Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.

Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress in DS is associated with neurodevelopmental defects, neuronal dysfunction, and a dementia onset resembling Alzheimer\'s disease. Additionally, chronic oxidative stress contributes to cardiovascular diseases and certain cancers prevalent in DS individuals. This study investigates the impact of ageing on oxidative stress and liver fibrosis using a DS murine model (Ts2Cje mice). Our results show that DS mice show increased liver oxidative stress and impaired antioxidant defenses, as evidenced by reduced glutathione levels and increased lipid peroxidation. Therefore, DS liver exhibits an altered inflammatory response and mitochondrial fitness as we showed by assaying the expression of HMOX1, CLPP, and the heat shock proteins Hsp90 and Hsp60. DS liver also displays dysregulated lipid metabolism, indicated by altered expression of PPARα, PPARγ, FATP5, and CTP2. Consistently, these changes might contribute to non-alcoholic fatty liver disease development, a condition characterized by liver fat accumulation. Consistently, histological analysis of DS liver reveals increased fibrosis and steatosis, as showed by Col1a1 increased expression, indicative of potential progression to liver cirrhosis. Therefore, our findings suggest an increased risk of liver pathologies in DS individuals, particularly when combined with the higher prevalence of obesity and metabolic dysfunctions in DS patients. These results shed a light on the liver\'s role in DS-associated pathologies and suggest potential therapeutic strategies targeting oxidative stress and lipid metabolism to prevent or mitigate liver-related complications in DS individuals.

ABCD syndrome (ABnormal Calcium, Calcinosis, and Creatinine in Down syndrome) is characterized by an association of hypercalcemia, hypercalciuria, nephrocalcinosis, and impaired kidney function in patients with Down syndrome. Only 7 cases have been published worldwide, although it is believed to be underdiagnosed. This report describes 2 new patients with ABCD syndrome and compares them with the cases reported to date. Although it is a rare cause of pediatric hypercalcemia, it should be considered in children with Down syndrome once other more common etiologies have been ruled out. Once this diagnosis is confirmed, the recommended treatment is to reduce dietary calcium intake and work with an interdisciplinary team to maintain an adequate calorie and protein intake.
El síndrome ABCD (por sus siglas en inglés, ABnormal Calcium, Calcinosis and Creatinine in Down syndrome) se caracteriza por la asociación de hipercalcemia, hipercalciuria, nefrocalcinosis y alteración de la función renal en pacientes con síndrome de Down. Existen solo 7 casos previamente publicados en el mundo, aunque se cree que está subdiagnosticado. En este reporte, presentamos 2 nuevos pacientes con este síndrome y realizamos una comparación con los casos informados hasta el momento. Si bien es una causa rara de hipercalcemia pediátrica, debe considerarse en niños con síndrome de Down una vez descartadas otras etiologías más frecuentes. Al confirmarse este diagnóstico, el tratamiento recomendado es la reducción de calcio en la dieta, trabajando de manera interdisciplinaria para mantener un aporte calórico proteico adecuado.

BACKGROUND: Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer\'s disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs.
METHODS: Cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes.
RESULTS: Four hundred nine DS adults (mean age = 44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age.
CONCLUSIONS: These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics.
CONCLUSIONS: There is rapid increase in prevalence of amyloid beta (Aβ) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aβ PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aβ PET positivity and clinical symptom onset in DS.

BACKGROUND: Cognitive impairment is a core feature of Down syndrome (DS), and the underlying neurobiological mechanisms remain unclear. Translation dysregulation is linked to multiple neurological disorders characterized by cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis.
METHODS: We used genetic and pharmacological methods to suppress eEF2K in two lines of DS mouse models. We further applied multiple approaches to evaluate the effects of eEF2K inhibition on DS pathophysiology.
RESULTS: We found that eEF2K signaling was overactive in the brain of patients with DS and DS mouse models. Inhibition of eEF2 phosphorylation through suppression of eEF2K in DS model mice improved multiple aspects of DS-associated pathophysiology including de novo protein synthesis deficiency, synaptic morphological defects, long-term synaptic plasticity failure, and cognitive impairments.
CONCLUSIONS: Our data suggested that eEF2K signaling dysregulation mediates DS-associated synaptic and cognitive impairments.
CONCLUSIONS: Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) is increased in the Down syndrome (DS) brain. Suppression of the eEF2 kinase (eEF2K) alleviates cognitive deficits in DS models. Suppression of eEF2K improves synaptic dysregulation in DS models. Cognitive and synaptic impairments in DS models are rescued by eEF2K inhibitors.

