The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex.

BACKGROUND: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. METHODS: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

Quick, Effective Screening Tasks Identify Children With Medical Conditions or Disabilities Needing Physical Literacy Support.

PURPOSE: This study evaluated screening tasks able to identify children with medical conditions or disabilities who may benefit from physical literacy. METHOD: Children completed ≤20 screening tasks during their clinic visit and then the Canadian Assessment of Physical Literacy (2nd edition) at a separate visit. Total Canadian Assessment of Physical Literacy scores <30th percentile were categorized as potentially needing physical literacy support. Receiver operator characteristic curves identified assessment cut points with 80% sensitivity and 40% specificity relative to total physical literacy scores. RESULTS: 223 children (97 girls; 10.1 [2.6] y) participated. Physical activity adequacy, predilection, and physical competence achieved ≥80% sensitivity and ≥40% specificity in both data sets. Adequacy ≤ 6.5 had 86% to 100% sensitivity and 48% to 49% specificity. Daily screen time >4.9 hours combined with Adequacy ≤6.15 had 88% to 10% sensitivity and 53% to 56% specificity. CONCLUSIONS: Activity adequacy, alone or with screen time, most effectively identified children likely to benefit from physical literacy support. Adequacy and screen time questionnaires are suitable for clinical use. Similar results regardless of diagnosis suggest physical competence deficits are not primary determinants of active lifestyles. Research to enhance screening specificity is required.

Congenital tremor and myopathy secondary to novel MYBPC1 variant.

Congenital myopathy with tremor (MYOTREM) is a recently described disorder characterized by mild myopathy and a postural and intention tremor present since early infancy. MYOTREM is associated with pathogenic variants in MYBPC1 which encodes slow myosin-binding protein C, a sarcomere protein with regulatory and structural roles. Here, we describe a family with three generations of variably affected members exhibiting a novel variant in MYBPC1 (c.656 T > C, p.Leu219Pro). Among the unique features of affected family members is the persistence of tremor in sleep. We also present the first muscle magnetic resonance images for this disorder, and report muscle atrophy and fatty infiltration.

Tone management: An environmental scan of current management practices across Canada.

BACKGROUND: Currently, there are no standardized approaches to care or evaluation for tone dysfunction in Canada. The study authors hypothesize that there is significant practice variation across the country. This environmental scan is aimed to describe the current practice for management of paediatric patients with hypertonia across Canada. METHODS: A web-based survey was developed by the authors with a multi-disciplinary approach and sent to representative paediatric rehabilitation sites in each province in Canada. Disciplines at the rehabilitation sites surveyed included all or some of the following disciplines: physiatry, neurology, neurosurgery, plastic surgery, orthopaedic surgery, physiotherapy and occupational therapy. All statistical analyses were performed using the R statistical software version 4.0. Fifteen rehabilitation sites were contacted, and 12 sites were used for the final analysis. RESULTS: Cerebral palsy was found to be the most common diagnosis for tone dysfunction, with 58% of sites diagnosing greater than 20 new patients per year. In 67% of sites, patients were seen within a formal multidisciplinary clinic to manage hypertonia. All 12 sites utilized oral baclofen and gabapentin, and 92% of sites utilized trihexyphenidyl. Botulinum toxin injections were offered at 50% of sites. Upper and lower extremity surgical procedures were offered in 83% of the sites. CONCLUSION: The information gained from this study provides some insight into the current practice across Canada for children with hypertonia. This study may assist in the development of a national, standardized strategy to tone management, potentially facilitating more equitable access to care for patients.

A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis.

Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/ß, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2.

Generation of the human iPSC lines AKOSi011-A carrying the mutation p.Pro65Ser/p.Asp35T and AKOSi012-A, carrying the mutation p.Tyr231His, derived from FAHN patient fibroblasts.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a hereditary neurodegenerative disease caused by mutations in the FA2H gene. Patients show a wide range of neurological symptoms and an abnormal myelination. Here we describe the generation of the human induced pluripotent stem cell (hiPSC) lines AKOSi011-A and AKOSi012-A, derived from FAHN-patient fibroblasts, carrying the compound heterozygous mutation p.Pro65Ser/p.Asp35Tyr and the homozygous mutation p.Tyr231His, respectively. The hiPSC lines were generated using a non-integrating Sendai virus. The obtained hiPSCs show an unobtrusive karyotype, carry the mutations of the original fibroblasts, express pluripotency markers and can differentiate into cells of the three germ layers.

The White Matter Rounds experience: The importance of a multidisciplinary network to accelerate the diagnostic process for adult patients with rare white matter disorders.

