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Noonan syndrome (NS) is an autosomal dominant condition characterized by facial dysmorphism, congenital heart disease, development delay, growth retardation and lymphatic disease. It is caused by germline pathogenic variants in genes encoding proteins in the Ras/mitogen-activated protein kinase signaling pathway. Nerve enlargement is not generally considered as a feature of NS, although some cases have been reported. High-resolution nerve ultrasound enables detailed anatomical assessment of peripheral nerves and can show enlarged nerves. This retrospective cohort study aims to describe the sonographic findings of patients with NS performed during a 1-year time period. Data on the degree of enlargement, the relation to increasing age, pain in extremities, genotype on the gene level and clinical features were collected. Twenty-nine of 93 patients visiting the NS Center of Expertise of the Radboud University Medical Center Nijmegen underwent high-resolution ultrasound. In 24 patients (83%) nerve enlargement was found. Most of them experienced pain. We observed a weak correlation with increasing age and the degree of nerve enlargement but no association with pain, genotype at the gene level or clinical features. This study shows that patients with NS have a high predisposition for sonographic nerve enlargement and that the majority experience pain.
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INTRODUCTION/AIMS: There is clear evidence for brain involvement in childhood myotonic dystrophy type 1 (DM1) from imaging studies and the prevalence of intellectual impairment and neurodevelopmental disorders. The cognitive profile of children with DM1 however is poorly understood. The aim of this study was to assess the cognitive profile of children with DM1. METHODS: Neuropsychological examination reports of 45 children aged 2-17 y were analyzed. All cognitive subtests used in this cohort were pooled in 10 cognitive domains. For every patient a composite z-score was calculated for every assessed domain. Composite scores were classified as average (z > -1), mild cognitive impairment (-1 ≥ z > -2), or major cognitive impairment (z ≤ -2). RESULTS: The nature and extent of neuropsychological examinations differed between centers and patients. The domains with the highest frequency of major cognitive impairment were social cognition (4/9 children tested; 44%), attention (13/32; 41%), and fine motor skills (3/10; 30%). Combining mild and major cognitive impairment, working memory (20/28; 71%), attention (21/32; 66%), and visuospatial functions (16/28; 57%) were the most frequently affected domains. Long-term memory was least affected, with mild impairment only in 5/29 (17%). DISCUSSION: Children with DM1 may have specific cognitive deficits, most frequently affecting working memory, attention, and visuospatial functions, in addition to the previously described global intellectual impairments. We recommend including a standardized neuropsychological examination in the standards of care for DM1 children. Early recognition of cognitive deficits and behavioral disorders in children with DM1 can improve their management.
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Transtornos Cognitivos , Disfunção Cognitiva , Distrofia Miotônica , Humanos , Distrofia Miotônica/diagnóstico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Testes Neuropsicológicos , Fenótipo , CogniçãoRESUMO
We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
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Epilepsia Generalizada , Síndromes Epilépticas , Deficiência Intelectual , Canal de Sódio Disparado por Voltagem NAV1.6 , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/genética , Estudos de Associação Genética , Humanos , Lactente , Deficiência Intelectual/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Prognóstico , Convulsões/tratamento farmacológico , Convulsões/genética , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
This study is aimed at describing the findings of high-resolution nerve ultrasound in children with Noonan syndrome (NS) and related disorders experiencing pain in their legs. This retrospective cohort study was conducted in the NS expert center of the Radboud University Medical Center in the Netherlands. Patients were eligible if they were younger than 18 years, clinically and genetically diagnosed with NS or a NS related disorder, and experienced pain in their legs. Anamneses and physical examination were performed in all children. In addition, high-resolution nerve ultrasound was used to assess nerve hypertrophy and, if needed, complemented spinal magnetic resonance imaging was performed. Over a period of 6 months, four children, three with NS and one child with NS with multiple lentigines, who experienced pain of their legs were eligible for inclusion. Muscle weakness was found in two of them. High-resolution nerve ultrasound showed (localized) hypertrophic neuropathy in all patients. One child underwent additional spinal magnetic resonance imaging, which showed profound thickening of the nerve roots and plexus. Conclusion: In the four children included with a NS and related disorders, pain was concomitant with nerve hypertrophy, which suggests an association between these two findings. The use of high-resolution nerve ultrasound and spinal magnetic resonance imaging might result in better understanding of the nature of this pain and the possible association to nerve hypertrophy in patients with NS and related disorders. What is Known: ⢠Children with Noonan syndrome and related disorders may report pain in their legs, which is often interpreted as growing pain. ⢠Some adults with Noonan syndrome and related disorders have hypertrophic neuropathy as a possible cause of neuropathic pain. What is New: ⢠This is the first study using high-resolution nerve ultrasound in children with Noonan syndrome and related disorders experiencing pain in their legs. ⢠Hypertrophic neuropathy was diagnosed as possible cause of pain in four children with Noonan syndrome and related disorders.
