Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.

OBJECTIVE: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders. METHODS: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. RESULTS: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients. INTERPRETATION: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.

Relevance of enteroviruses in neonatal meningitis.

INTRODUCTION: Enterovirus (EV) infections are the most frequent infections in the neonatal period and in many cases lead to hospital admission of the newborn (NB). The aim of this study was to determine the incidence of EV in the etiology of neonatal meningitis and to define the clinical characteristics of newborns with EV meningitis. MATERIAL AND METHOD: Retrospective observational cohort study. Including 91 NBs with meningitis and gestational age greater than 34 weeks gestational age (GA) attended in our center over a period of 16 years. RESULTS: The percentage of NBs with EV meningitis was higher than that of NBs with bacterial meningitis (BM) and accounted for 78% (n=71). Half of the NBs with EV infection had a history of epidemic environment among their caregivers. Fever was present in 96% of cases as a clinical sign and, in general, sensory disturbances represented the main neurological alterations. Antibiotics (ATB) were given to 71.4% of patients with EV infection. Detection of EV in CSF samples showed a high sensitivity for the diagnosis of EV meningitis. The most frequently implicated EV types were echovirus 11, coxsackievirus B5, echovirus 18, 25 and 7. CONCLUSIONS: The results of this series show that enterovirus infection is a common cause of neonatal meningitis. These data underline the importance of rapid EV testing of infants with suspected meningitis. This allows early diagnosis and reduces antibiotic treatment, hospitalization time and related costs.

Seizures in children undergoing stem cell transplantation.

BACKGROUND: Neurological complications (NCs) are of major concern following hematological stem cell transplantation (HSCT), most of which present with seizures. PROCEDURES: We performed a retrospective study (2002-2018) of patients undergoing HSCT in order to analyze the incidence and aetiologies related to seizures. RESULTS: Of 155 children undergoing HSCT, 27 (17.4%) developed seizures at some point in 2 years of follow-up. The most frequent etiologies were central nervous system (CNS) infection (n = 10), drug toxicity (n = 8), and vascular disease (n = 5). A statistically significant association was found between seizure and the HSCT type (lower risk for a related identical donor, p = .010), prophylactic or therapeutic mycophenolate use (p = .043 and .046, respectively), steroid use (p = .023), selective CD45RA+ depletion (p = .002), pre-engraftment syndrome (p = .007), and chronic graft-versus-host disease (GVHD) severity (p = .030). Seizures predicted evolution to life-threatening complications and admission to intensive care (p < .001) and higher mortality (p = .023). A statistically significant association was also found between seizures and sequelae in survivors (p = .029). Children who developed seizures had a higher risk of CNS infection and vascular disease (odds ratio 37.25 [95% CI: 7.45-186.05] and 12.95 [95% CI 2.24-74.80], respectively). CONCLUSIONS: Neurological complications highly impact survival and outcomes and need to be addressed when facing an HSCT procedure.

Non-pharmacological therapeutic needs in people with Dravet syndrome.

Dravet syndrome (DS) is a genetic rare disease, which is usually caused by a mutation in the SCN1A gene. DS is characterised by a drug-resistant epilepsy and by cognitive and behavioural disturbances. Thus, DS patients require both pharmacological and non-pharmacological treatments. However, there is a paucity of studies on non-pharmacological therapies and their potential benefits. The main aim of this study was to describe the non-pharmacological therapy modalities received by DS patients and their socio-economic impact on the family. Thus, we designed an online survey addressed to caregivers of DS patients. Our results indicated that up to 91.9% of the surveyed patients required non-pharmacological therapies, which were mainly directed to treat cognitive, sensory and motor impairments. In many cases, the economic costs of these therapies were borne entirely by the families. Nevertheless, patients required a deployment of resources not only at a health care level, but also at an educational level.

Characteristics of enterovirus infection associated neurologic disease associated in a pediatric population in Spain.