Introduction: Adult genetic leukoencephalopathies are rare neurological disorders that present unique diagnostic challenges due to their clinical and radiological overlap with more common white matter diseases, notably multiple sclerosis (MS). In this context, a strong collaborative multidisciplinary network is beneficial for shortening the diagnostic odyssey of these patients and preventing misdiagnosis. The White Matter Rounds (WM Rounds) are multidisciplinary international online meetings attended by more than 30 physicians and scientists from 15 participating sites that gather every month to discuss patients with atypical white matter disorders. We aim to present the experience of the WM Rounds Network and demonstrate the value of collaborative multidisciplinary international case discussion meetings in differentiating and preventing misdiagnoses between genetic white matter diseases and atypical MS. Methods: We retrospectively reviewed the demographic, clinical and radiological data of all the subjects presented at the WM Rounds since their creation in 2013. Results: Seventy-four patients (mean age 44.3) have been referred and discussed at the WM Rounds since 2013. Twenty-five (33.8%) of these patients were referred by an MS specialist for having an atypical presentation of MS, while in most of the remaining cases, the referring physician was a geneticist (23; 31.1%). Based on the WM Rounds recommendations, a definite diagnosis was made in 36/69 (52.2%) patients for which information was available for retrospective review. Of these diagnosed patients, 20 (55.6%) had a genetic disease, 8 (22.2%) had MS, 3 (8.3%) had both MS and a genetic disorder and 5 (13.9%) had other non-genetic conditions. Interestingly, among the patients initially referred by an MS specialist, 7/25 were definitively diagnosed with MS, 5/25 had a genetic condition (e.g., X-linked adrenoleukodystrophy and hereditary small vessel diseases like Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and COL4A1-related disorder), and one had both MS and a genetic demyelinating neuropathy. Thanks to the WM Rounds collaborative efforts, the subjects who currently remain without a definite diagnosis, despite extensive investigations performed in the clinical setting, have been recruited in research studies aimed at identifying novel forms of genetic MS mimickers. Conclusions: The experience of the WM Rounds Network demonstrates the benefit of collective discussions on complex cases to increase the diagnostic rate and decrease misdiagnosis in patients with rare or atypical white matter diseases. Networks of this nature allow physicians and scientists to compare and share information on challenging cases from across the world, provide a basis for future multicenter research studies, and serve as model for other rare diseases.

Generation of the human iPSC line AKOSi010-A from fibroblasts of a female FAHN patient, carrying the compound heterozygous mutation p.Gly45Arg/p.His319Arg.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare childhood onset neurodegenerative disease caused by mutations in the FA2H gene. Patients display abnormal myelination, cerebellar atrophy and some have iron deposition in the central nervous system. Here we describe the generation of AKOSi010-A, a human induced pluripotent stem cell (hiPSC) line derived from fibroblasts of a female patient carrying the compound heterozygous p.Gly45Arg/p.His319Arg, using non-integrating Sendai virus. The generated iPSCs express pluripotency markers, can differentiate into cell types of the three germ layers and show a normal karyotype. This cell line displays a unique source to study the pathophysiology of FAHN.

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus.

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

Characterization of physical literacy in children with chronic medical conditions compared with healthy controls: a cross-sectional study.

To determine the physical literacy, defined as the capability for a physically active lifestyle, of children with medical conditions compared with healthy peers, this multicenter cross-sectional study recruited children with medical conditions from cardiology, neurology (including concussion), rheumatology, mental health, respirology, oncology, hematology, and rehabilitation (including cerebral palsy) clinics. Participants aged 8-12 years (N = 130; mean age: 10.0 ± 1.44 years; 44% female) were randomly matched to 3 healthy peers from a normative database, based on age, gender, and month of testing. Total physical literacy was assessed by the Canadian Assessment of Physical Literacy, a validated assessment of physical literacy measuring physical competence, daily behaviour, knowledge/understanding, and motivation/confidence. Total physical literacy mean scores (/100) did not differ (t(498) = -0.67; p = 0.44) between participants (61.0 ± 14.2) and matched healthy peers (62.0 ± 10.7). Children with medical conditions had lower mean physical competence scores (/30; -6.5 [-7.44 to -5.51]; p < 0.001) but higher mean motivation/confidence scores (/30; 2.6 [1.67 to 3.63]; p < 0.001). Mean daily behaviour and knowledge/understanding scores did not differ from matches (/30; 1.8 [0.26 to 3.33]; p = 0.02;/10; -0.04 [-0.38 to 0.30]; p = 0.81; respectively). Children with medical conditions are motivated to be physically active but demonstrate impaired movement skills and fitness, suggesting the need for targeted interventions to improve their physical competence. Novelty: Physical literacy in children with diverse chronic medical conditions is similar to healthy peers. Children with medical conditions have lower physical competence than healthy peers, but higher motivation and confidence. Physical competence (motor skill, fitness) interventions, rather than motivation or education, are needed for these youth.

