Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders.

Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.

Do Early Relapses Predict the Risk of Long-Term Relapsing Disease in an Adult and Paediatric Cohort with MOGAD?

OBJECTIVE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer-term relapse risk is unknown. Here, we investigate whether early relapses increase longer-term relapse risk in patients with MOGAD. METHODS: A retrospective analysis of 289 adult- and pediatric-onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. "Early relapses" were defined as attacks within the first 12 months from onset, with "very early relapses" defined within 30 to 90 days from onset and "delayed early relapses" defined within 90 to 365 days. "Long-term relapses" were defined as relapses beyond 12 months. Cox regression modeling and Kaplan-Meier survival analysis were used to estimate the long-term relapse risk and rate. RESULTS: Sixty-seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long-term relapses if any "early relapses" were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long-term relapses (HR = 2.64, p = 0.026). INTERPRETATION: The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long-term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric-onset disease. ANN NEUROL 2023;94:508-517.

Evolution of brain MRI lesions in paediatric myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and its relevance to disease course.

BACKGROUND: Lesion resolution is often observed in children with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and asymptomatic lesions are less commonly reported in MOGAD than in multiple sclerosis (MS). OBJECTIVE: We aimed to evaluate brain MRI changes over time in paediatric MOGAD. METHODS: Retrospective study in eight UK paediatric neuroscience centres. Acute brain MRI and available follow-up MRIs were reviewed. Predictors for lesion dynamic were evaluated using multivariable regression and Kaplan-Meier survival analyses were used to predict risk of relapse, disability and MOG-Ab status. RESULTS: 200 children were included (MOGAD 97; MS 103). At first MRI post attack, new symptomatic and asymptomatic lesions were seen more often in MS versus MOGAD (52/103 vs 28/97; p=0.002 and 37/103 vs 11/97; p<0.001); 83% of patients with MOGAD showed at least one lesion's resolution at first follow-up scan, and 23% had normal MRI. Only 1 patient with MS had single lesion resolution; none had normal MRI. Disappearing lesions in MOGAD were seen in 40% after the second attack, 21% after third attack and none after the fourth attack.New lesions at first follow-up scan were associated with increased likelihood of relapse (p=0.02) and persistent MOG-Ab serostatus (p=0.0016) compared with those with no new lesions. Plasma exchange was associated with increased likelihood of lesion resolution (p=0.01). Longer time from symptom onset to steroids was associated with increased likelihood of new lesions; 50% increase at 20 days (p=0.01). CONCLUSIONS: These striking differences in lesion dynamics between MOGAD and MS suggest greater potential to repair. Early treatment with steroids and plasma exchange is associated with reduced likelihood of new lesions.

Natural History of Leigh Syndrome: A Study of Disease Burden and Progression.

OBJECTIVE: This observational cohort study aims to quantify disease burden over time, establish disease progression rates, and identify factors that may determine the disease course of Leigh syndrome. METHODS: Seventy-two Leigh syndrome children who completed the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) at baseline at 3.7 years (interquartile range [IQR] = 2.0-7.6) and follow-up assessments at 7.5 years (IQR = 3.7-11.0) in clinics were enrolled. Eighty-two percent of this cohort had a confirmed genetic diagnosis, with pathogenic variants in the MT-ATP6 and SURF1 genes being the most common cause. The total NPMDS scores denoted mild (0-14), moderate (15-25), and severe (>25) disease burden. Detailed clinical, neuroradiological, and molecular genetic findings were also analyzed. RESULTS: The median total NPMDS scores rose significantly (Z = -6.9, p < 0.001), and the percentage of children with severe disease burden doubled (22% → 42%) over 2.6 years of follow-up. Poor function (especially mobility, self-care, communication, feeding, and education) and extrapyramidal features contributed significantly to the disease burden (τb  ≈ 0.45-0.68, p < 0.001). These children also deteriorated to wheelchair dependence (31% → 57%), exclusive enteral feeding (22% → 46%), and one-to-one assistance for self-care (25% → 43%) during the study period. Twelve children (17%) died after their last NPMDS scores were recorded. These children had higher follow-up NPMDS scores (disease burden; p < 0.001) and steeper increase in NPMDS score per annum (disease progression; p < 0.001). Other predictors of poor outcomes include SURF1 gene variants (p < 0.001) and bilateral caudate changes on neuroimaging (p < 0.01). INTERPRETATION: This study has objectively defined the disease burden and progression of Leigh syndrome. Our analysis has also uncovered potential influences on the trajectory of this neurodegenerative condition. ANN NEUROL 2022;91:117-130.

