A cohort study on acute ocular motility disorders in pediatric emergency department

Background: Acute ocular motility disorders (OMDs) in children admitted to Emergency Department (ED) represents a not so rare condition with a wide spectrum of different etiologies. The emergency physician must be skilled in rapidly identifying patients with potentially life threatening (LT) forms, requiring further diagnostic procedures. The aim of the study was to assess characteristics of children with acute Ocular Motility Disorders (OMDs), and to identify "red flags" for recognition of underlying life-threatening (LT) conditions. Methods: A retrospective cohort study evaluated children (2 months-17 years) admitted to a tertiary Emergency Department in 2009-2014. A subgroup analysis was performed comparing children with and without LT conditions. Results: Of 192 visits for OMDs, the isolated strabismus occurred most frequently (55.6%), followed by pupil disorders (31.8%), ptosis (5.2%) and combined OMDs (11.5%). The majority of acute OMDs involved no underlying LT conditions (n = 136) and most of them were infants or toddlers (50%). In a multivariable analysis, LT conditions included especially children over 6 years of age, increasing the odds ratio by 2% for each months of age (p = 0.009). LT etiologies were 16 times more likely in combined OMDs (p = 0.018), were over 13 times more likely to report associated extra-ocular signs/symptoms (p = 0.017) and over 50 times more likely to report co-morbidity (p = 0.017). Conclusion: OMDs are not an uncommon presentation at ED. Although most of them involve non-LT conditions, the ED physician should consider potential "red flags" for appropriate management of children such as age > 6 years, combined OMDs, extra-ocular symptoms and co-morbidity

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals’ samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp−/− mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp−/− MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia

Acute Movement Disorders in Childhood

Acute-onset movement disorders (MDs) are an increasingly recognized neurological emergency in both adults and children. The spectrum of possible causes is wide, and diagnostic work-up is challenging. In their acute presentation, MDs may represent the prominent symptom or an important diagnostic clue in a broader constellation of neurological and extraneurological signs. The diagnostic approach relies on the definition of the overall clinical syndrome and on the recognition of the prominent MD phenomenology. The recognition of the underlying disorder is crucial since many causes are treatable. In this review, we summarize common and uncommon causes of acute-onset movement disorders, focusing on clinical presentation and appropriate diagnostic investigations. Both acquired (immune-mediated, infectious, vascular, toxic, metabolic) and genetic disorders causing acute MDs are reviewed, in order to provide a useful clinician’s guide to this expanding field of pediatric neurology

The crucial role of FBXO28 in the pathogenesis of the 1q41q42 microdeletion syndrome

no abstract availabl

Movement Disorders in Patients with Genetic Developmental and Epileptic Encephalopathies

Background and Objectives: Movement disorders (MDs) are underrecognized in the developmental and epileptic encephalopathies (DEEs). There are now more than 800 genes implicated in causing the DEEs; relatively few of these rare genetic diseases are known to be associated with MDs. We identified patients with genetic DEEs who had MDs, classified the nature of their MDs, and asked whether specific patterns correlated with the underlying mechanism.Methods: We classified the type of MDs associated with specific genetic DEEs in a large international cohort of patients and analyzed whether specific patterns of MDs reflected the underlying biological dysfunction.Results: Our cohort comprised 77 patients with a genetic DEE with a median age of 9 (range 1-38) years. Stereotypies (37/77, 48%) and dystonia (34/77, 44%) were the most frequent MDs, followed by chorea (18/77, 23%), myoclonus (14/77, 18%), ataxia (9/77, 12%), tremor (7/77, 9%), and hypokinesia (6/77, 8%). In 47% of patients, a combination of MDs was seen. The MDs were first observed at a median age of 18 months (range day 2-35 years). Dystonia was more likely to be observed in nonambulatory patients, while ataxia was less likely. In 46% of patients, therapy was initiated with medication (34/77, 44%), deep brain stimulation (1/77, 1%), or intrathecal baclofen (1/77, 1%). We found that patients with channelopathies or synaptic vesicle trafficking defects were more likely to experience dystonia; whereas, stereotypies were most frequent in individuals with transcriptional defects.Discussion: MDs are often underrecognized in patients with genetic DEEs, but recognition is critical for the management of these complex neurologic diseases. Distinguishing MDs from epileptic seizures is important in tailoring patient treatment. Understanding which MDs occur with different biological mechanisms will inform early diagnosis and management.</p

