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.

Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a rare Mendelian disorder characterised by central nervous system hypomyelination. PMD typically manifests in infancy or early childhood and is caused by mutations in proteolipid protein-1 (PLP1). However, variants in several other genes including gap junction protein gamma 2 (GJC2) can also cause a similar phenotype and are referred to PMD-like disease (PMLD).

mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis.

Objective: To explore the phenotypic spectrum and pathophysiology of human disease deriving from mutations in the gene.

Methods: In a field study on consanguineous Palestinian families, we identified 3 patients carrying homozygous mutations in the gene using whole-exome sequencing. An unrelated Irish family was detected by screening the GENESIS database for further mutations.

Contactin-Associated Protein 1 (CNTNAP1) Mutations Induce Characteristic Lesions of the Paranodal Region.

Congenital hypomyelinating neuropathy is a rare neonatal syndrome responsible for hypotonia and weakness. Nerve microscopic examination shows amyelination or hypomyelination. Recently, mutations in CNTNAP1 have been described in a few patients.

Neurophysiological profile of peripheral neuropathy associated with childhood mitochondrial disease.

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.

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.

Auditory neuropathy in Brown-Vialetto-Van Laere syndrome due to riboflavin transporter RFVT2 deficiency.

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.

Eye movement disorders are an early manifestation of CACNA1A mutations in children.

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.

Outcome of Early Juvenile Onset Metachromatic Leukodystrophy After Unrelated Cord Blood Transplantation: A Case Series and Review of the Literature.

The purpose of this study was to determine whether transplantation of umbilical cord blood from unrelated donors before the development of symptoms could halt the progression of early juvenile onset cases of MLD in whom the disease was diagnosed based on the family history. Three asymptomatic children (aged 2 years 4 months, 2 years 8 months and 5 years 5 months, two of whom were sisters) underwent unrelated umbilical cord blood transplantation (UCBT) and two untreated symptomatic siblings were included in the study. In 14-year and 6-year follow-ups after transplantation, clinical examination, ARSA enzyme levels, neurophysiological, neuroimaging, and psychological status were assessed.

Pathophysiology of motor dysfunction in a childhood motor neuron disease caused by mutations in the riboflavin transporter.

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.

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.

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.

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.

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.

GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes.

NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy.

Benign hereditary chorea caused by mutations in the NK2 homeobox 1 gene (NKX2-1), shares clinical features with ataxic and dyskinetic cerebral palsy (CP), resulting in the possibility of misdiagnosis. A father and his two children were considered to have ataxic CP until a possible diagnosis of benign familial chorea was made in the children in early teenage. The father's neurological condition had not been appreciated prior to examination of the affected son.

Validation of the Charcot-Marie-Tooth disease pediatric scale as an outcome measure of disability.

Objective: Charcot-Marie-Tooth disease (CMT) is a common heritable peripheral neuropathy. There is no treatment for any form of CMT, although clinical trials are increasingly occurring. Patients usually develop symptoms during the first 2 decades of life, but there are no established outcome measures of disease severity or response to treatment.

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.

Symmetry of foot alignment and ankle flexibility in paediatric Charcot-Marie-Tooth disease.

Background: Charcot-Marie-Tooth disease is the most common inherited nerve disorder and typically presents with pes cavus foot deformity and ankle equinus during childhood. Level in the variation of symmetry of musculoskeletal lower limb involvement across the clinical population is unknown, despite early reports describing gross asymmetry.

Methods: We measured foot alignment and ankle flexibility of the left and right limbs using accurate and reliable standardised paediatric outcome measures in 172 patients aged 3-20 years with a variety of disease subtypes recruited from the United States, United Kingdom, Italy and Australia.

Primary nerve repair following resection of a neurenteric cyst of the oculomotor nerve.

Neurenteric cysts are rare congenital lesions of endodermal origin occurring in the spinal canal and infrequently in the posterior cranial fossa. The authors report the case of a 3-year-old child who presented with a recurrent third cranial nerve palsy. Magnetic resonance imaging showed a large cystic mass lesion in the ambient cistern on the right side, with compression of the anterolateral aspect of the brainstem.

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.

Hereditary peripheral neuropathies of childhood: an overview for clinicians.

This review focuses on the "pure" hereditary peripheral neuropathies where peripheral nerve disease is the main manifestation and does not address neurodegenerative disorders associated with but not dominated by peripheral neuropathy. Aetiologies of childhood-onset peripheral neuropathies differ from those of adult-onset, with more inherited conditions, especially autosomal recessive. Charcot-Marie-Tooth disease is the commonest neuromuscular disorder.