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BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct demyelinating disease of the central nervous system. Immunoglobulin (Ig) has been used as a maintenance therapy to prevent relapses in MOGAD, but the impact of Ig on serum MOG-IgG titers is unclear. OBJECTIVE: To characterize the variation in serum MOG-IgG titers after initiation of Ig treatment in people with MOGAD. METHODS: We conducted a retrospective study of 10 patients with a diagnosis of MOGAD and available serum MOG-IgG titers before and after initiation of maintenance Ig treatment. RESULTS: We found that most of the patients remained MOG-IgG seropositive while on Ig treatment with a reduced or unchanged titer, despite a lack of disease activity. CONCLUSIONS: This case series suggests that the mechanism of action of Ig therapy in MOGAD is not exclusively dependent on MOG-IgG titer reduction.
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Cognición , Investigación , Humanos , Estudios Retrospectivos , Sistema Nervioso Central , Inmunoglobulina G , Glicoproteína Mielina-Oligodendrócito , AutoanticuerposRESUMEN
BACKGROUND: Drug shortages are a common issue that healthcare systems face and can result in adverse health outcomes for patients requiring inferior alternate treatment. The United States recently experienced a national drug shortage of intravenous immunoglobulin (IVIG). Several reported strategies to address the IVIG and other drug shortages have been proposed; however, there is a lack of evidence-based methods for protocol development and implementation. OBJECTIVE: To evaluate the efficacy of introducing a multidisciplinary task force and tier system of indications and to minimize adverse effects during a shortage of IVIG. METHODS: Faculty members across disciplines with expertise in IVIG use were invited to participate in a task force to address the shortage and ensure adequate supply for emergent indications. A tier system of IVIG indications was established according to the severity of diagnosis, urgency of indication, and quality of supporting evidence. Based on inventory, indications in selected tiers were auto-approved. Orders that could not be automatically approved were escalated for task force review. RESULTS: Overall, there were 342 distinct requests for IVIG during the study period (August 1, 2019 to December 31, 2019). All Tier 1 indications were approved. Of all requests, only 2.6% (9) of requests were denied, none of which resulted in adverse effects based on retrospective chart review. Seven patients who regularly receive IVIG had possible adverse effects due to dose reduction or spacing of treatment; however, each complication was multifactorial and not attributed to the shortage or tier system implementation alone. CONCLUSION: Implementation of a multidisciplinary task force and tier system to appropriately triage high-priority indications for limited pharmaceutical agents should be considered in health institutions faced with a drug shortage.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Inmunoglobulinas Intravenosas , Niño , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Estudios Retrospectivos , Atención Terciaria de Salud , Centros de Atención Terciaria , Inyecciones Intravenosas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológicoRESUMEN
OBJECTIVES: Celiac disease (CeD) has been associated with increased mental health disorders (MHD) and psychosocial distress in children, which may complicate treatment with the gluten-free diet (GFD). This single-center cross-sectional study examined psychological comorbidities in children with CeD to assess psychological needs in CeD care. METHODS: Participants were 73 parents (95% mothers) of children (ages 3-18) attending a multidisciplinary celiac disease clinic. Parents completed electronic surveys about their child's MHD history, psychological symptoms, and GFD experiences. Rates of MHD were calculated and compared with National Institute of Mental Health population-level data. Differences in psychosocial symptoms and GFD experiences were examined based on child age, time since CeD diagnosis, and MHD. RESULTS: Thirty-four percentage of children had at least 1 MHD; anxiety disorders (16%, Pâ<â0.001) and attention-deficit/hyperactivity disorder (ADHD; 16%, Pâ=â0.01) were more common than general population rates. More than 1 quarter of parents reported current child psychosocial distress (28%-39%), and approximately half reported parent stress (51%) and financial burden (46%) associated with the GFD. Parents of children with new CeD diagnoses reported lower confidence in the GFD (Pâ<â0.01) but MHD, stress, and financial burden did not differ by time since CeD diagnosis. Children with MHD had more anxiety, anger, overall distress, and parent distress than those without MHD (Psâ<â.05). CONCLUSIONS: Comorbid CeD and MHD was common and was associated with increased child and parent psychosocial distress. Our findings emphasize the importance of psychological screening and services to assess for and treat comorbid MHD and to mitigate psychosocial distress associated with the GFD.