Movement Disorders in Patients with Genetic Developmental and Epileptic Encephalopathies

Background and Objectives: Movement disorders (MDs) are underrecognized in the developmental and epileptic encephalopathies (DEEs). There are now more than 800 genes implicated in causing the DEEs; relatively few of these rare genetic diseases are known to be associated with MDs. We identified patients with genetic DEEs who had MDs, classified the nature of their MDs, and asked whether specific patterns correlated with the underlying mechanism.Methods: We classified the type of MDs associated with specific genetic DEEs in a large international cohort of patients and analyzed whether specific patterns of MDs reflected the underlying biological dysfunction.Results: Our cohort comprised 77 patients with a genetic DEE with a median age of 9 (range 1-38) years. Stereotypies (37/77, 48%) and dystonia (34/77, 44%) were the most frequent MDs, followed by chorea (18/77, 23%), myoclonus (14/77, 18%), ataxia (9/77, 12%), tremor (7/77, 9%), and hypokinesia (6/77, 8%). In 47% of patients, a combination of MDs was seen. The MDs were first observed at a median age of 18 months (range day 2-35 years). Dystonia was more likely to be observed in nonambulatory patients, while ataxia was less likely. In 46% of patients, therapy was initiated with medication (34/77, 44%), deep brain stimulation (1/77, 1%), or intrathecal baclofen (1/77, 1%). We found that patients with channelopathies or synaptic vesicle trafficking defects were more likely to experience dystonia; whereas, stereotypies were most frequent in individuals with transcriptional defects.Discussion: MDs are often underrecognized in patients with genetic DEEs, but recognition is critical for the management of these complex neurologic diseases. Distinguishing MDs from epileptic seizures is important in tailoring patient treatment. Understanding which MDs occur with different biological mechanisms will inform early diagnosis and management.</p

Severe early onset ethylmalonic encephalopathy with west syndrome

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive disorder characterized by early onset encephalopathy, chronic diarrhoea, petechiae, orthostatic acrocyanosis and defective cytochrome c oxidase (COX) in muscle and brain. High levels of lactic, ethylmalonic and methylsuccinic acids are detected in body fluids. EE is caused by mutations in ETHE1 gene, a mitochondrial sulfur dioxygenase. Neurologic signs and symptoms include progressively delayed development, hypotonia, seizures, and abnormal movements. We report on the clinical, electroencephalographic and MRI findings of a baby with a severe early onset encephalopathy associated with novel ETHE1 gene mutation. This is the first case described in literature with an early pure epileptic onset, presenting with West syndrome

Acute strabismus in neurological emergencies of childhood: a retrospective, single-centre study

Objectives: Acute strabismus (AS) is the most common ocular motility disorder in children. In the emergency setting evaluation, the primary concern is to exclude a potentially dangerous underlying condition, requiring immediate intervention. Our first aim was to describe the epidemiology, clinical features, and underlying causes of AS in a cohort of children presenting to the emergency department (ED). Our second aim was to identify clinical features associated with a significant risk of underlying neurological emergencies (NEs). Design and setting: Clinical records of all patients under 18 years presenting for AS to the ED of the Bambino Gesù Children's Hospital over a 10-year period were retrospectively reviewed. A logistic regression model was applied to detect predictive variables associated with a higher risk of NEs. Results: 208 patients (M:F = 1.19) were identified (0.35 cases per 1000 admission). Commonly associated symptoms included diplopia (18.3%), headache (23.1%), nausea or vomit (8.6%). Other ocular or neurological abnormalities were associated in 47.6% of patients. NEs accounted for 24.03% of all cases, mostly represented by brain tumours (8.65%). Ptosis, optic disk blurring, vomit, gait abnormalities and consciousness disorders were found to confer a significantly greater risk of an underlying NE. Conclusions: Potentially severe neurological conditions may affect almost one in four children presenting to the ED for AS. Brain malignancies are the most common dangerous cause. Presence of ptosis, papilledema, vomit, gait disorders, consciousness impairment, pupillary defects and multiple cranial nerves involvement should be considered as red flags