Peripheral nerve disease secondary to systemic conditions in children.

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.

Phenotypic insights into ADCY5-associated disease.

BACKGROUND: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. METHODS: In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing. RESULTS: Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. CONCLUSION: We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome.

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.

Confirmed enterovirus encephalitis with associated steroid-responsive acute disseminated encephalomyelitis: an overlapping infection and inflammation syndrome.

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.

Randomised controlled trial protocol of foot and ankle exercise for children with Charcot-Marie-Tooth disease.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neuromuscular diseases--there is no effective treatment. Foot and ankle weakness is a major problem for children with CMT, thus interventions that focus on maintaining and increasing strength may provide a solution. RESEARCH QUESTION: Is progressive resistance strength training an effective and safe intervention to improve strength, disability, gait and quality of life of children with CMT? PARTICIPANTS AND SETTING: Sixty children (6 to 17 years) with confirmed CMT who reside in Sydney, Australia will be recruited via referral from a paediatric neurologist, advertisements or the Australasian Paediatric CMT Registry. INTERVENTION: Participants will be randomised to undergo a 24-week, thrice weekly, high-intensity progressive resistance foot and ankle exercise programme (HIGH) or low-intensity foot and ankle exercise control programme (LOW). MEASUREMENTS: Out-come measures will be conducted at baseline, 6, 12 and 24 months.The primary outcome is isometric dorsiflexion strength measured by hand-held dynamometry. Secondary outcomes include disability, gait, quality of life, functional ankle instability and muscle volume and fatty infiltration of the anterior compartment of the lower leg (determined by MRI). PROCEDURE: Randomisation and allocation will be by a computer-generated algorithm, maintained and assigned by an external phone-based system, concealed to the investigators. Participants, parents and the outcome assessors will be blinded to group assignment. ANALYSIS: Treatment effect between groups is by intention-to-treat with a linear regression approach to analysis of covariance using 95% CI and p < 0.05. DISCUSSION: This study is the first randomised controlled trial to evaluate the risks and benefits of strengthening the affected muscles in children with CMT. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12613000552785.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

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.

Peripheral neuropathy associated with mitochondrial disease in children.

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.

Muscle cramp in pediatric Charcot-Marie-Tooth disease type 1A: prevalence and predictors.

OBJECTIVES: To identify correlates of calf cramp in children with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Throughout Australia, 81 children aged 2-16 years with CMT1A were recruited. Measures of strength, ankle range, foot posture, balance, agility, endurance, gait, and neurophysiology were collected. Post hoc logistic regression analyses were performed to identify independent predictors of calf cramp. RESULTS: Of the 81 children, 26 (32%) reported calf cramp, and 1 child each reported toe, quadriceps, or arm cramp. Calf cramp was associated (p < 0.05) with older age; the presence of hand tremor; stronger foot inversion, eversion, dorsiflexion, and plantarflexion; and better performance in long-jump and 9-hole peg tests. Logistic regression analysis revealed only increasing age (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.11-1.58; p = 0.002) and the presence of hand tremor (OR 3.81, 95% CI 1.18-12.56; p = 0.028) as independent predictors of calf cramp. CONCLUSION: Calf cramps are common in children with CMT1A and worsen with age. This study revealed a previously unrecognized link between cramp and hand tremor in children with CMT1A. Further investigation of proposed mechanisms and risk factors common to both cramp and tremor will contribute to our understanding of these common complications of CMT1A.

Randomized trial of botulinum toxin to prevent pes cavus progression in pediatric Charcot-Marie-Tooth disease type 1A.

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.

Cognitive screening for children and adolescents: general limits or ceiling effects?