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Trastorno por Déficit de Atención con Hiperactividad , Enfermedad Celíaca , Adolescente , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/epidemiología , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Salud Mental , Padres , Estrés Psicológico/epidemiología , Estrés Psicológico/etiologíaRESUMEN
This study aims to describe the psychological needs in children with celiac disease (CD) and to examine the feasibility of psychological consultation in a multidisciplinary clinic. Participants (N = 69) included children with CD and their parents who completed a pre-clinic mental health survey and a 30-min psychological consultation as part of a multidisciplinary clinic (including gastroenterology, nutrition, education, neurology, and neuropsychology). Quantitative and qualitative analyses examined psychological needs, experiences, and satisfaction. The psychologist identified clinically significant symptoms and provided referrals in 49% of children. There were no significant differences by time since CD diagnosis. During the psychology consultation, families discussed emotional adjustment, impact on life and physical well-being, and management of the gluten-free diet. Parents reported high levels of satisfaction from the clinic visit. We identified frequent psychological needs in pediatric CD. The multidisciplinary approach may be a feasible model for specialized, optimal treatment in this population.
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Enfermedad Celíaca/psicología , Enfermedad Celíaca/terapia , Servicios de Salud Mental , Adolescente , Niño , Dieta Sin Gluten/psicología , Escolaridad , Femenino , Humanos , Masculino , Padres/psicología , Satisfacción Personal , Encuestas y CuestionariosRESUMEN
BACKGROUND: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. OBJECTIVE: To determine the association between dietary factors and MS in children. METHODS: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed. RESULTS: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01). CONCLUSION: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.
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Dieta , Esclerosis Múltiple , Adolescente , Estudios de Casos y Controles , Niño , Encuestas sobre Dietas , Femenino , Humanos , Masculino , Factores de RiesgoRESUMEN
BACKGROUND: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. OBJECTIVE: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. METHODS: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). RESULTS: HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10-16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10-16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02. CONCLUSION: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.
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Predisposición Genética a la Enfermedad/genética , Cadenas HLA-DRB1/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Femenino , Pruebas Genéticas , Humanos , Modelos Logísticos , Masculino , Factores de Riesgo , SueciaAsunto(s)
Encefalomielitis Aguda Diseminada/diagnóstico , Encefalomielitis Aguda Diseminada/terapia , Mielitis Transversa/diagnóstico , Mielitis Transversa/terapia , Enfermedad Aguda , Niño , Diagnóstico Diferencial , Encefalomielitis Aguda Diseminada/etiología , Humanos , Mielitis Transversa/etiología , Pediatría , Recurrencia , Resultado del TratamientoRESUMEN
We describe an MRI phenotype seen in a series of patients with mutations in PTEN who have clinical features consistent with PTEN hamartoma tumor syndrome (PHTS). Retrospective review of clinical data and MRI was performed in 23 subjects evaluated in four different tertiary care centers with clinical programs in inherited disorders of the white matter. Patients were referred due to abnormal MRI features and abnormal PTEN sequencing was identified. All subjects had significant macrocephaly (on average >4 SD above the mean), developmental delay with or without autism spectrum disorder and uniform MRI features of enlarged perivascular spaces and multifocal periventricular white matter abnormalities. The phenotype of PHTS may include MRI abnormalities such as multifocal periventricular white matter abnormalities and enlarged perivascular spaces. These neuroimaging findings, in association with macrocephaly and developmental delay, should prompt consideration of PTEN as a diagnostic possibility.