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Early predictors of disability of paediatric-onset AQP4-IgG-seropositive neuromyelitis optica spectrum disorders.

OBJECTIVE: To describe onset clinical features predicting time to first relapse and time to long-term visual, motor and cognitive disabilities in paediatric-onset aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSDs). METHODS: In this retrospective UK multicentre cohort study, we recorded clinical data of paediatric-onset AQP4-IgG NMOSD. Univariate and exploratory multivariable Cox proportional hazard models were used to identify long-term predictors of permanent visual disability, Expanded Disability Status Scale (EDSS) score of 4 and cognitive impairment. RESULTS: We included 49 paediatric-onset AQP4-IgG patients (38.8% white, 34.7% black, 20.4% Asians and 6.1% mixed), mean onset age of 12±4.1 years, and 87.7% were female. Multifocal onset presentation occurred in 26.5% of patients, and optic nerve (47%), area postrema/brainstem (48.9%) and encephalon (28.6%) were the most involved areas. Overall, 52.3% of children had their first relapse within 1 year from disease onset. Children with onset age <12 years were more likely to have an earlier first relapse (p=0.030), despite showing no difference in time to immunosuppression compared with those aged 12-18 years at onset. At the cohort median disease duration of 79 months, 34.3% had developed permanent visual disability, 20.7% EDSS score 4 and 25.8% cognitive impairment. Visual disability was associated with white race (p=0.032) and optic neuritis presentations (p=0.002). Cognitive impairment was predicted by cerebral syndrome presentations (p=0.048), particularly if resistant to steroids (p=0.034). CONCLUSIONS: Age at onset, race, onset symptoms and resistance to acute therapy at onset attack predict first relapse and long-term disabilities. The recognition of these predictors may help to power future paediatric clinical trials and to direct early therapeutic decisions in AQP4-IgG NMOSD.

Isolated central nervous system familial hemophagocytic lymphohistiocytosis (fHLH) presenting as a mimic of demyelination in children.

Isolated central nervous system (CNS) presentations of haemophagocytic lymphohistiocytosis (HLH), traditionally a systemic inflammatory condition, have been reported in adults and children. We identified nine patients with a diagnosis of isolated CNS familial hemophagocytic lymphohistiocytosis (fHLH) with symptom onset <18 years of age, and one asymptomatic sibling. Children with atypical chronic/recurrent CNS inflammation should be considered for immunological and genetic panel testing for fHLH even in the absence of any systemic inflammatory features. Despite haematopoietic stem cell transplantation (HSCT) being a mainstay of treatment, treatment failure and high morbidity and mortality post-HSCT suggest that alternative immune therapies may be worth considering.

Incidence of paediatric multiple sclerosis and other acquired demyelinating syndromes: 10-year follow-up surveillance study.

AIM: To describe a 10-year follow-up of children (<16y) with acquired demyelinating syndromes (ADS) from a UK-wide prospective surveillance study. METHOD: Diagnoses were retrieved from the patients' records via the patients' paediatric or adult neurologist using a questionnaire. Demyelinating phenotypes at follow-up were classified by an expert review panel. RESULTS: Twenty-four out of 125 (19.2%) children (64 males, 61 females; median age 10y, range 1y 4mo-15y 11mo), identified in the original study, were diagnosed with multiple sclerosis (incidence of 2.04/million children/year); 23 of 24 fulfilled 2017 McDonald criteria at onset. Aquaporin-4-antibody neuromyelitis optica spectrum disorders were diagnosed in three (2.4%, 0.26/million children/year), and relapsing myelin oligodendrocyte glycoprotein antibody-associated disease in five (4%, 0.43/million children/year). Three out of 125 seronegative patients relapsed and 85 of 125 (68%) remained monophasic over 10 years. Five of 125 patients (4%) originally diagnosed with ADS were reclassified during follow-up: three children diagnosed initially with acute disseminated encephalomyelitis were subsequently diagnosed with acute necrotising encephalopathy (RAN-binding protein 2 mutation), primary haemophagocytic lymphohistiocytosis (Munc 13-4 gene inversion), and anti-N-methyl-d-aspartate receptor encephalitis. One child initially diagnosed with optic neuritis was later diagnosed with vitamin B12 deficiency, and one presenting with transverse myelitis was subsequently diagnosed with Sjögren syndrome. INTERPRETATION: The majority of ADS presentations in children are monophasic, even at 10-year follow-up. Given the implications for treatment strategies, multiple sclerosis and central nervous system autoantibody mimics warrant extensive investigation.