Association of outcomes in acute flaccid myelitis with identification of enterovirus at presentation: a Canadian, nationwide, longitudinal study.

BACKGROUND: Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. METHODS: In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. FINDINGS: 58 children with AFM (median age 5·1 years, IQR 3·8-8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV-) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1-9·5 vs EDSS 4·0, IQR 3·0-6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0-7·4 vs EDSS 3·0, IQR 1·5-4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0-7·0 vs EDSS 3·0, IQR 1·0-4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0-6·9 vs EDSS 2·5 IQR 0·3-3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). INTERPRETATION: Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. FUNDING: None.

Correction: GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

Clinical delineation of GTPBP2-associated neuro-ectodermal syndrome: Report of two new families and review of the literature.

The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.

PURPOSE: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. METHODS: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. RESULTS: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. CONCLUSION: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Severe TUBB4A-Related Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum: Novel Neuropathological Findings.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations.

Health-Related Quality of Life for Patients With Genetically Determined Leukoencephalopathy.

BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.

The spectrum of adult-onset heritable white-matter disorders.

Unique clinical presentations and magnetic resonance imaging patterns can help differentiate the various adult presentations of leukodystrophies and leukoencephalopathies. White-matter disorders are genetically based disorders affecting the central nervous system white matter, with or without peripheral nervous system involvement. These disorders predominantly affect patients in the pediatric population; however, a number of classic leukodystrophies can present in adulthood. Disease progression can be of variable onset with a broad range of symptoms, usually progressing from cognitive dysfunction. Recognition of specific disorders can have important implications for treatment, involvement of multidisciplinary services, and important conversations surrounding social issues the families may face. The focus of this chapter is to highlight the adult presentations of the classic childhood-onset leukodystrophies as well as to describe leukodystrophies which predominantly present in adulthood.

The impact of electronic consultation on a Canadian tertiary care pediatric specialty referral system: A prospective single-center observational study.

BACKGROUND: Champlain BASE™ (Building Access to Specialists through eConsultation) is a web-based asynchronous electronic communication service that allows primary-care- practitioners (PCPs) to submit "elective" clinical questions to a specialist. For adults, PCPs have reported improved access and timeliness to specialist advice, averted face-to-face specialist referrals in up to 40% of cases and high provider satisfaction. OBJECTIVE: To determine whether the expansion of eConsult to a pediatric setting would result in similar measures of improved healthcare system process and high provider acceptance reported in adults. DESIGN: Prospective observational cohort study. SETTING: Single Canadian tertiary-care academic pediatric hospital (June 2014-16) servicing 1.2 million people. PARTICIPANTS: 1. PCPs already using eConsult. 2.Volunteer pediatric specialists provided services in addition to their regular workload. 3.Pediatric patients (< 18 years-old) referred for none-acute care conditions. MAIN OUTCOMES AND MEASURES: Specialty service utilization and access, impact on PCP course-of-action and referral-patterns and survey-based provider satisfaction data were collected. RESULTS: 1064 eConsult requests from 367 PCPs were answered by 23 pediatric specialists representing 14 specialty-services. The top three specialties represented were: General Pediatrics 393 cases (36.9%), Orthopedics 162 (15.2%) and Psychiatry 123 (11.6%). Median specialist response time was 0.9 days (range <1 hour-27 days), most consults (63.2%) required <10minutes to complete and 21/21(100%) specialist survey-respondents reported minimal workload burden. For 515/1064(48.4%) referrals, PCPs received advice for a new or additional course of action; 391/1064(36.7%) referrals resulted in an averted face-to-face specialist visit. In 9 specialties with complete data, the median wait-time was significantly less (p<0.001) for an eConsult (1 day, 95%CI:0.9-1.2) compared with a face-to-face referral (132 days; 95%CI:127-136). The majority (>93.3%) of PCPs rated eConsult as very good/excellent value for both patients and themselves. All specialist survey-respondents indicated eConsult should be a continued service. CONCLUSIONS AND RELEVANCE: Similar to adults, eConsult improves PCP access and timeliness to elective pediatric specialist advice and influences their care decisions, while reporting high end-user satisfaction. Further study is warranted to assess impact on resource utilization and clinical outcomes.