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Imagen por Resonancia Magnética , Megalencefalia/diagnóstico , Megalencefalia/genética , Mutación , Fosfohidrolasa PTEN/genética , Encéfalo/patología , Cefalometría , Preescolar , Femenino , Síndrome de Hamartoma Múltiple/diagnóstico , Síndrome de Hamartoma Múltiple/genética , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Eosinophils in cerebrospinal fluid (CSF) are an uncommon finding most often associated with parasitic infections, but have also been described in some neuroinflammatory disorders. Eosinophilic infiltration is not thought to be a typical feature of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We aim to describe the rate of CSF eosinophil positivity in a cohort of pediatric MOGAD patients. METHODS: Single-center retrospective chart review of pediatric MOGAD patients. Clinical and laboratory data was collected from the electronic medical record and analyzed. RESULTS: Of 46 pediatric patients with positive serum myelin oligodendrocyte glycoprotein antibody (MOG-IgG) identified, 38 patients fulfilling internationally proposed MOGAD diagnostic criteria were included for analysis. 6 patients with MOGAD were excluded as no CSF data was available, and 2 patients with positive MOG-IgG but diagnosis more consistent with MS were excluded. Median age was 7.3 years, and 19/38 (50 %) were female. Acute disseminated encephalomyelitis (ADEM) was the most common presenting phenotype (23/38, 61 %), and other phenotypes included optic neuritis (10/38, 26 %), transverse myelitis (3/38, 8 %), and neuromyelitis optica spectrum disorder (NMOSD) (2/38, 5 %). 12 of 36 (33 %) patients with all lumbar puncture (LP) data available had CSF eosinophils present, with eosinophil mean of 3 % and range from 1 % to 18 % of CSF while blood cells. CONCLUSION: CSF eosinophils were present in one third of pediatric MOGAD patients, which is a higher rate than previously reported in either MOGAD or aquaporin-4 antibody positive NMOSD cohorts. Understanding the CSF composition of pediatric MOGAD patients helps to facilitate more prompt diagnosis and treatment and may shed light onto underlying pathologic mechanisms of disease with the goal to inform future therapeutic targets.
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Autoanticuerpos , Eosinófilos , Glicoproteína Mielina-Oligodendrócito , Humanos , Glicoproteína Mielina-Oligodendrócito/inmunología , Femenino , Masculino , Niño , Estudios Retrospectivos , Eosinófilos/inmunología , Preescolar , Adolescente , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Encefalomielitis Aguda Diseminada/inmunología , Encefalomielitis Aguda Diseminada/líquido cefalorraquídeo , Encefalomielitis Aguda Diseminada/sangre , Encefalomielitis Aguda Diseminada/diagnóstico , Neuromielitis Óptica/líquido cefalorraquídeo , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/sangre , Lactante , Mielitis Transversa/inmunología , Mielitis Transversa/líquido cefalorraquídeo , Mielitis Transversa/sangre , Neuritis Óptica/inmunología , Neuritis Óptica/líquido cefalorraquídeo , Neuritis Óptica/sangre , Enfermedades Autoinmunes Desmielinizantes SNC/líquido cefalorraquídeo , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Enfermedades Autoinmunes Desmielinizantes SNC/sangreRESUMEN
BACKGROUND: Isolated psychiatric symptoms can be the initial symptom of pediatric anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE. METHODS: This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18 years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data was performed. RESULTS: Of 249 children included, 12 (5%) had only psychiatric symptoms without other typical clinical features of autoimmune encephalitis at presentation. All but one (11 of 12 = 92%) had at least one abnormal finding on initial ancillary testing: eight of 12 (67%) had an abnormal EEG, six of 12 (50%) had an abnormal MRI, and five of 12 (42%) demonstrated CSF pleocytosis. The single patient with a normal MRI, EEG, and CSF profile had low positive CSF NMDA antibody (titer of 1:1), and symptoms improved without immunotherapy. CONCLUSIONS: Isolated first-episode psychiatric symptoms in pNMDARE are uncommon, and the majority of children will exhibit additional neurodiagnostic abnormalities. Delaying immunotherapy in a child with isolated psychiatric symptoms and normal neurodiagnostic testing may be warranted while awaiting confirmatory antibody testing.
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BACKGROUND AND OBJECTIVES: Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS: This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS: MS cases (64% female, mean age 15.4 years, SD 2.8) were demographically similar to controls (60% female, mean age 14.9 years, SD 3.9). Cases were less likely to have a mother with a bachelor's degree or higher (OR 0.42, 95% CI 0.22-0.80, p = 0.009) and were more likely to experience childhood neighborhood disadvantage (OR 1.04 for each additional point on the neighborhood socioeconomic disadvantage score, 95% CI 1.00-1.07; p = 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION: Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.