Primary progressive multiple sclerosis presenting under the age of 18 years: Fact or fiction?

Previous cohort studies on paediatric multiple sclerosis (MS) have reported very low frequencies for a primary progressive MS (PPMS) course ranging from 0% to 7%. We identified six patients presenting prior to the age of 18 years and fulfilling the 2017 McDonald Criteria for PPMS. Presentation with progressive neurological symptoms and signs in young people should prompt evaluation for genetic causes such as leukodystrophies, hereditary spastic paraparesis and mitochondrial diseases given the rarity of primary progressive course in paediatric MS. In the absence of an alternative diagnosis, with new therapeutic options becoming available for PPMS, this diagnosis should then be considered.

Opsoclonus-myoclonus in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is a rare genetic neuroinflammatory disorder caused by abnormal upregulation of type 1 interferon signalling. Opsoclonus-myoclonus syndrome is a rare autoimmune phenotype demonstrating a disturbance in the humoral immune response mostly seen in the context of paraneoplastic or postinfectious states, although its pathophysiology is incompletely understood. We report the first three children described with AGS demonstrating transient opsoclonus and myoclonus after irritability and/or developmental regression, suggesting a pathological association. We describe the presentation, clinical features, progress, cerebrospinal fluid (CSF) inflammatory markers, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings in these children. Two patients had developmental regression but demonstrated a positive response to JAK1/2 inhibition clinically and on serial examination of CSF inflammatory markers. These findings suggest that AGS should be considered in children presenting with opsoclonus-myoclonus, and that the association between AGS and opsoclonus-myoclonus further supports the role of immune dysregulation as causal in the rare neurological phenomenon opsoclonus and myoclonus. What this paper adds There is a phenotypic association between opsoclonus-myoclonus syndrome and Aicardi-Goutières syndrome. There is clinical evidence of immune dysregulation in the pathogenesis of opsoclonus and myoclonus.

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort.

OBJECTIVE: To compare the performance of the 2017 McDonald criteria with that of the 2010 criteria for the diagnosis of multiple sclerosis (MS) in children in the clinical setting. METHODS: In this retrospective, multi-centre study, we identified children who presented with symptoms suggestive of a clinically isolated syndrome (CIS) and were followed up for at least 2 years or until their second attack. RESULTS: Of 156 children with CIS followed up for a median of 4.17 years, 94 (60.3%) were diagnosed with MS. In all, 83 (88.3%) of these fulfilled the 2010 dissemination in space (DIS) criteria at onset. Three additional children fulfilled the 2017 DIS criteria because of the inclusion of symptomatic lesions. Of the 59 children with MS who underwent post-gadolinium magnetic resonance imaging (MRI), 44 (74.6%) fulfilled the 2010 dissemination in time (DIT) criteria at baseline. When the presence of oligoclonal bands (OCBs) was used to substitute DIT, an additional 35 children (79/94, 84.0%) were diagnosed with MS according to the 2017 criteria. The 2017 criteria had higher accuracy (87.2% vs 66.7%), higher sensitivity (84.0% vs 46.8%), but reduced specificity (91.9% vs 96.8%) when compared to the 2010 criteria. CONCLUSION: The improved performance of the 2017 criteria when compared to the 2010 criteria was predominantly due to the inclusion of intrathecal OCBs.

Early predictors of epilepsy and subsequent relapse in children with acute disseminated encephalomyelitis.