Children with Down syndrome (DS) are at high risk of sleep-disordered breathing (SDB). The American Academy of Pediatrics recommends a polysomnogram (PSG) in children with DS prior to the age of 4. This retrospective study examined the frequency of SDB, gas exchange abnormalities, co-morbidities, and surgical management in children with DS aged 2-4 years old at Seattle Children\'s Hospital from 2015-2021. A total of 153 children underwent PSG, with 75 meeting the inclusion criteria. The mean age was 3.03 years (SD 0.805), 56% were male, and 54.7% were Caucasian. Comorbidities included (n, %): cardiac (43, 57.3%), dysphagia or aspiration (24, 32.0%), prematurity (17, 22.7%), pulmonary (16, 21.3%), immune dysfunction (2, 2.7%), and hypothyroidism (23, 30.7%). PSG parameter data collected included (mean, SD): obstructive AHI (7.9, 9.4) and central AHI (2.4, 2.4). In total, 94.7% met the criteria for pediatric OSA, 9.5% met the criteria for central apnea, and 9.5% met the criteria for hypoventilation. Only one child met the criteria for hypoxemia. Overall, 60% had surgical intervention, with 88.9% of these being adenotonsillectomy. There was no statistically significant difference in the frequency of OSA at different ages. Children aged 2-4 years with DS have a high frequency of OSA. The most commonly encountered co-morbidities were cardiac and swallowing dysfunction. Among those with OSA, more than half underwent surgical intervention, with improvements in their obstructive apnea hypopnea index, total apnea hypopnea index, oxygen saturation nadir, oxygen desaturation index, total arousal index, and total sleep duration. This highlights the importance of early diagnosis and appropriate treatment. Our study also suggests that adenotonsillar hypertrophy is still a large contributor to upper airway obstruction in this age group.

Background: People with Down syndrome (DS) are deficient in verbal memory but relatively preserved in visuospatial perception. Verbal memories are related to semantic knowledge. Receptive ability is better than expressive ability in people with DS but still seriously lags behind their age-matched controls. This lag may result in the weak semantic integration of people with DS. Aims: This study aimed to examine the ability of semantic integration of people with DS by using false-memory tasks. Possible differences in the number of false memories induced by nouns and verbs were of focus. Methods and Procedures: Two phases were involved in the false-memory task. In the study phase, ten-word lists with semantically related associates were presented. In the recognition phase, judgments were to be made about whether the words presented had been heard before. Three types of words were tested: previously presented associates, semantically related lures, and semantically unrelated new words. Outcomes and Results: People with DS overall showed the lowest accuracy among groups in response to tested word types. In the processing of lures, people with DS were worse in recognition than MA controls. In processing unrelated words, people with DS responded least accurately to all types of words compared to control groups. In the processing of associates, people with DS showed similar recognition rates as the MA controls but were less accurate than the CA controls. No difference was observed between nouns and verbs in recognizing word types among groups, though faster responses to nouns than to verbs emerged in college students. Further analyses on topic-wised comparisons of errors across syntactic categories revealed differences in specific concepts among groups, suggesting people with DS were atypical in semantic organization. Conclusions and Implications: People with DS showed mixed patterns in semantic integration by false-memory tasks with delay to associates and deviance to lures together with unrelated words. People with DS showed distinct patterns in processing nouns and verbs while conducting topic-wise comparisons, suggesting that they formed false memories differently based on distinct syntactic categories. We concluded that people with DS develop a deviant semantic structure, hence showing problems in language and social cognition. Category-based rehabilitation is suggested to be implemented for people with DS to improve their semantic knowledge through lexical connections.