INTRODUCTION: Enteroviruses are a type of RNA-strained virus with more than 100 different genotypes. Infection can be asymptomatic, and, if any, symptoms can range from mild to severe. Some patients can develop neurological involvement, such as aseptic meningitis, encephalitis, or even cardiorespiratory failure. However, in children, the risk factors for developing severe neurological involvement are not well understood. The aim of this retrospective study was to analyze some characteristics associated with severe neurological involvement in children hospitalized for neurological disease after enterovirus infection. METHODS: retrospective observational study analyzing clinical, microbiological and radiological data of 174 children hospitalized from 2009 to 2019 in our hospital. Patients were classified according to the World Health Organization case definition for neurological complications in hand, foot and mouth disease. RESULTS: Our findings showed that, in children between 6 months old and 2 years of age, the appearance of neurological symptoms within the first 12h from infection onset-especially if associated with skin rash-was a significant risk factor for severe neurological involvement. Detection of enterovirus in cerebrospinal fluid was more likely in patients with aseptic meningitis. By contrast, other biological samples (e.g., feces or nasopharyngeal fluids) were necessary to detect enterovirus in patients with encephalitis. The genotype most commonly associated with the most severe neurological conditions was EV-A71. E-30 was mostly associated with aseptic meningitis. CONCLUSIONS: Awareness of the risk factors associated with worse neurological outcomes could help clinicians to better manage these patients to avoid unnecessary admissions and/or ancillary tests.

Neurologic Complications in Pediatric Allogeneic Stem Cell Transplantation: Analysis of Risk Factors and Outcome.

Neurologic complications following stem cell transplantation are of utmost importance owing to their high morbimortality. Although many studies have been performed in the adult population, reports in children are scarce. Our objective was to determine the most common neurologic complications in a pediatric population and to analyze possible risk factors for their development. We performed an exploratory retrospective study of neurologic complications in pediatric patients who had allogeneic stem cell transplantation over the last 18 years. We identified 66 neurologic complications in 178 allogeneic stem cell transplantations. The most frequent neurologic complications were those involving the peripheral nervous system and those related to drug toxicity. Survival decreased significantly in the presence of neurologic complications. Multivariate logistic regression analysis showed that independent risk factors for developing neurologic complications were development of chronic extensive graft-vs-host disease requiring treatment, cytomegalovirus reactivation, and central nervous system radiation. Prompt diagnosis and preemptive treatment, if possible, are necessary to avoid long-term sequelae or mortality.

Long-term Efficacy of Perampanel in a Child with Dravet Syndrome.

Dravet syndrome is a genetic developmental and epileptic encephalopathy (DEE) mostly due to mutations in SCN1A gene. Perampanel is a selective and non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. There is increasing experience in the use of perampanel in this syndrome; however, there is still a lack of evidence of sustained benefit years after the beginning of the treatment. We report a twelve-year-old girl who was diagnosed with Dravet Syndrome when she was 2 years old and has been on perampanel since she was 7. Her genetic test showed a de novo previously described heterozygous SCN1A mutation in the 24th exon (c.4547C>A, p.Ser1516*). She received previous antiseizure drug combinations with little benefit. When perampanel was started, there was a complete resolution of her spontaneous seizures that has continued five years later. More studies are needed to investigate if there is an association between this excellent response and the genotype of our patient.

Excellent Response to Plasma Exchange in Three Patients With Enterovirus-71 Neurological Disease.

The clinical spectrum of Enterovirus-71-associated neurological disease includes acute flaccid paralysis, encephalomyelitis, or brainstem encephalitis with autonomic dysfunction. As no specific antiviral treatments are available, intravenous human immunoglobulin is used in early stages of the illness, decreasing serum proinflammatory cytokines, and improving clinical outcomes. Plasma exchange aims to eliminate pathogenic autoantibodies and proinflammatory cytokines, and is used in diverse immune-mediated neurologic conditions. However, its effect in Enterovirus-71 infections is unknown. We report three cases of severe Enterovirus-71 neurological disease treated with plasma exchange during an outbreak in Catalonia (Spain) in 2016. We observed a striking improvement in all three patients within 48 h of starting plasma exchange. Patients received four to six sessions every other day. Good outcomes were confirmed at the 1-year follow-up visit. Our observations suggest that plasma exchange is an effective complementary therapy for severe Enterovirus-71 neurological disease.

