygous missense mutation in TUBB2B that results in an E421K amino acid substitution in a family who segregates congenital fibrosis of the extraocular muscles (CFEOM) with polymicrogyria. Diffusion tensor imaging of brains of affected family members reveals aberrations in the trajectories of commissural projection neurons, implying a paucity of homotopic connections. These observations led us to ask whether axon dysinnervation is a primary phenotype, and why the E421K, but not other, TUBB2B substitutions cause CFEOM. Expression of exogenous Tubb2b-E421K in developing callosal projection neurons is sufficient to perturb homotopic connectivity, without affecting neuronal production or migration. Using in vitro biochemical assays and yeast genetics, we find that TUBB2B-E421K αβ-heterodimers are incorporated into the microtubule network where they alter microtubule dynamics and can reduce kinesin localization. These data provide evidence that TUBB2B mutations can cause primary axon dysinnervation. Interestingly, by incorporating into microtubules and altering their dynamic properties, the E421K substitution behaves differently than previously identified TUBB2B substitutions, providing mechanistic insight into the divergence between resulting phenotypes. Together with previous studies, these findings highlight that β-tubulin isotypes function in both conserved and divergent ways to support proper human nervous system development.

Charcot-Marie-Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4 sequencing identified a compound heterozygous I41T/K278YfsX5 genotype. CMT4J secondary to FIG4 mutations should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy, especially if there is a background history of a more slowly progressive neuropathy.

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

Objective: To identify the most useful clinical and histologic markers that facilitate early diagnosis in LMNA -related muscular dystrophy and to assess the usefulness of Western blotting (WB) for lamin A/C. Methods: We analyzed the clinical and histologic features and WB results of all patients with laminopathies diagnosed in a research-based diagnostic service over 8 years. Results: Although patients with congenital muscular dystrophy (MDCL) (n = 5) and Emery-Dreifuss muscular dystrophy (EDMD) (n = 5) had distinctive early clinical features, the lack of a suggestive clinical phenotype significantly delayed diagnosis in 2 of 3 patients with limb-girdle muscular dystrophy (LGMD) (n = 3). In addition, 6 of 20 muscle biopsy samples were considered nondystrophic, which contributed to delays in diagnosis in some patients. Neck extensor involvement (weakness or contractures) was the most consistent clinical sign, present in all patients. Reduced lamin A/C levels on WB were seen in 5 of 9 patients with laminopathies. Conclusion: Clinical features provide the best clues for diagnosing MDCL and EDMD early in the disease, and we urge clinicians to become familiar with those phenotypes. WB for lamin A/C may contribute to diagnosis but requires technical expertise, and results are normal in many individuals with LMNA mutations. Because of the survival benefit of early diagnosis and treatment, we recommend that LMNA gene sequencing be performed in all patients with undiagnosed congenital muscular dystrophy and neck extensor weakness, all patients with genetically undiagnosed LGMD, and those with suggestive clinical signs and nonspecific histologic abnormalities.