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ATPase, class 1, type 8 A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings born from a consanguineous, first-cousin union from Sudan presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.
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AIM: We sought to explore the experiences and perceptions of the quality of life of adolescents with pediatric-onset multiple sclerosis and assess their readiness for academic, employment and/or health care-related transitions. BACKGROUND: Adolescents with pediatric-onset multiple sclerosis face unique challenges in managing a chronic illness while navigating future scholastic, social and occupational goals. We conducted a qualitative study with in-depth, semi-structured interviews from July 2017 to March 2019. Adolescents with pediatric-onset multiple sclerosis were recruited from a pediatric neurology subspeciality practice until reaching data saturation. A total of 17 interviews were completed via telephone with participants ages 15 through 26. RESULTS: Through content analysis of the interviews, we identified five major themes: (1) receiving a new diagnosis; (2) adapting to life with pediatric-onset multiple sclerosis; (3) evaluating education/career transition preparedness; (4) adjusting within family life and establishing support systems; and (5) assessing current medical services and preparedness for adult medical care. CONCLUSIONS: Autonomy in health care management, adequate control of physical symptoms and sufficient family support impacted perceptions of quality of life. Implementing a dedicated transition visit, including the parent(s) of those with pediatric-onset multiple sclerosis, early in adolescence may provide an avenue for appropriate anticipatory guidance regarding available services, independent medical management and continuity of care.
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Esclerosis Múltiple , Investigación Cualitativa , Calidad de Vida , Transición a la Atención de Adultos , Humanos , Adolescente , Esclerosis Múltiple/psicología , Esclerosis Múltiple/terapia , Femenino , Masculino , Adulto Joven , Adulto , Adaptación Psicológica , Entrevistas como AsuntoAsunto(s)
Enfermedades Genéticas Congénitas , Púrpura Trombocitopénica Trombótica , Enfermedades Vasculares , Adolescente , Femenino , Enfermedades Genéticas Congénitas/diagnóstico por imagen , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Enfermedades Genéticas Congénitas/genética , Humanos , Púrpura Trombocitopénica Trombótica/diagnóstico por imagen , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Púrpura Trombocitopénica Trombótica/genética , Enfermedades Vasculares/diagnóstico por imagen , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/genéticaAsunto(s)
Enfermedades Virales del Sistema Nervioso Central/diagnóstico , Debilidad Muscular/etiología , Mielitis/diagnóstico , Enfermedades Neuromusculares/diagnóstico , Incontinencia Urinaria/etiología , Adolescente , Enfermedades Virales del Sistema Nervioso Central/complicaciones , Femenino , Humanos , Extremidad Inferior , Mielitis/complicaciones , Enfermedades Neuromusculares/complicacionesRESUMEN
This retrospective chart review examined children with documented Lyme disease serology in New Jersey aged <21 years presenting with facial nerve palsy. The presence of symptoms including tick bite, fever, headache, and arthritis was recorded. Data were categorized based on demographic factors, and multivariate regression was employed. We enrolled 122 children, 54% female (mean age of 11.4 ± 5.1 years); 22.1% had Lyme disease. Fever was a significant predictor of Lyme disease (P = .01), confirmed by multivariate regression (odds ratio [OR] = 16.11, 95% confidence interval [CI] = 2.04, 366.14), as was male gender (P = .01, OR = 3.68, 95% CI = 1.21, 12.89). This association held especially true in Lyme-endemic regions (prevalence ≥ 0.35). The combination of headache with fever was also significantly predictive (P = .01). We found no significant predictive value in the remaining symptoms. These findings suggest that clinical predictors may be useful in diagnosing Lyme disease and initiating early empiric treatment.
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ATPase, class 1, type 8A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.
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Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and immunohistochemical features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 causative variant to a Bethlem muscular dystrophy phenotype.