OBJECTIVE: To identify predictors of epilepsy and clinical relapses in children presenting with acute disseminated encephalomyelitis (ADEM). METHODS: Children presenting with ADEM between 2005 and 2017 and tested clinically for MOG-Ab were identified from three tertiary paediatric neurology centres in the United Kingdom. Patients were followed up for a median of 6 years (range, 1-16 years). RESULTS: A total of 74 children were studied (38 females; median age at first presentation: 4.5 years (range, 1.4-16 years)). MOG-Ab was positive in 50/74 (67.6%) of cases, and 27 (54%) of MOG-Ab positive children presented with a neurological relapse over time. MOG-Ab was more frequently positive in the relapsing group than in the monophasic group (27/31 vs 23/43; odds ratio 5.9 (95% CI: 1.8-19.7); p = 0.002). 16/74 (22%) children had seizures during the acute presentation with ADEM and 12/74 (16.2%) patients were diagnosed with post-ADEM epilepsy. The diagnosis of post-ADEM epilepsy was more frequently observed in children with relapsing disease than monophasic disease (10/31 vs 2/43; odds ratio 9.8 (95% confidence interval (CI): 2.0-48.7); p = 0.003), in children who had positive intrathecal oligoclonal bands than those with negative bands (4/7 vs 4/30; odds ratio 8.7 (95% CI: 1.4-54.0); p = 0.027) and in children who had positive MOG-Ab than negative MOG-Ab cases (11/12 vs 39/62; odds ratio 6.5 (95% CI:0.8-53.6); p = 0.051). CONCLUSION: A higher relapse rate and a greater risk of post-ADEM epilepsy in children with MOG-Ab-associated disease may indicate a chronic disease with immune-mediated seizures in these children.

Implementation and Early Evaluation of a Quantitative Electroencephalography Program for Seizure Detection in the PICU.

OBJECTIVES: To describe implementation and early evaluation of using quantitative electroencephalography for electrographic seizure detection by PICU clinician staff. DESIGN: Prospective observational study of electrographic seizure detection by PICU clinicians in patients monitored with quantitative electroencephalography. Quantitative electroencephalography program implementation included a continuous education and training package. Continuous quantitative electroencephalography monitoring consisted of two-channel amplitude-integrated electroencephalography, color density spectral array, and raw-electroencephalography. SETTING: PICU. PATIENTS: Children less than 18 years old admitted to the PICU during the 14-month study period and deemed at risk of electrographic seizure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Real time electrographic seizure detection by a PICU team was analyzed for diagnostic accuracy and promptness, against electrographic seizure identification by a trained neurophysiologist, retrospectively reading the same quantitative electroencephalography and blinded to patient details. One-hundred one of 1,510 consecutive admissions (6.7%) during the study period underwent quantitative electroencephalography monitoring. Status epilepticus (35%) and suspected hypoxic-ischemic injury (32%) were the most common indications for quantitative electroencephalography. Electrographic seizure was diagnosed by the neurophysiologist in 12% (n = 12) of the cohort. PICU clinicians correctly diagnosed all 12 patients (100% sensitivity and negative predictive value). An additional eleven patients had a false-positive diagnosis of electrographic seizure (false-positive rate = 52% [31-73%]) leading to a specificity of 88% (79-94%). Median time to detect seizures was 25 minutes (5-218 min). Delayed recognition of electrographic seizure (> 1 hr from onset) occurred in five patients (5/12, 42%). CONCLUSIONS: Early evaluation of quantitative electroencephalography program to detect electrographic seizure by PICU clinicians suggested good sensitivity for electrographic seizure detection. However, the high false-positive rate is a challenge. Ongoing work is needed to reduce the false positive diagnoses and avoid electrographic seizure detection delays. A comprehensive training program and regular refresher updates for clinical staff are key components of the program.

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy.

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.

A framework for measurement and harmonization of pediatric multiple sclerosis etiologic research studies: The Pediatric MS Tool-Kit.