Eculizumab in a child with atypical haemolytic uraemic syndrome and haemophagocytic lymphohistiocytosis triggered by cytomegalovirus infection.

We present the case of a 21-month-old girl with two rare and life-threatening conditions, atypical haemolytic uraemic syndrome (aHUS) and haemophagocytic lymphohistiocytosis (HLH), triggered by a cytomegalovirus (CMV) infection. Soon after admission, the girl became anuric and required continuous venovenous haemodiafiltration.Initial treatments included methylprednisolone, fibrinogen and plasma infusion (for HLH), plasmapheresis (for thrombotic microangiopathy), immunoglobulins (for inflammation), ganciclovir (for CMV infection) and the antibiotic cefotaxime. On day 5, eculizumab (600 mg) was given for aHUS, with rapid improvement in haematological and nephrological parameters. Despite a subsequent isolated episode of right heart thrombosis that resolved with heparin treatment, the patient showed a favourable response to eculizumab (300 mg/15 days), with improved renal function, normal haematological values, and no treatment complications. In conclusion, eculizumab effectively treated aHUS in this case despite a comorbid immunological disease.

Autoimmune post-herpes simplex encephalitis of adults and teenagers.

OBJECTIVE: To report 14 patients with immune-mediated relapsing symptoms post-herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children. METHODS: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously. RESULTS: Among the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037). CONCLUSION: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.

[Etiology, clinical presentation and outcome of severe viral acute childhood encephalitis (ECOVE study)]. / Etiologia, presentacion clinica y evolucion neurologica de las encefalitis viricas graves en la edad pediatrica (estudio ECOVE).

INTRODUCTION: Viral encephalitis are rare and potentially serious conditions with different etiologist, and not always identifiable. Our aim is to describe the etiological, clinical presentation and neurological outcome of viral encephalitis admitted in Paediatrics Intensive Care Units (PICUs) in Spain. PATIENTS AND METHODS: Observational prospective multicenter study. Children with viral encephalitis admitted to 14 PICUs, for a period of 3 years (2010-2013) were included. Polymerase chain reaction for the etiological diagnosis and neurotropic virus serology in blood and cerebrospinal fluid were used. Personal history, clinical presentation, evolution and neurological status at discharge were recorded. RESULTS: 80 patients were included with a mean age of 5 years, 70% male. The most relevant clinical symptoms were decreased consciousness (86%), fever (82.4%), seizures (67%), vomiting (42%), headache (27%), agitation (25%) and dis-orientation (23%). The etiologic diagnosis was established in 35%, being more frequent herpes simplex virus and enterovirus. The outcome was discharge without sequelae in 55 patients (69%), mild to moderate sequelae in 19 (23.5%) and severe in 6 (7.5%). Two patients died. CONCLUSIONS: In the Spanish PICU etiological diagnosis was established only in a third of cases of children with suspected acute viral encephalitis. Despite the clinical severity we observed a low mortality and morbidity rate. At discharge from the PICU, most children had no neurological sequelae or were mild.

