Down Syndrome and Autoimmune Disease.

Down syndrome is the most common genetic cause of intellectual disability and has previously been associated with a variety of autoimmune disorders affecting multiple organ systems. The high prevalence of autoimmune disease, in conjunction with other inflammatory and infectious diseases, in this population suggests an intrinsic immune dysregulation associated with triplication of chromosome 21. Emerging data on the role of chromosome 21 in interferon activation, cytokine production, and activation of B-cell mediated autoimmunity are emerging hypotheses that may explain the elevated prevalence of autoimmune thyroid disease, celiac disease, type I diabetes, autoimmune skin disease, and a variety of autoimmune neurologic conditions. As the life expectancy for individuals with Down syndrome increases, knowledge of the epidemiology, clinical features, management and underlying causes of these conditions will become increasingly important. Disorders such as Hashimoto's thyroiditis are prevalent in between 13 and 34% of individuals with Down syndrome but only 3% of the neurotypical population, a pattern similarly recognized in individuals with Celiac Disease (5.8% v 0.5-2%), alopecia areata (27.7% v. 2%), and vitiligo (4.4% v. 0.05-1.55%), respectively. Given the chronicity of autoimmune conditions, early identification and management can significantly impact the quality of life of individuals with Down syndrome. This comprehensive review will highlight common clinical autoimmune conditions observed in individuals with Down syndrome and explore our current understanding of the mechanisms of disease in this population.

Safety and tolerability of intravenous immunoglobulin infusion in Down syndrome regression disorder.

Three large multi-center studies have identified the clinical utility of intravenous immunoglobulin (IVIg) in the treatment of Down syndrome regression disorder (DSRD). Yet the tolerability of infusions in individuals with DS and the safety of IVIg remains unknown in this population. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD compared to a real-world cohort of individuals with pediatric onset neuroimmunologic disorders. A single-center, retrospective chart review evaluating clinically documented infusion reactions was performed for individuals meeting international consensus criteria for DSRD and having IVIg infusions between 2019 and 2023. Infusion reactions were evaluated for severity and need for alterations in infusion plan. This cohort was compared against an age and sex matched cohort of children with neuroimmunologic conditions who had also received IVIg infusions. In total, 127 individuals with DSRD and 186 individuals with other neuroimmunologic disorders were enrolled. There was no difference in the overall rate of adverse reactions (AEs) between the DSRD and general neuroimmunology cohorts (p = 0.31, 95% CI: 0.80-2.00), but cardiac-related AEs specifically were more common among the DSRD group (p = 0.02, 95% CI: 1.23-17.54). When AEs did occur, there was no difference in frequency of pharmacologic intervention (p = 0.12, 95% CI: 0.34-1.13) or discontinuation of therapy (p = 0.74, 95% CI: 0.06-7.44). There was a higher incidence of lab abnormalities on IVIG among the general neuroimmunology cohort (p = 0.03, 95% CI: 0.24-0.94) compared to the DSRD cohort. Transaminitis was the most common laboratory abnormality in the DSRD group. In a large cohort of individuals with DSRD, there were no significant differences in the safety and tolerability of IVIg compared to a cohort of children and young adults with neuroimmunologic conditions.

The Genetic Landscape of Ischemic Stroke in Children - Current Knowledge and Future Perspectives.

Stroke in childhood has multiple etiologies, which are mostly distinct from those in adults. Genetic discoveries over the last decade pointed to monogenic disorders as a rare but significant cause of ischemic stroke in children and young adults, including small vessel and arterial ischemic stroke. These discoveries contributed to the understanding that stroke in children may be a sign of an underlying genetic disease. The identification of these diseases requires a detailed medical and family history collection, a careful clinical evaluation for the detection of systemic symptoms and signs, and neuroimaging assessment. Establishing an accurate etiological diagnosis and understanding the genetic risk factors for stroke are essential steps to decipher the underlying mechanisms, optimize the design of tailored prevention strategies, and facilitate the identification of novel therapeutic targets in some cases. Despite the increasing recognition of monogenic causes of stroke, genetic disorders remain understudied and therefore under-recognized in children with stroke. Increased awareness among healthcare providers is essential to facilitate accurate diagnosis in a timely manner. In this review, we provide a summary of the main single-gene disorders which may present as ischemic stroke in childhood and describe their clinical manifestations. We provide a set of practical suggestions for the diagnostic work up of these uncommon causes of stroke, based upon the stroke subtype and imaging characteristics that may suggest a monogenic diagnosis of ischemic stroke in children. Current hurdles in the genetic analyses of children with ischemic stroke as well as future prospectives are discussed.

Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease.

Objective: To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population. Methods: A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression. Results: The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively (p < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times (p < 0.001, 95% CI: 1.82-5.58) higher than the idiopathic moyamoya group and 1.5 times (p = 0.002, 95% CI: 1.17-1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder (p = 0.05, 95%CI: 1.08-6.08). Interpretation: This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.

Electroclinical Features of Generalized Paroxysmal Fast Activity in Typical Absence Seizures.

PURPOSE: Generalized paroxysmal fast activity (GPFA) is a diffuse, paroxysmal, frontal predominant activity described in patients with generalized epilepsies. Studies specifically focusing on electroclinical features of typical absence seizures in children have not reported any GPFA-like features. We sought to identify GPFA in children with typical absence seizures, study its incidence, characteristic electroclinical features, and effect on their epilepsy. METHODS: We performed a retrospective review of electroencephalograms of children with diagnosis of absence epilepsy. A total of 173 subjects were identified. In subjects with GPFA on their electroencephalograms, GPFA characteristics were collected (i.e., predominant location, duration, amplitude, frequency, provocation factors, and if GPFA was followed by spike-wave discharges). In GPFA-positive subjects, further data sets were collected examining their demographics, duration of epilepsy, and pharmacoresponsiveness to epilepsy. RESULTS: Generalized paroxysmal fast activity was identified in 10 subjects (5.78%) with female to male ratio of 9:1. Median age of subjects was 17 years, and median duration of illness was 9.5 years. Mean maximum GPFA amplitude was 88.3 µV with posterior predominance in 9/10 subjects. Generalized paroxysmal fast activity frequency ranged between 11 and 20 Hz with duration of 1 to 4 seconds. Generalized paroxysmal fast activity was provoked with eye closure, hyperventilation, and photic stimulation. Antiseizure medications had no effect on GPFA, and epilepsy was well controlled in most subjects. CONCLUSIONS: Generalized paroxysmal fast activity is uncommon in children with typical absence seizures and has medium voltage, posterior predominance, and marked female preponderance. Generalized paroxysmal fast activity is seen during both pharmacoresponsive and drug-resistant epilepsy, and is not affected by antiseizure medications. It may serve as an independent marker of lifelong epilepsy.

Pediatric Iatrogenic Movement Disorders.

The acute development of a movement disorder is often a dramatic and frightening experience for patients and families, often requiring urgent or emergent evaluation by a neurologist. In the assessment of these patients, one relies on the history, physical and neurologic examination to determine the etiology of the condition. We aim to demonstrate that a thorough medication history is an incredibly critical part of this evaluation as iatrogenic movement disorders can arise from exposure not only to psychoactive medications, but from drugs prescribed for a variety of nonneurologic disorders. This comprehensive review is organized by movement disorder semiology so that the reader can more readily develop a differential diagnosis when evaluating a patient with a movement disorder.