BACKGROUND: While studying the etiology of multiple sclerosis (MS) in children has several methodological advantages over studying etiology in adults, studies are limited by small sample sizes. OBJECTIVE: Using a rigorous methodological process, we developed the Pediatric MS Tool-Kit, a measurement framework that includes a minimal set of core variables to assess etiological risk factors. METHODS: We solicited input from the International Pediatric MS Study Group to select three risk factors: environmental tobacco smoke (ETS) exposure, sun exposure, and vitamin D intake. To develop the Tool-Kit, we used a Delphi study involving a working group of epidemiologists, neurologists, and content experts from North America and Europe. RESULTS: The Tool-Kit includes six core variables to measure ETS, six to measure sun exposure, and six to measure vitamin D intake. The Tool-Kit can be accessed online ( www.maelstrom-research.org/mica/network/tool-kit ). CONCLUSION: The goals of the Tool-Kit are to enhance exposure measurement in newly designed pediatric MS studies and comparability of results across studies, and in the longer term to facilitate harmonization of studies, a methodological approach that can be used to circumvent issues of small sample sizes. We believe the Tool-Kit will prove to be a valuable resource to guide pediatric MS researchers in developing study-specific questionnaire.

Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency.

The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain keto acids (BCKAs) with undetectable l-allo-isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide-ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein-restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.

Paediatric multiple sclerosis: a new era in diagnosis and treatment.

Multiple sclerosis is a chronic immune-mediated demyelinating disease of the central nervous system. The diagnosis of multiple sclerosis in children, as in adults, requires evidence of dissemination of inflammatory activity in more than one location in the central nervous system (dissemination in space) and recurrent disease over time (dissemination in time). The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) and aquaporin-A antibodies (AQP4-Ab), and the subsequent discovery of their pathogenic mechanisms, have led to a shift in the classification of relapsing demyelinating syndromes. This is reflected in the 2017 revised criteria for the diagnosis of multiple sclerosis, which emphasizes the exclusion of multiple sclerosis mimics and aims to enable earlier diagnosis and thus treatment initiation. The long-term efficacy of individual therapies initiated in children with multiple sclerosis is hard to evaluate, owing to the small numbers of patients who have the disease, the relatively high number of patients who switch therapy, and the need for long follow-up studies. Nevertheless, an improvement in prognosis with a globally reduced annual relapse rate in children with multiple sclerosis is now observed compared with the pretreatment era, indicating a possible long-term effect of therapies. Given the higher relapse rate in children compared with adults, and the impact multiple sclerosis has on cognition in the developing brain, there is a question whether rapid escalation or potent agents should be used in children, while the short- and long-term safety profiles of these drugs are being established. With the results of the first randomized controlled trial of fingolimod versus interferon-ß1a in paediatric multiple sclerosis published in 2018 and several clinical trials underway, there is hope for further progress in the field of paediatric multiple sclerosis. WHAT THIS PAPER ADDS: Early and accurate diagnosis of multiple sclerosis is crucial. The discovery of antibody-mediated demyelination has changed the diagnosis and management of relapsing demyelination syndromes. Traditional escalation therapy is being challenged by induction therapy.

ESCLEROSIS MÚLTIPLE PEDIÁTRICA: UNA NUEVA ERA EN EL DIAGNÓSTICO Y TRATAMIENTO: La esclerosis múltiple es una enfermedad desmielinizante crónica mediada por el sistema inmunitario del sistema nervioso central. El diagnóstico de esclerosis múltiple en niños, como en adultos, requiere evidencia de diseminación de actividad inflamatoria en más de un lugar en el sistema nervioso central (diseminación en el espacio) y enfermedad recurrente a lo largo del tiempo (diseminación en el tiempo). La identificación de los anticuerpos de la glicoproteína oligodendrocítica de la mielina (MOG-Ab) y los anticuerpos de la acuaporina-A (AQP4-Ab), y el posterior descubrimiento de sus mecanismos patógenos, han conducido a un cambio en la clasificación de los síndromes desmielinizantes recurrentes. Esto se refleja en los criterios revisados ​​de 2017 para el diagnóstico de esclerosis múltiple, que enfatiza la exclusión de los imitadores de la esclerosis múltiple y tiene como objetivo permitir un diagnóstico más temprano y, por lo tanto, el inicio del tratamiento. La eficacia a largo plazo de las terapias individuales iniciadas en niños con esclerosis múltiple es difícil de evaluar, debido a la pequeña cantidad de pacientes que tienen la enfermedad, la cantidad relativamente alta de pacientes que cambian de terapia y la necesidad de estudios de seguimiento prolongados. Sin embargo, ahora se observa una mejora en el pronóstico con una tasa de recaída anual globalmente reducida en niños con esclerosis múltiple en comparación con la era anterior al tratamiento previo, lo que indica un posible efecto a largo plazo de las terapias. Debido a la mayor tasa de recaída en niños en comparación con los adultos, y el impacto que tiene la esclerosis múltiple en la cognición en el cerebro en desarrollo, existe la duda de si se deben usar agentes de aumento rápido o potentes en niños, mientras que los perfiles de seguridad a corto y largo plazo de estos medicamentos se están estableciendo. Con los resultados del primer ensayo controlado aleatorio de fingolimod versus interferón-ß1a en esclerosis múltiple pediátrica publicado en 2018 y varios ensayos clínicos en curso, existe la esperanza de un mayor progreso en el campo de la esclerosis múltiple pediátrica.