TITLE: Etiologia, presentacion clinica y evolucion neurologica de las encefalitis viricas graves en la edad pediatrica (estudio ECOVE).Introduccion. Las encefalitis viricas son procesos raros y potencialmente graves, con etiologia diversa y no siempre identificable. El objetivo es describir las caracteristicas etiologicas, la presentacion clinica y la evolucion neurologica de las encefalitis viricas que ingresaron en las unidades de cuidados intensivos pediatricos (UCIP) en España. Pacientes y metodos. Estudio prospectivo multicentrico observacional. Se incluyeron los niños ingresados en 14 UCIP con diagnostico de encefalitis virica durante un periodo de tres años (2010-2013). Para el diagnostico etiologico se utilizo reaccion en cadena de la polimerasa y serologia a virus neurotropos en la sangre y el liquido cefalorraquideo. Se registraron los antecedentes personales, la presentacion clinica, la evolucion y la situacion neurologica en el momento del alta. Resultados. Se incluyeron 80 pacientes con edad media de 5 años; el 70%, varones. Los sintomas clinicos mas relevantes fueron disminucion de conciencia (86%), fiebre (82,4%), convulsiones (67%), vomitos (42%), cefalea (27%), agitacion (25%) y desorientacion (23%). Se llego al diagnostico etiologico en un 35%, y los mas frecuentes fueron virus herpes simple y enterovirus. La evolucion fue curacion sin secuelas en 55 pacientes (69%, sobre todo enterovirus, rotavirus y virus respiratorios), secuelas leves-moderadas en 19 (23,5%) y graves en seis (7,5%). Dos pacientes fallecieron. Conclusiones. En las UCIP españolas solo se realizo el diagnostico etiologico en un tercio de los niños con sospecha de encefalitis virica grave. A pesar de la gravedad clinica, hemos observado una tasa de mortalidad y morbilidad baja. La amplia mayoria son dados de alta de la UCIP con ninguna o escasa secuela neurologica.

Vanishing white matter disease in a spanish population.

Vanishing white matter (VWM) leukoencephalopathy is one of the most prevalent hereditary white matter diseases. It has been associated with mutations in genes encoding eukaryotic translation initiation factor (eIF2B). We have compiled a list of all the patients diagnosed with VWM in Spain; we found 21 children. The first clinical manifestation in all of them was spasticity, with severe ataxia in six patients, hemiparesis in one child, and dystonic movements in another. They suffered from progressive cognitive deterioration and nine of them had epilepsy too. In four children, we observed optic atrophy and three also had progressive macrocephaly, which is not common in VWM disease. The first two cases were diagnosed before the 1980s. Therefore, they were diagnosed by necropsy studies. The last 16 patients were diagnosed according to genetics: we found mutations in the genes eIF2B5 (13 cases), eIF2B3 (2 cases), and eIF2B4 (1 case). In our report, the second mutation in frequency was c.318A>T; patients with this mutation all followed a slow chronic course, both in homozygous and heterozygous states. Previously, there were no other reports to confirm this fact. We also found some mutations not described in previous reports: c.1090C>T in eIF2B4, c.314A>G in eIF2B5, and c.877C>T in eIF2B5.

[Five years' experience in a paediatric epilepsy unit]. / Experiencia de cinco años en una unidad de epilepsia pediátrica.

INTRODUCTION AND AIMS: The epilepsy monitoring unit is a space inside a hospital, which objective is to reproduce epileptic seizures in order to better study of an epileptic patient. We have analysed data from all the patients admitted to our pediatric epilepsy unit in the last 5 years. PATIENTS AND METHODS: 191 patients have been admitted in our unit, and we have obtained seizures in 186 admissions (monitoring efficacy, 85.9%). In this report we summarize characteristics of these children, type of seizures and treatment. RESULTS: The most frequent cause of epilepsy in our series is cortical development malformation. Patients are often late in their admission, with a median time of 3 to 4 years from epileptic onset to admission in the epilepsy unit. After the study, 22 patients underwent functional epilepsy surgery, all of them with excellent results, 9 patients underwent vagal nerve stimulator implantation and in 66 patients their previous pharmacological treatment was modified. CONCLUSIONS: The efficacy of our monitoring unit is similar to previously published, 85.9%. After the admission, we have changed diagnose in 57% of the patients and pharmacological treatment in 29%. We recommend the study in a monitoring epilepsy unit of every patient with refractory epilepsy, meaning an epilepsy that does not respond to 2-3 different appropriate treatments.