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Síndrome de Noonan , Adulto , Humanos , Criança , Síndrome de Noonan/complicações , Síndrome de Noonan/diagnóstico , Estudos Retrospectivos , Hipertrofia/complicações , Dor/etiologia , Proteína Tirosina Fosfatase não Receptora Tipo 11RESUMO
AIM: Respiratory insufficiency can be a presenting symptom of congenital myasthenic syndromes (CMS) but is rarely recognised as such. In this study, we aim to raise awareness of CMS to paediatricians. METHODS: We performed a retrospective case study of infants and preschool children treated in the past 5 years in Amalia Children's Hospital, Radboud University Medical Center in Nijmegen, the Netherlands for respiratory insufficiency as presenting symptom of CMS. RESULTS: Five children aged 2 weeks to 5 years experienced severe to life-threatening episodes of respiratory insufficiency, especially during viral infections, due to respiratory muscle weakness. During infections, they often also had progression of their otherwise mild ocular, facial, and limb muscle weakness. They were eventually diagnosed with genetically proven CMS. In these five children, treatment with pyridostigmine, an acetylcholinesterase inhibitor, resulted in clinical improvement. CONCLUSION: CMS should be considered in every patient with unexplained recurrent respiratory insufficiency, or with an unusually severe course of a normally mild respiratory infection, especially in combination with mild muscle weakness outside periods of illness. Early diagnosis of CMS is crucial for early treatment, which may help avoiding sudden infant death, severe respiratory insufficiency and further deterioration of the muscle strength.
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Síndromes Miastênicas Congênitas , Insuficiência Respiratória , Lactente , Pré-Escolar , Humanos , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Estudos Retrospectivos , Acetilcolinesterase/genética , Acetilcolinesterase/uso terapêutico , Proteínas Musculares/genética , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Debilidade Muscular , MutaçãoRESUMO
AIM: Congenital myasthenic syndromes (CMS) are a rare and diverse group of treatable neuromuscular transmission disorders. Diagnosis is often substantially delayed. This study aimed to identify common symptoms of CMS in children and their manifestation to aid diagnosis and early intervention. METHODS: We performed a retrospective cohort study, including 18 children (median age 13 years, range 9 years 5 months-18 years 0 month) with CMS. Data on CMS symptoms and their manifestation were extracted from patients' charts and supplemented with parental telephone interviews. Descriptive analyses were used to identify common symptoms. RESULTS: A median diagnostic delay of 4 years and 7 months (interquartile range: 51 months) was observed. Proximal muscle weakness (100%), ptosis (89%), clumsy gait (82%), difficulty eating solid foods (78%) and recurrent respiratory tract infections (72%) were most common in these patients. Symptoms mostly co-occurred and frequently had a fluctuating character, aggravated by infections or fatigue. CONCLUSION: Early referral to diagnose CMS is crucial to enable timely initiation of treatment. Heightened attention to a combination of symptoms related to muscle weakness, rather than individual symptoms, should support paediatricians in flagging these neuromuscular disorders. Medical history taking should be tailored to parents' perceptions, asking questions about recognisable symptoms of muscle weakness.
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Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.
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Deficiência Intelectual/genética , Mutação , Proteína Fosfatase 2/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Células HEK293 , Haploinsuficiência/genética , Humanos , Masculino , Ligação Proteica/genética , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , SíndromeRESUMO
PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.
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Epilepsia , Deficiência Intelectual , Epilepsia/genética , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Mutação , Fenótipo , Receptores de GABA-A/genéticaRESUMO
BACKGROUND: This study explores the prevalence, clinical characteristics, and treatment of epilepsy and sleep disorders in α thalassemia mental retardation (ATR-X) syndrome. DESIGN: In this cross-sectional study, 37 participants with ATR-X syndrome aged 1.8 to 44 years were studied using a customized epilepsy questionnaire, review of electroencephalography (EEG) findings, the modified Sleep Questionnaire of Simonds and Parraga and 2-week sleep diary. RESULTS: Eleven participants had a clinical diagnosis of generalized epilepsy (29.7%). Seizure types were generalized tonic-clonic seizures, absences, and myoclonia. Interictal EEG recordings in participants with GTCS showed no epileptic discharges in 78%. Similarly, EEG recordings during myoclonia and absences often demonstrated no epileptic discharges. Sleep problems (difficulty falling or maintaining sleep, and early awakening) were reported in 70%. Participants with reported sleep problems went to bed earlier (p = 0.027) and had a lower sleep efficiency (p < 0.01) than participants without sleep problems, but as a group they both had a sufficient total sleep time (9 hours and 52 minutes vs. 10 hours and 55 minutes). Sixteen participants (43.2) used medication to improve sleep (predominantly melatonin n = 10), being effective in only two. CONCLUSION: One-third of participants with ATR-X syndrome had a clinical diagnosis of epilepsy, but the absence of EEG abnormalities in suspected epileptic seizures questions this diagnosis in these patients. EEG recording during seizure like symptoms is warranted before making an epilepsy diagnosis. Seventy percent experienced sleep problems, although total sleep time was normal in most participants. Long bedtimes might have a negative influence on sleep efficiency.