ESCLEROSE MÚLTIPLA PEDIÁTRICA: UMA NOVA ERA NO DIAGNÓSTICO E TRATAMENTO: A esclerose múltipla é uma doença desmielinizante imunomediada crônica do sistema nervoso central. O diagnóstico de esclerose múltipla em crianças, como em adultos, exige evidência de disseminação da atividade inflamatória em mais de um local no sistema nervoso central (disseminação no espaço) e doença recorrente ao longo do tempo (disseminação no tempo). A identificação de anticorpos anti-glicoproteína de mielina do oligodendrócito (MOG-Ab) e anticorpos anti-aquaporina A (AQP4-Ab), e a subsequente descoberta de seus mecanismos patogênicos, levaram a uma mudança na classificação das síndromes desmielinizantes recidivantes. Isso se reflete nos critérios revisados de 2017 para o diagnóstico de esclerose múltipla, que enfatizam a exclusão de transtornos que mimetizam esclerose múltipla e visam permitir o diagnóstico precoce e, portanto, o início do tratamento. É difícil avaliar a eficácia a longo prazo de terapias individuais iniciadas em crianças com esclerose múltipla, devido ao pequeno número de pacientes que têm a doença, o número relativamente alto de pacientes que trocam de terapia e a necessidade de estudos de acompanhamento a longo prazo. No entanto, uma melhora no prognóstico com uma taxa de recaída anual globalmente reduzida em crianças com esclerose múltipla é agora observada em comparação com a era pré-tratamento, indicando um possível efeito a longo prazo das terapias. Dada a maior taxa de recaída em crianças em comparação com adultos, e o impacto da esclerose múltipla na cognição no cérebro em desenvolvimento, há uma questão se a escalada rápida ou agentes potentes devem ser usados em crianças, enquanto os perfis de segurança de curto e longo prazo destas drogas estão sendo estabelecidos. Com os resultados do primeiro estudo controlado randomizado de fingolimode versus interferon-ß1a na esclerose múltipla pediátrica publicado em 2018 e vários ensaios clínicos em andamento, há esperança de mais progressos no campo da esclerose múltipla pediátrica.

Utility and safety of plasma exchange in paediatric neuroimmune disorders.

AIM: Our aim was to ascertain the indications, side effects, and outcomes in children receiving therapeutic plasma exchange (TPE) for neurological disorders. METHOD: Medical records were retrospectively reviewed for 58 consecutive children (age ≤16y) undergoing 67 courses of TPE across four tertiary centres. Patient characteristics, treatment schedules, complications, and outcomes were analysed. RESULTS: Median age at initiation of TPE was 9 years (range 1-15y). Indications included peripheral nervous system (PNS; n=18) and central nervous system (CNS; n=40) disorders. Courses comprised a median six exchanges (range 2-179) over 8 days (range 3-466). Forty-two out of 58 (73%) children were severely disabled (bedridden) at initiation and 24 out of 58 (41%) were admitted to intensive care units. Treating clinicians' impression of response was positive in 16 out of 18 of those with PNS disorders versus 22 out of 40 with CNS disorders (p=0.016). Improvements in disability (modified Rankin Scale) occurred in 13 out of 58 (22%) children by completion of TPE (p=0.003). Complications occurred in 40 out of 67 (60%) courses, of which 16 out of 67 (24%) were line related. Potentially life-threatening complications occurred in 2 out of 67 (3%) courses. INTERPRETATION: This cohort study provides safety and efficacy information for clinicians and families and a basis for future prospective studies. WHAT THIS PAPER ADDS: Disability scores for severe neuroimmune disorders remained stable or improved during therapeutic plasma exchange treatment. Complications occurred frequently but were typically mild and correctable.