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Experiencias Adversas de la Infancia , Edad de Inicio , Esclerosis Múltiple , Factores Socioeconómicos , Humanos , Femenino , Adolescente , Estudios de Casos y Controles , Masculino , Esclerosis Múltiple/epidemiología , Niño , Adulto Joven , Preescolar , Experiencias Adversas de la Infancia/estadística & datos numéricos , Adulto , Estados Unidos/epidemiologíaRESUMEN
The current diagnostic criteria for pediatric onset multiple sclerosis (POMS) are summarized, as well as the evidence for performance of the most recent iteration of McDonald criteria in the pediatric population. Next, the varied roles of MRI in POMS are reviewed, including diagnostic considerations and research-based utilization. The primary role of bloodwork and cerebrospinal fluid studies in the diagnosis of POMS is to rule out disease mimics. Prognostically, POMS portends a more inflammatory course with higher relapse rate and disability reached at younger ages compared with AOMS counterparts. As such, there is an emerging trend toward the earlier use of highly efficacious disease modifying therapies to target prompt immunomodulatory disease control. Current POMS disease modifying therapies (DMTs) and active clinical POMS trials are detailed.
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Esclerosis Múltiple , Niño , Humanos , Edad de Inicio , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/terapia , Guías como AsuntoRESUMEN
OBJECTIVES: How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS: This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS: A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION: Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Humanos , Niño , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico por imagen , Encefalitis Antirreceptor N-Metil-D-Aspartato/patología , Estudios Retrospectivos , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Lóbulo OccipitalRESUMEN
OBJECTIVE: Heterozygous mutations in the GBA1 gene elevate the risk of Parkinson disease and dementia with Lewy bodies; both disorders are characterized by misprocessing of α-synuclein (SNCA). A loss in lysosomal acid-ß-glucosidase enzyme (GCase) activity due to biallelic GBA1 mutations underlies Gaucher disease. We explored mechanisms for the gene's association with increased synucleinopathy risk. METHODS: We analyzed the effects of wild-type (WT) and several GBA mutants on SNCA in cellular and in vivo models using biochemical and immunohistochemical protocols. RESULTS: We observed that overexpression of all GBA mutants examined (N370S, L444P, D409H, D409V, E235A, and E340A) significantly raised human SNCA levels to 121 to 248% of vector control (p < 0.029) in neural MES23.5 and PC12 cells, but without altering GCase activity. Overexpression of WT GBA in neural and HEK293-SNCA cells increased GCase activity, as expected (ie, to 167% in MES-SNCA, 128% in PC12-SNCA, and 233% in HEK293-SNCA; p < 0.002), but had mixed effects on SNCA. Nevertheless, in HEK293-SNCA cells high GCase activity was associated with SNCA reduction by ≤32% (p = 0.009). Inhibition of cellular GCase activity (to 8-20% of WT; p < 0.0017) did not detectably alter SNCA levels. Mutant GBA-induced SNCA accumulation could be pharmacologically reversed in D409V-expressing PC12-SNCA cells by rapamycin, an autophagy-inducer (≤40%; 10µM; p < 0.02). Isofagomine, a GBA chaperone, showed a related trend. In mice expressing two D409Vgba knockin alleles without signs of Gaucher disease (residual GCase activity, ≥20%), we recorded an age-dependent rise of endogenous Snca in hippocampal membranes (125% vs WT at 52 weeks; p = 0.019). In young Gaucher disease mice (V394Lgba+/+//prosaposin[ps]-null//ps-transgene), which demonstrate neurological dysfunction after age 10 weeks (GCase activity, ≤10%), we recorded no significant change in endogenous Snca levels at 12 weeks of age. However, enhanced neuronal ubiquitin signals and axonal spheroid formation were already present. The latter changes were similar to those seen in three week-old cathepsin D-deficient mice. INTERPRETATION: Our results demonstrate that GBA mutants promote SNCA accumulation in a dose- and time-dependent manner, thereby identifying a biochemical link between GBA1 mutation carrier status and increased synucleinopathy risk. In cell culture models, this gain of toxic function effect can be mitigated by rapamycin. Loss in GCase activity did not immediately raise SNCA concentrations, but first led to neuronal ubiquitinopathy and axonal spheroids, a phenotype shared with other lysosomal storage disorders.