BACKGROUND: Mosaic Down syndrome is a triplication of chromosome 21 in some but not all cells. Little is known about the epidemiology of mosaic Down syndrome. We described prevalence of mosaic Down syndrome and the co-occurrence of common chronic conditions in 94,533 Medicaid enrolled adults with any Down syndrome enrolled from 2016 to 2019.
METHODS: We identified mosaic Down syndrome using the International Classification of Diseases and Related Health Problems, tenth edition code for mosaic Down syndrome and compared to those with nonmosaic Down syndrome codes. We identified chronic conditions using established algorithms and compared prevalence by mosaicism.
RESULTS: In total, 1966 (2.08%) had claims for mosaic Down syndrome. Mosaicism did not differ by sex or race/ethnicity with similar age distributions. Individuals with mosaicism were more likely to present with autism (13.9% vs. 9.6%) and attention deficit hyperactivity disorder (17.7% vs. 14.0%) compared to individuals without mosaicism. In total, 22.3% of those with mosaic Down syndrome and 21.5% of those without mosaicism had claims for Alzheimer\'s dementia (Prevalence difference: 0.8; 95% Confidence interval: -1.0, 2.8). The mosaic group had 1.19 times the hazard of Alzheimer\'s dementia compared to the nonmosaic group (95% CI: 1.0, 1.3).
CONCLUSIONS: Mosaicism may be associated with a higher susceptibility to certain neurodevelopmental and neurodegenerative conditions, including Alzheimer\'s dementia. Our findings challenge previous assumptions about its protective effects in Down syndrome. Further research is necessary to explore these associations in greater depth.

BACKGROUND: This study aimed to report the screening performance of cell-free DNA (cfDNA) testing for chromosomal abnormalities in twins, triplets, and vanishing twin pregnancies.
METHODS: Data were obtained from pregnant women with a multiple pregnancy or a vanishing twin pregnancy at ≥10 weeks\' gestation who requested self-financed cfDNA testing between May 2015 and December 2021. Those that had positive screening results had diagnostic confirmatory procedures after counseling and consent. The performance of screening of the cfDNA test was determined by calculating confirmation rate and combined false-positive rate (cFPR).
RESULTS: Data from 292 women were included after exclusion of those lost to follow-up, with no-result on cfDNA testing, or had reductions. Of the 292 pregnancies, 10 (3.4%) were triplets, including no cases of trisomy 21 and trisomy 18; 249 (85.3%) were twins, including 3 cases of trisomy 21 and no cases of trisomy 18 and 13; and 33 (11.3%) were vanishing twins, including 3 cases of trisomy 21 and 1 case of trisomy 18. The median (IQR) maternal age was 34 years (31-37). For triplet pregnancies, the initial no-result rate was 10.3% (95% confidence interval [CI] 3.6-26.4), all with results after redraw. For twin pregnancies, the initial no-result rate was 12.9% (95% CI 9.6-17.0), and the no-result rate after redraw was 1.6% (95% CI 0.7-3.6). For vanishing twins, there were no cases with no-result. All triplets had low-risk cfDNA results. The confirmation rate for trisomy 21 was 100% with a FPR at 0% due to the small number of positive cases for twins. For vanishing twins, one high-risk case for trisomy 21 and the only high-risk case for trisomy 18 were confirmed with a cFPR of 8.3% (n = 2/24; 95% CI 2.3-25.9).
CONCLUSIONS: cfDNA testing in twin pregnancies has sufficient screening performance for trisomy 21 but the number of affected cases for other conditions is limited to draw any meaningful conclusion. The use of cfDNA testing in triplet pregnancies and vanishing twins remains an area for further research.

Caregiving for disabled individuals among Neanderthals has been known for a long time, and there is a debate about the implications of this behavior. Some authors believe that caregiving took place between individuals able to reciprocate the favor, while others argue that caregiving was produced by a feeling of compassion related to other highly adaptive prosocial behaviors. The study of children with severe pathologies is particularly interesting, as children have a very limited possibility to reciprocate the assistance. We present the case of a Neanderthal child who suffered from a congenital pathology of the inner ear, probably debilitating, and associated with Down syndrome. This child would have required care for at least 6 years, likely necessitating other group members to assist the mother in childcare.