UTILIDAD Y SEGURIDAD DEL INTERCAMBIO DE PLASMA EN TRASTORNOS NEUROINMUNES PEDIÁTRICOS: OBJETIVO: Nuestro objetivo fue determinar las indicaciones, los efectos secundarios y los resultados en niños que recibieron intercambio terapéutico de plasma (TPE) para trastornos neurológicos. MÉTODO: Se revisaron retrospectivamente los registros médicos de 58 niños consecutivos (≤16 años) que se sometieron a 67 cursos de TPE en cuatro centros terciarios. Se analizaron las características de los pacientes, los esquemas de tratamiento, las complicaciones y los resultados. RESULTADOS: La edad mediana al inicio de la TPE fue de 9 años (rango 1-15 años). Las indicaciones incluían trastornos del sistema nervioso periférico (SNP; n = 18) y del sistema nervioso central (SNC; n = 40). Los cursos comprendieron una mediana de 6 intercambios (rango 2-179) durante 8 días (rango 3-466). Cuarenta y dos de 58 (73%) niños presentaban un grado de discapacidad severa (postrados en cama) al inicio y 24 de 58 (41%) fueron ingresados en unidades de cuidados intensivos. El tratamiento de la impresión de respuesta de los médicos fue positivo en 16 de 18 de las personas con trastornos de SNP versus 22 de 40 en trastornos del SNC (p = 0,016). Las mejoras en la discapacidad (escala de Rankin modificada) se produjeron en 13 de los 58 (22%) niños al completar el TPE (p = 0,003). Las complicaciones ocurrieron en 40 de 67 cursos (60%), de los cuales 16 de 67 (24%) estaban relacionados con la línea. Complicaciones potencialmente peligrosas para la vida ocurrieron en 2 de 67 (3%) cursos. INTERPRETACIÓN: Este estudio de cohorte proporciona información de seguridad y eficacia para profesionales y familiares y una base para futuros estudios prospectivos.

UTILIDADE E SEGURANÇA DA TRANSFERÊNCIA DE PLASMA EM TRANSTORNOS NEUROIMUNES PEDIÁTRICOS: OBJETIVO: Nosso objetivo foi verificar as indicações, efeitos colaterais, e resultados em crianças recebendo transferência terapêutica de plasma (TTP) para transtornos neurológicos. MÉTODO: Registros médicos foram retrospectivamente revisados para 58 crianças (idade ≤16a) passando por 67 cursos de TTP em quatro centros terciários. Características dos pacientes, rotina de tratamento, complicações e resultados foram analisados. RESULTADOS: A idade mediana ao início da TTP foi 9 anos (variação 1-15 anos). Indicações incluíram transtornos do sistema nervoso periférico (SNP; n = 18) e sistema nervoso central (SNC; n = 40) disorders. Os cursos compreenderam uma mediana de seis transferências (variação 2-179) em 8 dias (variação 3-466). Quarenta e duas em 58 (73%) crianças estavam severamente incapacidadas (acamadas) no início e 24 em 58 (41%) foram admitidas em unidades de cuidado intensivo. A impressão de resposta dos clínicos que as tratavam foi positiva em 16 de 18 daquelas com transtornos do SNP versus 22 de 40 daquelas com desordens do SNC (p = 0,016). Melhoras na incapacidade (Escala de Rankin modificada) ocorreram em 13 de 58 (22%) crianças ao final da TTP (p = 0,003). Complicações ocorreram em 40 de 67 (60%) cursos, dos quais 16 em 67 (24%) eram relacionados à linha. Complicações com potencial risco de vida ocorreram em 2 de 67 (3%) cursos. INTERPRETAÇÃO: Este estudo de coorte fornece informação sobre a segurança e eficácia para clínicos e famílias, e uma base para futuros estudos prospectivos.