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Enfermedad de Gaucher/genética , Glucosilceramidasa/genética , Enfermedad por Cuerpos de Lewy/genética , Mutación/genética , Enfermedad de Parkinson/genética , alfa-Sinucleína/metabolismo , Animales , Catepsina D/deficiencia , Catepsina D/genética , Línea Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Inmunosupresores/farmacología , Ratones , Ratones Noqueados , Mutagénesis Sitio-Dirigida/métodos , Ratas , Sirolimus/farmacología , Transfección , alfa-Sinucleína/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: The objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls. METHODS: Data collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls. RESULTS: There was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p < 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives. DISCUSSION: The increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS.
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Enfermedades Autoinmunes/epidemiología , Esclerosis Múltiple/epidemiología , Adolescente , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/genética , Estudios de Casos y Controles , Niño , Familia , Femenino , Humanos , Masculino , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/genética , Factores de RiesgoRESUMEN
OBJECTIVE: Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis. METHODS: GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. RESULTS: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. INTERPRETATION: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.
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MicroARNs/genética , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Adolescente , Sitios de Unión , Biomarcadores , California , Niño , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Transducción de SeñalRESUMEN
BACKGROUND: We previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory. METHODS: Pediatric MS cases (N = 290) and healthy controls (N = 442) were included as part of an ongoing case-control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk-Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases. RESULTS: Fine particulate matter (PM 2.5), carbon monoxide (CO), sulfur dioxide (SO 2), and lead air emissions were associated with increased odds for pediatric MS (P < 0.01) for those residing within 20 miles of an MS center. Most study participants (75%) resided within 5 miles of at least one TRI site; however, the mean total pounds of stack air releases was higher for sites near MS cases (81,000 tons) compared to those near healthy controls (35,000 tons, P = 0.002). Average RSEI scores did not differ significantly between cases and controls. CONCLUSION: Out of several air pollutants examined, we show that fine particulate matter and three other criteria pollutants (SO 2, CO, and lead) were statistically associated with higher odds for pediatric MS.
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OBJECTIVE: While prior Epstein-Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections. METHODS: Cases with pediatric-onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses-1 (HSV-1) and -2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA-DRB1:1501 status. RESULTS: A total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV-viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5-12.0, P < 0.001). Seropositivity for HSV-1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06-2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35-3.52, P < 0.001) and those negative for HLA-DRB1*1501 (OR = 1.89, 95% CI 1.17-3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA-DRB1*15:01 status. INTERPRETATION: EBV seropositivity is strongly associated with pediatric MS, as is HSV-1 seropositivity in subjects negative for HLA-DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.
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OBJECTIVE: We sought to determine if early infectious exposures such as daycare, early use of antibiotics, vaccinations and other germ exposures including pacifier use and playing on grass are associated with multiple sclerosis (MS) risk in children. METHODS: This was a case-control study of children with MS or clinically isolated syndrome (CIS) and healthy controls enrolled at sixteen clinics participating in the US Network of Pediatric MS Centers. Parents completed a comprehensive environmental questionnaire that captured early infectious exposures, habits, and illnesses in the first five years of life. A panel of at least two pediatric MS specialists confirmed diagnosis of participants. Association of early infectious variables with diagnosis was assessed via multivariable logistic regression analyses, adjusting for age, sex, race, ethnicity, US birth region, and socioeconomic status (SES). RESULTS: Questionnaire responses for 326 eligible cases (mean age 14.9, 63.5% girls) and 506 healthy pediatric subjects (mean age 14.4, 56.9% girls) were included in analyses. History of flu with high fever before age five (pâ¯=â¯0.01), playing outside in grass and use of special products to treat head lice or scabies (pâ¯=â¯0.04) were associated with increased risk of MS in unadjusted analyses. In the multivariable model adjusted for age, sex, race, ethnicity, and mother's highest educational attainment, these results were not statistically significant. Notably, antibiotic use (pâ¯=â¯0.22) and regular daycare attendance before age 6 (pâ¯=â¯0.09) were not associated with odds of developing MS. CONCLUSION: Early infectious factors investigated in this study were not associated with MS risk.