A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

Effectiveness of ketoacidosis prevention campaigns at diagnosis of type 1 diabetes in children: A systematic review and meta-analysis

Aim: To determine if diabetes awareness campaigns are an effective intervention to reduce diabetes ketoacidosis at diagnosis of type 1 diabetes in children and youth. Methods: Search strategies included PubMed, Scopus, CINAHL and WOS electronic databases, hand search of select journals and a grey literature search “Google” search to include all relevant information. Studies included community-based interventions focused on children younger than 18 years old. The difference in the frequency of DKA was measured in two separate comparisons; before and after perform awareness campaigns in the same area, and between areas with and without intervention campaigns. Results: Of 1136 records identified, 14 studies were eligible for the analysis. The first group of 12 studies measured DKA at diagnosis, before (n = 6548 individuals) and after (n = 4931 individuals) the awareness campaigns. The pooled difference was a reduction of 7.20% (95%CI: 0.99–13.41). The second group of four studies measured the difference in an area with no intervention (n = 338 individuals) and in an area with an awareness campaign (n = 187 individuals). The pooled difference in DKA was 35.71% (95%CI: 5.81–65.61). Conclusions: This review demonstrated that DKA awareness campaigns are effective to reduce DKA among children and adolescents with type 1 diabetes and the core components that explain why these campaigns are effective. Back to top

Epilepsy, electroclinical features, and long-term outcomes in Pitt–Hopkins syndrome due to pathogenic variants in the TCF4 gene

Background and purpose: Pitt–Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. Methods: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. Results: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5–8). The median time of follow-up was 7.9 years (range = 2–27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003–0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. Conclusions: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life

Characteristics of acute nystagmus in the pediatric emergency department

OBJECTIVES: Acute nystagmus (AN) is an uncommon neurologic sign in children presenting to pediatric emergency departments. We described the epidemiology, clinical features, and underlying causes of AN in a large cohort of children, aiming at identifying features associated with higher risk of severe underlying urgent conditions (UCs). METHODS: Clinical records of all patients aged 0 to 18 years presenting for AN to the pediatric emergency departments of 9 Italian hospitals in an 8-year period were retrospectively reviewed. Clinical and demographic features and the underlying causes were analyzed. A logistic regression model was applied to detect predictive variables associated with a higher risk of UCs. RESULTS: A total of 206 patients with AN were included (male-to-female ratio: 1.01; mean age: 8 years 11 months). The most frequently associated symptoms were headache (43.2%) and vertigo (42.2%). Ataxia (17.5%) and strabismus (13.1%) were the most common neurologic signs. Migraine (25.7%) and vestibular disorders (14.1%) were the most common causes of AN. Idiopathic infantile nystagmus was the most common cause in infants,1 year of age. UCs accounted for 18.9% of all cases, mostly represented by brain tumors (8.3%). Accordant with the logistic model, cranial nerve deficits, ataxia, or strabismus were strongly associated with an underlying UC. Presence of vertigo or attribution of a nonurgent triage code was associated with a reduced risk of UCs. CONCLUSIONS: AN should be considered an alarming finding in children given the risk of severe UCs. Cranial nerve palsy, ataxia, and strabismus should be considered red flags during the assessment of a child with AN

Characteristics of acute nystagmus in the pediatric emergency department

OBJECTIVES: Acute nystagmus (AN) is an uncommon neurologic sign in children presenting to pediatric emergency departments. We described the epidemiology, clinical features, and underlying causes of AN in a large cohort of children, aiming at identifying features associated with higher risk of severe underlying urgent conditions (UCs). METHODS: Clinical records of all patients aged 0 to 18 years presenting for AN to the pediatric emergency departments of 9 Italian hospitals in an 8-year period were retrospectively reviewed. Clinical and demographic features and the underlying causes were analyzed. A logistic regression model was applied to detect predictive variables associated with a higher risk of UCs. RESULTS: A total of 206 patients with AN were included (male-to-female ratio: 1.01; mean age: 8 years 11 months). The most frequently associated symptoms were headache (43.2%) and vertigo (42.2%). Ataxia (17.5%) and strabismus (13.1%) were the most common neurologic signs. Migraine (25.7%) and vestibular disorders (14.1%) were the most common causes of AN. Idiopathic infantile nystagmus was the most common cause in infants,1 year of age. UCs accounted for 18.9% of all cases, mostly represented by brain tumors (8.3%). Accordant with the logistic model, cranial nerve deficits, ataxia, or strabismus were strongly associated with an underlying UC. Presence of vertigo or attribution of a nonurgent triage code was associated with a reduced risk of UCs. CONCLUSIONS: AN should be considered an alarming finding in children given the risk of severe UCs. Cranial nerve palsy, ataxia, and strabismus should be considered red flags during the assessment of a child with AN

Time in Range in Children with Type 1 Diabetes Using Treatment Strategies Based on Nonautomated Insulin Delivery Systems in the Real World

Background: Glucose sensors consist of real-time continuous glucose monitoring (rtCGM) and intermittently scanned CGM (isCGM). Their clinical use has been widely increasing during the past 5 years. The aim of this study is to evaluate percentage of time in range (TIR) in a large group of children with type 1 diabetes (T1D) using glucose sensors with nonautomated insulin delivery systems, in a real-world setting. Methods: An 11-center cross-sectional study was conducted during January-May 2019. Children with T1D 1 year, treated with multiple daily injections (MDI) or nonautomated insulin pump (IP), were recruited consecutively. Clinical data, HbA1c measurement, and CGM downloaded data were collected by each center and included in a centralized database for the analysis. Glucose metrics of four treatment strategies were analyzed: isCGM-MDI, rtCGM-MDI, isCGM-IP, and rtCGM-IP. Results: Data from 666 children with T1D (51% male and 49% female), median age 12 years, diabetes duration 5 years, were analyzed. An rtCGM was used by 51% of the participants, and a nonautomated IP by 46%. For isCGM-MDI, rtCGM-MDI, isCGM-IP, and rtCGM-IP, the median TIR 70-180 mg/dL values were 49%, 56%, 56%, and 61% (P 180 mg/dL and lower HbA1c. If there are no barriers, an upgrade of the treatment strategy with a higher performing technology should be offered to all children who do not achieve blood glucose metrics within the suggested range

Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment