A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

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.

Epidemiología y características de la infección por SARS-COV-2 en el recién nacido y la gestante. Transferencia transplacentaria de inmunoglobulina / Epidemiology and characteristics of SARS-CoV-2 infection in the newborn and pregnant woman. Transplacemental transfer of immunoglobulins

Introducción La infección por SARS-CoV-2 durante la gestación y su repercusión en el recién nacido eran, en los primeros meses de la pandemia, desconocidas. Recientes estudios han aportado información sobre la afectación clínica en el recién nacido y su evolución. En este trabajo se muestra cómo varía la inmunidad pasiva en el recién nacido con relación al momento de infección SARS-CoV-2 materno. Población y método Estudio observacional, prospectivo y longitudinal en un hospital de tercer nivel. Se recogieron datos epidemiológicos y clínicos de las madres y sus recién nacidos desde mayo del 2020 hasta junio del 2021. Resultados Se ha incluido a un total de 109 madres y 109 neonatos. El 28,4% de las infecciones maternas fueron en el primer trimestre, el 24,8% en el segundo y el 58,8% en el tercero. El 56% de las infecciones maternas fueron sintomáticas, solo una gestante con infección respiratoria grave ingresó en Cuidados Intensivos. La edad gestacional media de los recién nacidos fue de 39 semanas, con un peso medio de 3.232g y un perímetro craneal de 35cm. Ocho recién nacidos hijos de madre con SARS-CoV-2 requirieron ingreso en la UCI neonatal: 2 por ictericia, 2 por distrés respiratorio, uno por prematuridad moderada y 3 por otras causas no relacionadas con infección atribuible a SARS-CoV-2. Los anticuerpos tipo IgG fueron positivas en el 56,9% de los recién nacidos. De las madres infectadas durante el primer trimestre, las IgG fueron positivas en el 32,2% de los recién nacidos, en el segundo trimestre resultaron positivos el 81,5% y en el tercero, el 58,8%. Ningún neonato presentó IgM positivas. Conclusiones La infección por SARS-CoV-2 durante la gestación proporciona anticuerpos IgG a la mitad de los recién nacidos. La presencia de anticuerpos en el recién nacido es más probable cuando la infección se ha producido en el segundo trimestre de gestación (AU)

Introduction SARS-CoV-2 infection during pregnancy and its impact on the newborn were, in the first months of the pandemic, unknown. Recent studies have provided information on the clinical involvement in the newborn and its evolution. This work shows how passive immunity varies in the newborn in relation to the moment of maternal SARS-CoV-2 infection during pregnancy. Population and method Observational, prospective and longitudinal study in a third level hospital. Epidemiological and clinical data from mothers and their newborns were collected from May 2020 to June 2021. Results A total of 109 mothers and 109 neonates have been included. 28.4% of maternal infections were in the first trimester, 24.8% during the second and 58.8% in the third. 56% of maternal infections were symptomatic and only one pregnant woman with severe respiratory infection was admitted to intensive care. The mean gestational age of the newborns was 39 weeks, with a mean weight of 3232g and a head circumference of 35cm. Eight newborns born from mothers with SARS-CoV-2 required admission to the neonatal ICU: 2 due to jaundice, 2 due to respiratory distress, 1 due to moderate prematurity, and 3 due to other causes unrelated to infection attributable to SARS-CoV-2. IgG-type antibodies were positive in 56.9% of newborns. Of the mothers infected during the 1st trimester, IgG were positive in 32.2% of the newborns, in the second trimester 81.5% were positive and in the third 58.8%. No neonate had positive IgM. Conclusions SARS-CoV-2 infection during pregnancy provides IgG antibodies to half of newborns. The presence of antibodies in the newborn is more likely when the infection has occurred in the second trimester of pregnancy (AU)

Sclerotic Bone Lesions as a Clue in the Diagnosis of Three Generations of Tuberous Sclerosis Complex: Case Report and Review of Literature.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that can involve multiple organ systems. Diagnosis is based on independent clinical diagnostic criteria and genetic diagnostic criteria (pathogenic variants on TSC1 and TSC2 genes). To make a definitive diagnosis can be especially difficult in oligosymptomatic or asymptomatic patients and in those patients with genetic variants of uncertain significance (VUS). Early diagnosis and lifelong surveillance are paramount to avoid morbidity and potentially life-threatening complications. To increase diagnostic sensibility, less known manifestations of TSC can be helpful. Herein we show a case in which SBLs were used as a diagnostic clue to help diagnose three generations of oligosymptomatic TSC carrying a VUS in TSC1. SBLs are commonly detected in imaging studies of patients with TSC and have been recently included as a minor clinical diagnostic criterion. Clinicians and radiologists should be aware of their significance as they can be mistaken with osteoblastic metastases.

Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients.

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised by tortuosity and elongation of the aorta and medium-sized arteries. It is considered an extremely rare disease; only 106 individuals with genetically confirmed ATS have been identified to date. Four cases of ATS from two families are described, contributing to the clinical delineation of this condition. A patient with microcephaly and a complex uropathy and two cases with diaphragmatic hernia are noticed. Regarding the vascular involvement, a predominant supra-aortic involvement stands out and only 1 patient with significant arterial stenoses was described. All presented severe tortuosity of the intracranial arteries. To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed. A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was detected in a proband; it has an allegedly deleterious effect in compound heterozygous state with the pathogenic variant c.417T>A (p.Tyr139Ter). The other 3 patients, siblings born to healthy consanguineous parents, had a variant in homozygous state: c.510G>A (p.Trp170Ter).

Case report: De novo pathogenic variant in WFS1 causes Wolfram-like syndrome debuting with congenital bilateral deafness.

Background: Congenital deafness could be the first manifestation of a syndrome such as in Usher, Pendred, and Wolfram syndromes. Therefore, a genetic study is crucial in this deficiency to significantly improve its diagnostic efficiency, to predict the prognosis, to select the most adequate treatment required, and to anticipate the development of other associated clinical manifestations. Case presentation: We describe a young girl with bilateral congenital profound deafness, who initially received a single cochlear implant. The genetic study of her DNA using a custom-designed next-generation sequencing (NGS) panel detected a de novo pathogenic heterozygous variant in the WFS1 gene related to Wolfram-like syndrome, which is characterized by the presence of other symptoms such as optic atrophy. Due to this diagnosis, a second implant was placed after the optic atrophy onset. The speech audiometric results obtained with both implants indicate that this work successfully allows the patient to develop normal speech. Deterioration of the auditory nerves has not been observed. Conclusion: The next-generation sequencing technique allows a precise molecular diagnosis of diseases with high genetic heterogeneity, such as hereditary deafness, while this was the only symptom presented by the patient at the time of analysis. The NGS panel, in which genes responsible for both syndromic and non-syndromic hereditary deafness were included, was essential to reach the diagnosis in such a young patient. Early detection of the pathogenic variant in the WFS1 gene allowed us to anticipate the natural evolution of the disease and offer the most appropriate management to the patient.

The Charlotte Project: Recommendations for patient-reported outcomes and clinical parameters in Dravet syndrome through a qualitative and Delphi consensus study.

Objective: The appropriate management of patients with Dravet Syndrome (DS) is challenging, given the severity of symptoms and the burden of the disease for patients and caregivers. This study aimed to identify, through a qualitative methodology and a Delphi consensus-driven process, a set of recommendations for the management of DS to guide clinicians in the assessment of the clinical condition and quality of life (QoL) of DS patients, with a special focus on patient- and caregiver-reported outcomes (PROs). Methods: This study was conducted in five phases, led by a multidisciplinary scientific committee (SC) including pediatric neurologists, epileptologists, a neuropsychologist, an epilepsy nurse, and members of DS patient advocates. In phases 1 and 2, a questionnaire related to patients' QoL was prepared and answered by caregivers and the SC. In phase 3, the SC generated, based on these answers and on a focus group discussion, a 70-item Delphi questionnaire, covering six topic categories on a nine-point Likert scale. In phase 4, 32 panelists, from different Spanish institutions and with a multidisciplinary background, answered the questionnaire. Consensus was obtained and defined as strong or moderate if ≥80% and 67-79% of panelists, respectively, rated the statement with ≥7. Phase 5 consisted of the preparation of the manuscript. Results: The panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. The experts' recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers' education in the routine clinical management of patients with DS. Conclusions: This consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS.

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype−phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype−phenotype correlations and improve prognostic outcomes.

[Epidemiology and characteristics of SARS-CoV-2 infection in the newborn and pregnant woman. Transplacemental transfer of immunoglobulins]. / Epidemiología y características de la infección por SARS-COV-2 en el recién nacido y la gestante. Transferencia transplacentaria de inmunoglobulinas.

Introduction: SARS-CoV-2 infection during pregnancy and its impact on the newborn were, in the first months of the pandemic, unknown. Recent studies have provided information on the clinical involvement in the newborn and its evolution.This work shows how passive immunity varies in the newborn in relation to the moment of maternal SARS-CoV-2 infection during pregnancy. Population and method: Observational, prospective and longitudinal study in a third level hospital. Epidemiological and clinical data from mothers and their newborns were collected from May 2020 to June 2021. Results: A total of 109 mothers and 109 neonates have been included. 28.4% of maternal infections were in the first trimester, 24.8% during the second and 58.8% in the third. 56% of maternal infections were symptomatic and only one pregnant woman with severe respiratory infection was admitted to intensive care. The mean gestational age of the newborns was 39 weeks, with a mean weight of 3232 g and a head circumference of 35 cm. Eight newborns born from mothers with SARS-CoV-2 required admission to the neonatal ICU: 2 due to jaundice, 2 due to respiratory distress, 1 due to moderate prematurity, and 3 due to other causes unrelated to infection attributable to SARS-CoV-2. IgG-type antibodies were positive in 56.9% of newborns. Of the mothers infected during the 1 st trimester, IgG were positive in 32.2% of the newborns, in the second trimester 81.5% were positive and in the third 58.8%. No neonate had positive IgM. Conclusions: SARS-CoV-2 infection during pregnancy provides IgG antibodies to half of newborns. The presence of antibodies in the newborn is more likely when the infection has occurred in the second trimester of pregnancy.

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.

Canvis en les característiques de les intoxicacions en menors de 18 anys. Revisió de casos en un servei d’urgències (2011-2018) / Cambios en las características de las intoxicaciones en menores de 18 años. Revisión de casos en un servicio de urgencias (2011-2018) / Changes in the pattern of poisonings in patients under 18 years. A review of cases in an emergency department (2011–2018)

Fonament. Les intoxicacions han sofert canvis al llarg deltemps en relació amb l’etiologia, el maneig i les complicacions. Conèixer-ne l’epidemiologia ajuda a generar mesurespreventives.Objectiu. Analitzar les característiques epidemiològiques iclíniques, el pronòstic i la mortalitat de les intoxicacions enun servei d’urgències pediàtriques.Mètode. Estudi descriptiu, retrospectiu, observacional. Període: vuit anys. Es van incloure menors de divuit anys ambsospita d’intoxicació atesos a urgències que van requeriringrés hospitalari o observació. Anàlisi feta mitjançant elprograma SPSS.Resultats. Es van incloure cinquanta-dos pacients, delsquals trenta-tres van ser menors de sis anys (63,5%) i dinou majors de dotze anys (36,5%). Tots els successos enels menors de sis anys van ser involuntaris. El 94,7% deles intoxicacions en els majors de dotze anys van ser intencionades, de les quals el 72,2% tenien intenció suïcida.Els tòxics més freqüents van ser els medicaments (63,4%),seguits de les drogues il·lícites (15,4%). El 50% del totald’intoxicacions va presentar alteració del nivell de consciència i el 28,8% va requerir suport respiratori. Enl’11,5% es va fer rentat gàstric i en el 30% es va administrar carbó activat. L’alteració del nivell de consciència vaser l’únic factor significatiu (p<0,05) associat a l’ingrés ala Unitat de Cures Intensives Pediàtriques (UCIP).Conclusions. Les intoxicacions predominaren en els menors de sis anys. Del total d’intoxicacions, la medicamentosa va ser la causa més freqüent, seguida de les drogues il·lícites.El factor clínic més relacionat amb l’ingrés a la UCIP va serl’alteració de la consciència. (AU)

Fundamento. Las intoxicaciones han sufrido cambios a lo largo del tiempo en etiología, manejo y complicaciones. Conocer su epidemiología ayuda a generar medidas preventivas. Objetivo. Analizar las características epidemiológicas y clínicas, el pronóstico y la mortalidad de las intoxicaciones en un servicio de urgencias pediátricas. Método. Estudio descriptivo, retrospectivo, observacional. Periodo:8 años. Se incluyó a los menores de 18 años con sospecha de intoxicación atendidos en urgencias que requirieron ingreso u observación. Análisis realizado mediante el programa SPSS. Resultados. Se incluyeron 52 pacientes, de los cuales 33 fueron menores de 6 años (63,5%) y 19 mayores de 12 años (36,5%).Todos los eventos en los menores de 6 años fueron involuntarios. El 94,7% de las intoxicaciones en los mayores de 12 años fueron intencionadas, de las cuales el 72,2% tenían intención suicida. La causa medicamentosa (63,4%) fue la más frecuente, seguida por las drogas ilícitas (15,4%). El 50% del total de intoxicaciones presentaron alteración del nivel de consciencia y el 28,8% precisó soporte respiratorio. En el 11,5% se realizó lavado gástrico y en el30% se administró carbón activado. La alteración del nivel de consciencia fue el único factor significativo (p<0,05) asociado con el ingreso en la unidad de cuidados intensivos pediátricos (UCIP).Conclusiones. Las intoxicaciones predominaron en los menores de6 años. Del total de intoxicaciones, la medicamentosa fue la causa más frecuente, seguida por las drogas ilícitas. El factor clínico más relacionado con el ingreso a UCIP fue la alteración del nivel de consciencia. (AU)

Background. Poisonings in pediatrics have undergone changes overtime in terms of etiology, management, and complications. It is important to know the epidemiology to generate preventive measures. Objective. To analyze the epidemiology, clinical characteristics,prognosis, and mortality of poisonings in pediatric patients caredfor in the emergency department.Method. This is a descriptive, retrospective and observationalstudy. Period: 8 years. Patients under 18 with suspected poisoningadmitted in the emergency department were included. The statistical analysis was performed using the SPSS program.Results. 52 patients were selected, 33 under 6 years of age (63.5%)and 19 over 12 years (36.5%). All events in children under 6 wereunintentional. 94.7% of poisonings in patients over 12 years of agewere intentional, of which 72.2% had a suicidal intention. Pharmacologic agents (63.4%) were the most frequently identified ingestedsubstance, followed by illicit drugs (15.4%). 50% of all cases hadaltered level of consciousness and 28.8% required respiratory support. Gastric lavage was performed in 11.5% and activated charcoalwas administered in 30%. Altered level of consciousness was theonly significant factor (p<0.05) associated with admission to thepediatric intensive care unit (PICU).Conclusions. Poisoning cases were more frequent in children under6 years. Pharmacologic agents were the most frequently identifiedpoisoning substances, followed by illicit drugs. Decreased consciousness was the most significant clinical factor leading to admission to the PICU. (AU)

A case report of PHF6 mosaicism: Beyond the classic Börjeson-Forssman-Lehmann syndrome.

We report a 6-year-old female with linear skin hyperpigmentation on the axillae and groin, intellectual disability, dysplastic teeth and nails, and facial dysmorphism who was diagnosed with a novel PHF6 pathogenic splicing variant. Males with PHF6 mutations have been associated with the X-linked recessive disorder Börjeson-Forssman-Lehmann, but females have a distinct phenotype which is likely modulated by X-inactivation.

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype.

BACKGROUND: The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS), and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate. METHODS: We studied in detail the clinical features of the patients and performed a genomic analysis by using TruSight One Expanded Sequencing Panel. Subsequently, we determined the ATP7A and ATP7B expression levels, mitochondrial membrane potential, and redox balance in cultured fibroblasts of Patient 1. RESULTS: We found a novel ATP7A late truncated mutation p.Lys1412AsnfsX15 in the two affected members of this family. The co-occurrence of OHS and dHMN in Patient 1 reveals the variable phenotypic expressivity of the variant. A severe clinical and neurophysiologic worsening was observed in the dHMN of Patient 1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn. Functional studies revealed that the patient had low levels of both ATP7A and ATP7B, the other copper transporter, and high levels of superoxide ion in the mitochondria. CONCLUSIONS: Our findings broaden the clinical spectrum of ATP7A-related disorders and demonstrate that two clinical phenotypes can occur in the same patient. The copper-induced toxicity and low levels of both ATP7A and ATP7B in our patient suggest that copper accumulation in motor neurons is the pathogenic mechanism in ATP7A-related dHMN.

Neurologic Care of COVID-19 in Children.

Most children with SARS-CoV-2 infection have relatively mild clinical symptoms without fever or pneumonia, although severe cases with multiple-organ failure have been reported. Neurological symptoms, which have been mainly reported in adults, are very rare in children. This article will review 2 different aspects of neurological involvement related to this infection in children. In the first part, we will review the neurological abnormalities reported in children caused by this viral infection. Adults frequently report muscle pain, headache, anosmia, dysgeusia, and occasionally more severe central or peripheral nervous system damage. Neurological involvement seems infrequent in children, although some cases have been reported. In the second part, we will discuss the COVID-19 pandemic impact on the healthcare system of some countries, causing collateral damage to general pediatric care and in particular to those children affected with chronic diseases, mainly neurological conditions, including autism, intellectual disability, attention deficit and hyperactivity disorder (ADHD), neuromuscular disorders, cerebral palsy, and epilepsy, and patients needing neurosurgical procedures.

Less common manifestations in TSC.

Tuberous sclerosis complex (TSC) is due to pathogenic variants in TSC1 or TSC2 genes resulting in hyperactivation of the mTOR pathway. Many organ systems can be affected, such as brain, skin, eye, heart, bone, kidney, or lung. Typical lesions of TSC usually are those included as major criteria, including angiofibromas, hypomelanotic macules, tubers, subependymal nodules, angiomyolipomas, cardiac rhabdomyomas, and lymphangioleiomyomatosis. However, there are many other manifestations less frequent and/or less well known, many of them not included as clinical diagnostic criteria that are part of the clinical spectrum of TSC. The focus of this review will be on these less common and less well-known manifestations of TSC. Among the rare manifestations, we will discuss some clinical findings including arteriopathy, arachnoid cysts, lymphatic involvement, chordomas, gynecological, endocrine, and gastrointestinal findings. Among the manifestations that are very frequent but much less well known, we find the sclerotic bone lesions. Although they are very frequent in TSC they have been largely overlooked and not considered diagnostic criteria, mainly because they are asymptomatic. However, it is important to know their typical characteristics to avoid misdiagnosing them as metastasis.

Cerebellar lesions are associated with TSC2 mutations in tuberous sclerosis complex: a retrospective record review study.

AIM: Cerebellar lesions are present in approximately 30% of patients with tuberous sclerosis complex. Although several prior studies have characterized these lesions, our study provides the first description of the specific distribution of these lesions within the cerebellum and the first genotype-phenotype correlation yet to be published. METHOD: We retrospectively reviewed magnetic resonance images from 220 paediatric and adult patients with tuberous sclerosis complex (95 males, 125 females; mean age 22.7y, range 9mo-81y). Sex, age, and genotype of patients with cerebellar lesions were recorded and specific characteristics, including signal intensity, number, shape, presence of enhancement, calcification or haemorrhage, and location within the cerebellar lobules were noted. RESULTS: Fifty-eight patients (26.4%) had 106 cerebellar lesions (62 right, 44 left). The mean number of cerebellar lesions per patient was 1.8 (range 1-6). Enhancement was present in 42.4% of lesions and folial retraction in 84%. Calcification was detected in 86.8% of lesions. Patients with calcified lesions were older (mean age 21.6y) than patients without calcification (11.5y). TSC2 mutations were detected in 41/42 (97.6%) of patients with cerebellar tubers who had genetic testing and one patient had no mutation identified. None of the patients had TSC1 mutation. INTERPRETATION: We provide new information regarding cerebellar lesions in tuberous sclerosis complex: cerebellar lesions are significantly much more frequent in patients with TSC2 mutations than TSC1 mutations or patients with no mutation identified, and Crus II is the most frequent location of cerebellar lesions. New studies are needed to assess the clinical significance of these lesions.