RESUMEN
Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.
RESUMEN
BACKGROUND AND OBJECTIVES: Pompe disease (PD) results from a deficiency of lysosomal acid α-glucosidase that leads to glycogen accumulation in lysosomes in multiple tissues. There are two phenotypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The objective was to evaluate the diagnostic and follow-up outcomes of children identified with PD through newborn screening (NBS) in the state of Minnesota over a 4-year period. METHODS: This study is a retrospective analysis of infants born in Minnesota between August 1, 2017, and July 31, 2021, by the Minnesota Department of Health NBS Program for Pompe disease. Newborn screening and clinical diagnostic data are summarized for all newborns with positive newborn screens for Pompe disease. RESULTS: Children with IOPD had abnormal biomarkers necessitating immediate initiation of treatment. Children with LOPD are asymptomatic to date (1.25-4.58 years) with normal biomarkers including creatine kinase, urine glucotetrasaccharides, liver function tests, and echocardiogram. The estimated birth prevalence of PD is 1:15,160. The positive predictive value for PD was 81% with a false positive rate of 1.9 per 10 positive screens. 32% of the children with LOPD were lost to follow up among which 66% were from minority ethnic groups. CONCLUSION: This emphasizes the disparity in access to health care among specific demographics, as well as the importance of a primary care provider's early involvement in educating these families. To accomplish this, and ensure equality in follow-up care, the Minnesota Pompe Disease Consortium has been formed.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II , Lactante , Niño , Recién Nacido , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , Tamizaje Neonatal , Estudios Retrospectivos , alfa-Glucosidasas , Glucano 1,4-alfa-Glucosidasa , BiomarcadoresRESUMEN
Newborn screening has evolved since its introduction in 1963. The disorders that are being screened for continue to evolve as new treatments and new technologies advance. In this review, the authors discuss the current state of newborn screening in the United States, including the disorders currently being screened for and how newborn screening is performed. They also discuss the special considerations and limitations of newborn screening in sick and premature infants and as well as some ethical issues related to newborn screening. Finally, new disorders being considered for testing and new technologies that may be used in the future of newborn screening are discussed.
Asunto(s)
Enfermedades del Recién Nacido/diagnóstico , Tamizaje Neonatal/métodos , Humanos , Recién Nacido , Tamizaje Neonatal/ética , Estados UnidosRESUMEN
Children and adolescents are increasingly presenting to the hospital and emergency department with aggressive behavior and psychiatric emergencies. The rise in pediatric mental health problems, coupled with a lack of much needed resources, necessitates that pediatricians safely diagnose and treat patients presenting with aggressive behavior. In this article, we discuss the broad differential diagnosis that should be considered when initially evaluating a patient presenting with aggression or altered mental status; underlying causes include predisposing factors, comorbid conditions, and acute organic causes involving almost every organ system. Emergency and hospital physicians should tailor their examination and testing individually based on the patient's history and presentation. [Pediatr Ann. 2018;47(10):e402-e407.].
Asunto(s)
Agresión/psicología , Trastornos Mentales/diagnóstico , Adolescente , Niño , Diagnóstico Diferencial , Servicio de Urgencia en Hospital , Médicos Hospitalarios , Humanos , Trastornos Mentales/etiología , PediatrasRESUMEN
After reviewing the various etiologies that can contribute to a presentation of aggressive behavior in a child (see part 1), a physician should conduct a thorough history and physical examination. The history should be obtained from the patient and caregivers, both together and separately in adolescents. A good physical examination starts with assessment and interpretation of vital signs, followed by a head-to-toe examination focusing on the skin, eyes, and thyroid, and then a neurologic examination. The testing and observation should be tailored to the individual patient, including laboratory results, imaging, and specialist consultation. Management of aggressive behavior can often be achieved through a combination of environmental modifications and verbal techniques, with special consideration given to children with neurodevelopmental problems such as autism. Pharmacologic agents are a good next step, and physical restraints can be used as a last resort. Evaluation of suicidality with thorough and complete questioning as well as assessment of a safety plan can aid in determining patient disposition such as need for admission to a psychiatric facility. [Pediatr Ann. 2018;47(10):e408-e412.].