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Importance: Many disease-modifying therapies (DMTs) have been approved for multiple sclerosis (MS) in the past 2 decades. Research evaluating how these approvals have changed real-world prescribing patterns is scarce. Objective: To evaluate patterns in DMT initiations between 2001 and 2020 among commercially insured US adults and children with MS. Design, Setting, and Participants: This serial cross-sectional study was conducted from 2001 through 2020 (mean patient enrollment duration, 4.8 years) and used US commercial claims data (MarketScan). Analysis took place between January 2022 and March 2023. Of 287â¯084 patients with MS identified, 113â¯583 patients (113â¯095 adults and 488 children) with MS newly initiated at least 1 DMT. Exposure: New initiation episode of a DMT, defined as no claim for the same DMT in the previous year. Main Outcome Measure: The proportion of total DMT initiations per year attributable to each DMT. Trends in initiations were evaluated annually. Results: The study team identified 153â¯846 DMT initiation episodes among adults (median age, 46 [IQR, 38-53) years]; 86â¯133 female [76.2%]) and 583 among children (median age, 16 (IQR, 14-17) years; 346 female [70.9%]). Among adults, use of platform injectables showed an absolute decline of 73.8% over the study period, driven by a 61.2% reduction in interferon ß initiations (P < .001 for trend). In contrast, the 2010 introduction of oral DMTs led to a rise in their use from 1.1% (2010) to 62.3% (2020) of all DMT initiations (P = .002 for trend). Infusion therapy initiations remained relatively low, accounting for 3.2% of all initiations since their introduction in 2004 but increased modestly annually after ocrelizumab was introduced (2017), reaching 8.2% of all initiations in 2020 (P < .001 for trend). Children showed similar initiation patterns, except for preferred oral therapy. Between 2019 and 2020, dimethyl fumarate was the most commonly initiated DMT in adults (23.3% to 27.2% of all initiations), while in children fingolimod was the most commonly initiated (34.8% to 68.8%). Conclusions and Relevance: Current MS treatment guidelines emphasize shared decision-making between patients and clinicians to balance treatment efficacy, safety, cost, and convenience. This study found that oral DMTs were the predominant DMT type initiated by 2020. The cause of this shift cannot be determined from this study, but may reflect several factors, including convenience of administration, direct-to-consumer advertising, or insurance restrictions.
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Esclerosis Múltiple , Humanos , Adulto , Niño , Femenino , Persona de Mediana Edad , Adolescente , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/epidemiología , Inmunosupresores , Estudios Transversales , Clorhidrato de Fingolimod , Interferón betaRESUMEN
BACKGROUND AND OBJECTIVES: Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes. METHODS: We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria. RESULTS: One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification. CONCLUSION: Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient.
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Enfermedades Autoinmunes del Sistema Nervioso , Enfermedades Desmielinizantes , Esclerosis Múltiple , Humanos , Niño , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/epidemiología , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/epidemiología , Progresión de la Enfermedad , Imagen por Resonancia Magnética , Estudios RetrospectivosRESUMEN
Diffusion tensor imaging (DTI) is a sensitive tool for detecting microstructural tissue damage in vivo. In this study, we investigated DTI abnormalities in individuals with relapsing remitting multiple sclerosis (RRMS) and examined the relations between imaging-based measures of white matter injury and cognitive impairment. DTI-derived metrics using tract-based spatial statistics (TBSS) were compared between 37 individuals with RRMS and 20 healthy controls. Cognitive impairment was assessed with three standard tests: the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed and visual working memory, the Rey Auditory Verbal Learning Test (RAVLT), which examines verbal memory, and the Paced Auditory Serial Addition Test (PASAT), which assesses sustained attention and working memory. Correlations between DTI-metrics and cognition were explored in regions demonstrating significant differences between the RRMS patients and the control group. Lower fractional anisotropy (FA) was found in RRMS participants compared to controls across the tract skeleton (0.40 ± 0.03 vs. 0.43 ± 0.01, p<0.01). In areas of reduced FA, mean diffusivity was increased and was dominated by increased radial diffusivity with no significant change in axial diffusivity, an indication of the role of damage to CNS myelin in MS pathology. In the RRMS group, voxelwise correlations were found between FA reduction and cognitive impairment in cognitively-relevant tracts, predominantly in the posterior thalamic radiation, the sagittal stratum, and the corpus callosum; the strongest correlations were with SDMT measures, with contributions to these associations from both lesion and normal-appearing white matter. Moreover, results using threshold-free cluster enhancement (TFCE) showed more widespread white matter involvement compared to cluster-based thresholding. These findings indicate the important role for DTI in delineating mechanisms underlying MS-associated cognitive impairment and suggest that DTI could play a critical role in monitoring the clinical and cognitive effects of the disease.
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Encéfalo/patología , Trastornos del Conocimiento/patología , Imagen de Difusión Tensora , Esclerosis Múltiple Recurrente-Remitente/patología , Adulto , Trastornos del Conocimiento/etiología , Femenino , Humanos , Masculino , Esclerosis Múltiple Recurrente-Remitente/complicacionesRESUMEN
Coronavirus SARS-CoV2 has emerged as one of the greatest infectious disease health challenges in a century. Patients with multiple sclerosis (MS) have a particular vulnerability to infections through their use of immunosuppressive disease-modifying therapies (DMTs). Specific DMTs pose particular risk based on their mechanisms of action (MOA). As a result, patients require individualized approaches to starting new treatments and continuation of therapy. Additionally, vaccinations must be considered carefully, and individuals on long-term B cell-depleting therapies may have diminished immune responses to vaccination, based on preserved T cells and diminished but present antibody titers to influenza vaccines. We review the immunology behind these treatments and their impact on COVID-19, as well as the current recommendations for best practices for use of DMTs in patients with MS.
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COVID-19 , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/terapia , Pandemias , Antirreumáticos/efectos adversos , Humanos , Inmunosupresores/uso terapéutico , Medición de RiesgoRESUMEN
AIM: Epilepsy is associated with difficulties in cognition and behavior in children. These problems have been attributed to genetics, ongoing seizures, psychosocial issues, underlying abnormality of the brain, and/or antiepileptic drugs. In a previous study, we found baseline cognitive differences between children with partial versus generalized and convulsive versus non-convulsive seizures. Measures in that study focused primarily on IQ scores. In the present study, we assessed baseline function with respect to new learning, attention, and memory, thus providing a more comprehensive profile than our previous study. METHOD: We examined 57 children (42 females, 15 males), aged 6 to 17 years (mean 10y 1mo, SD 2y 9mo), with new-onset, idiopathic epilepsy, using tests of cognitive function reflective of new learning, memory, and attention. Seizures were classified as generalized convulsive (n=5), generalized non-convulsive (n=18), or focal (n=34). Focal seizures were divided into unilateral versus bilateral independent foci, and presence versus absence of secondary generalization. RESULTS: Attention was a particular area of weakness across all groups. The Vocabulary score of an intelligence screen was higher for the focal seizure groups (p=0.012), primarily because of a difference between the unilateral focal and the primary generalized groups (p<0.047). Children with generalized, non-convulsive seizures performed significantly worse than the focal group on a measure of short-term auditory memory (p=0.019). All groups performed poorly on a test of visual-motor speed. INTERPRETATION: These findings suggest intrinsic abnormalities in children with new-onset, idiopathic epilepsy at baseline.
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Trastornos de la Conducta Infantil/diagnóstico , Trastornos del Conocimiento/diagnóstico , Epilepsias Parciales/diagnóstico , Epilepsia Generalizada/diagnóstico , Trastornos de la Destreza Motora/diagnóstico , Pruebas Neuropsicológicas/estadística & datos numéricos , Determinación de la Personalidad/estadística & datos numéricos , Adolescente , Niño , Trastornos de la Conducta Infantil/psicología , Trastornos del Conocimiento/psicología , Femenino , Humanos , Inteligencia , Masculino , Trastornos de la Destreza Motora/psicología , Psicometría/estadística & datos numéricos , Reproducibilidad de los ResultadosAsunto(s)
Alopecia/etiología , Esclerodermia Localizada/complicaciones , Esclerodermia Localizada/diagnóstico , Corticoesteroides/uso terapéutico , Niño , Fármacos Dermatológicos/uso terapéutico , Diagnóstico Diferencial , Femenino , Humanos , Metotrexato/uso terapéutico , Esclerodermia Localizada/tratamiento farmacológicoRESUMEN
OBJECTIVE: As treatment options for epilepsy have increased, there has been a commensurate increase in interest in the side effect profiles of these drugs. METHODS: In this study, children between the ages of 6 and 17 with a diagnosis of new-onset, idiopathic epilepsy were evaluated at baseline (n=57) and 6 (n=45) and 12 (n=31) months after initiation of antiepileptic drug therapy. RESULTS: There was improvement in the cognitive functioning of children after 12 months of treatment. A transient drop in performance of children with generalized seizures (10 of 11 of whom had absence seizures) at 6 months may have been due to persistent seizures, the drugs used to treat them (predominantly ethosuximide), or both. Worsening of reaction time and reaction time variability in the focal seizure group, the only scores showing persistent deterioration over 12 months, may be attributable to the medications used for this group, the most common of which was carbamazepine. CONCLUSIONS: There were few adverse effects of antiepileptic drug treatment in the group followed over 12 months. Carbamazepine may have been responsible for persistent impairment of reaction time and reaction time variability.