Cognitive screening tools designed for children can also be used with adolescents. However, early studies suggest that scores can approach a maximum at about age 10 or 11 years. The initial hypothesis was this apparent ''ceiling effect'' is due to limits in the materials, where items can be insufficiently challenging for some adolescents. The alternative hypothesis is that general cognitive screening has a true limit by early adolescence. Participants (N = 85) were 10 to 15-year-old girls and boys, with a database (N = 1249) of 4 to 12-year-old children. The School-Years Screening Test for the Evaluation of Mental Status (SYSTEMS) cognitive screening was extended by more difficult items. Results show that scores increase rapidly for young children and tend toward a maximum in early adolescence. This characteristic asymptotic curve explained a substantial proportion of the variance. We can conclude that, although specific functions continue to develop, there is an upper limit in early adolescence for such general cognitive functioning. The findings support cognitive screening across a broad age range and suggest worthwhile research and clinical applications.

Quality of life in children with Charcot-Marie-Tooth disease.

The authors studied the health-related quality of life of children aged 5 to 18 years with Charcot-Marie-Tooth disease of varying types and severity and compared it with the general pediatric population. To capture and compare the quality-of-life data across a broad range of ages, the Child Health Questionnaire was completed by parents of 127 children with Charcot-Marie-Tooth disease. Affected children exhibited lower physical, psychological, and social well-being than the general pediatric population, with subsequent worsening of many domains with age. The type of Charcot-Marie-Tooth disease influenced some physical and behavioral quality-of-life domains, while gender, body size, and ethnicity did not. Parent characteristics had generally little impact on the reporting of their child's quality of life, although parents with Charcot-Marie-Tooth disease reported higher bodily pain in their children than those without. Overall, quality of life is negatively affected by the presence and severity of Charcot-Marie-Tooth disease in childhood.

Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.

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.

Effect of oral curcumin on Déjérine-Sottas disease.

Curcumin is the newest therapeutic agent for ameliorating the clinical and neuropathologic phenotype of a mouse model of Déjérine-Sottas disease. We undertook a 12-month dose-escalation safety trial of oral curcumin in a 15-year-old Caucasian girl with Déjérine-Sottas disease (point mutation, Ser72Leu) complicated by severe weakness, scoliosis, and respiratory impairment. The patient received 50 mg/kg/day oral curcumin for the first 4 months and 75 mg/kg/day thereafter, to complete a 12-month trial. Outcome measures included muscle strength, pulmonary function, upper/lower extremity disability, neurophysiologic studies, and health-related quality of life. After 12 months, the patient experienced no adverse events, and reported good compliance. There was little improvement in objective outcome measures. Knee flexion and foot strength increased slightly, but hand and elbow strength decreased. Pulmonary function, hand function, and measures of upper/lower extremity disability were stable or reduced. Her neurophysiologic findings were unchanged. Parent-reported quality of life improved for most domains, especially self-esteem, during the 12 months of treatment. Child-reported quality of life, assessed at the final visit, mirrored these results, with overall feelings of happiness and contentment. Further studies are required to explore the efficacy and safety of curcumin for severe demyelinating neuropathies of infancy and early childhood.

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

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor function and is caused by the duplication of PMP22, the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A. METHODS: This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2-16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, Number 12606000481572. FINDINGS: 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1.7 m/s, 95% CI -0.1 to 3.4; p=0.06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events. INTERPRETATION: 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached.

Evolution of foot and ankle manifestations in children with CMT1A.

We studied the timing and progression of foot and ankle changes in 81 children with genetically confirmed Charcot-Marie-Tooth disease type 1A (CMT1A) and determined their impact on motor function and walking ability. Foot deformity, weakness, pain, cramps, and instability were a common feature of CMT1A. Foot structure evolved toward pes cavus from early childhood to adolescence, although a subgroup with normal and planus feet remained. Foot strength increased with age, although compared to age-equivalent norms it declined from 4 years. Factors associated with evolving foot deformity included muscle weakness/imbalance, restricted ankle flexibility, and joint hypermobility. Regression modeling identified dorsiflexion weakness, global foot weakness, and difficulty toe-walking as independent predictors of motor dysfunction, while pes cavus and difficulty heel-walking were predictors of poor walking ability. Foot problems are present from the earliest stages of the disease and can have a negative impact on function. Early foot and ankle intervention may prevent long-term disability and morbidity in CMT1A.

Congenital myasthenic syndromes.

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.

Hand involvement in children with Charcot-Marie-Tooth disease type 1A.

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.