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Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Cognición/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Conducta Verbal/efectos de los fármacos , Adolescente , Análisis de Varianza , Anticonvulsivantes/efectos adversos , Niño , Epilepsia/clasificación , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Inteligencia , Masculino , Pruebas Neuropsicológicas , Tiempo de Reacción/efectos de los fármacos , Estudios Retrospectivos , Factores de TiempoRESUMEN
Ribose-5-phosphate isomerase deficiency, a disorder of the pentose phosphate shunt, was described in 1999. There are 2 previously reported cases of ribose-5-phosphate isomerase deficiency. Here, we describe the clinical course, diagnostic odyssey, and molecular findings in the third case of ribose-5-phosphate isomerase deficiency to further delineate the syndrome. Whole-exome sequencing demonstrated 2 mutations in the ribose-5-phosphate isomerase gene, RPIA, in a child with neonatal onset leukoencephalopathy and psychomotor delays. Urine polyols were elevated confirming deficiency of ribose-5-phosphate isomerase (RPI, EC. 5.3.1.6) and pathogenicity of the variants. Measurement of urine polyols should be considered in cases of early-onset white-matter disease.
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Isomerasas Aldosa-Cetosa/deficiencia , Errores Innatos del Metabolismo de los Carbohidratos/genética , Leucoencefalopatías/genética , Mutación/genética , Polineuropatías/genética , Isomerasas Aldosa-Cetosa/genética , Errores Innatos del Metabolismo de los Carbohidratos/complicaciones , Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico por imagen , Preescolar , Discapacidades del Desarrollo/etiología , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Humanos , Leucoencefalopatías/complicaciones , Leucoencefalopatías/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Polineuropatías/complicaciones , Polineuropatías/diagnóstico por imagen , Proteínas de Transporte VesicularRESUMEN
INTRODUCTION: The understanding of the immunopathogenesis of multiple sclerosis (MS) has expanded with more research into T-cell subtypes, cytokine contributors, B-cell participation, mitochondrial dysfunction, and more. Treatment options have rapidly expanded with three relatively recent oral therapy alternatives entering the arena. AREAS COVERED: In the following review, we discuss current mechanisms of immune dysregulation in MS, how they relate to current treatments, and the impact these findings will have on the future of therapy. Expert commentary: The efficacy of these medications and understanding their mechanisms of actions validates the immunopathogenic mechanisms thought to underlie MS. Further research has exposed new targets, while new promising therapies have shed light on new aspects into the pathophysiology of MS.
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Linfocitos B/inmunología , Sistema Nervioso Central/inmunología , Inmunoterapia/métodos , Esclerosis Múltiple/inmunología , Linfocitos T/inmunología , Animales , Autoanticuerpos/líquido cefalorraquídeo , Citocinas/metabolismo , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoterapia/tendencias , Esclerosis Múltiple/terapiaRESUMEN
Pediatric multiple sclerosis (MS) represents a particular MS subgroup with unique diagnostic challenges and many unanswered questions. Due to the narrow window of environmental exposures and clinical disease expression, children with MS may represent a particularly important group to study to gain a better understanding of MS pathogenesis. Acute disseminated encephalomyelitis (ADEM) is more common in children than in adults, often making the differential diagnosis of MS, particularly a clinically isolated syndrome, quite difficult. Although both disorders represent acute inflammatory disorders of the central nervous system and have overlapping symptoms, ADEM is typically (not always) self-limiting. The presence of encephalopathy is much more characteristic of ADEM and may help in distinguishing between the two. Young children (under ten years old) with MS differ the most from adults. They have a lower frequency of oligoclonal bands in their cerebrospinal fluid and are less likely to have discrete lesions on MRI. Problems of cognitive dysfunction and psychosocial adjustment have particularly serious implications in both children and teenagers with MS. Increased awareness of these difficulties and interventions are needed. While clinical research on therapies to alter the disease course is limited, the available data fortunately suggests that disease-modifying therapy is well tolerated and likely to be effective. Ultimately, multinational research studies are necessary to advance our knowledge of the causes, symptoms, and treatment of pediatric MS and such collaborations are currently underway.