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Epilepsia Generalizada , Epilepsia , Mioclonia , Transtornos do Sono-Vigília , Talassemia alfa , Proteínas Mutadas de Ataxia Telangiectasia , Estudos Transversais , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/etiologia , Humanos , Deficiência Intelectual Ligada ao Cromossomo X , Mioclonia/diagnóstico , Convulsões/diagnóstico , Sono , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/etiologiaRESUMO
BackgroundAcute flaccid myelitis (AFM) is a polio-like condition affecting mainly children and involving the central nervous system (CNS). AFM has been associated with different non-polio-enteroviruses (EVs), in particular EV-D68 and EV-A71. Reliable incidence rates in European countries are not available.AimTo report AFM incidence in children in the Netherlands and its occurrence relative to EV-D68 and EV-A71 detections.MethodsIn 10 Dutch hospitals, we reviewed electronic health records of patients diagnosed with a clinical syndrome including limb weakness and/or CNS infection and who were < 18 years old when symptoms started. After excluding those with a clear alternative diagnosis to AFM, those without weakness, and removing duplicate records, only patients diagnosed in January 2014-December 2019 were retained and further classified according to current diagnostic criteria. Incidence rates were based on definite and probable AFM cases. Cases' occurrences during the study period were co-examined with laboratory-surveillance detections of EV-D68 and EV-A71.ResultsAmong 143 patients included, eight were classified as definite and three as probable AFM. AFM mean incidence rate was 0.06/100,000 children/year (95% CI: -0.03 to 0.14). All patient samples were negative for EV-A71. Of respiratory samples in seven patients, five were EV-D68 positive. AFM cases clustered in periods with increased EV-D68 and EV-A71 detections.ConclusionsAFM is rare in children in the Netherlands. The temporal coincidence of EV-D68 circulation and AFM and the detection of this virus in several cases' samples support its association with AFM. Increased AFM awareness among clinicians, adequate diagnostics and case registration matter to monitor the incidence.
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Viroses do Sistema Nervoso Central , Enterovirus Humano A , Enterovirus Humano D , Infecções por Enterovirus , Mielite , Poliomielite , Humanos , Criança , Adolescente , Países Baixos/epidemiologia , Mielite/diagnóstico , Mielite/epidemiologia , Viroses do Sistema Nervoso Central/diagnóstico , Viroses do Sistema Nervoso Central/epidemiologia , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/epidemiologiaRESUMO
We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.
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Anormalidades Múltiplas/genética , Proteínas de Membrana/genética , Hipotonia Muscular/genética , Convulsões/genética , Espasmos Infantis/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/metabolismo , Criança , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/patologia , Mutação de Sentido Incorreto , Fenótipo , Convulsões/diagnóstico , Convulsões/metabolismo , Espasmos Infantis/metabolismo , Espasmos Infantis/patologia , Sequenciamento do ExomaRESUMO
The ketogenic diet (KD), containing high levels of fat and low levels of carbohydrates, has been used to treat refractory epilepsy since the 1920s. In the past few decades, there has been more interest in less restrictive KDs such as the modified Atkins diet (MAD). PURPOSE: Our aim was to review all evidence regarding the efficacy and tolerability of the KD and MAD from randomized controlled trials (RCTs) in children and adolescents with refractory epilepsy. METHODS: We reviewed the current literature using Cochrane, EMBASE, and MEDLINE (using PubMed). We implemented predefined criteria regarding dataextraction and study quality. RESULTS: We identified five RCTs that generated seven publications and recruited 472 children and adolescents with refractory epilepsy (≤ 18 years). The primary outcome (seizure frequency reduction (SFR) ≥ 50%) was attained in 35-56.1% of the participants in the intervention group, compared with 6-18.2% in the control group. Our meta-analysis underlined the significant efficacy of the KD compared with the control group: RR = 5.1 (95% CI 3.18-8.21, p < 0.001). Additionally, only two studies mentioned possible biomarkers to objectively evaluate the efficacy. Secondary outcomes, such as seizure severity and quality of life, were studied in three trials, leading to indecisive generalization of these findings. Gastro-intestinal adverse effects were the most prevalent, and no severe adverse effects were reported. CONCLUSION: Despite the heterogeneity between all studies, the beneficial results underline that dietary interventions should be considered for children and adolescents with refractory epilepsy who are not eligible for epilepsy surgery. Future studies should be multi-center and long-term, and evaluate potential biomarkers and adverse effects.
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Dieta Cetogênica , Epilepsia Resistente a Medicamentos , Epilepsia , Adolescente , Criança , Humanos , Convulsões , Resultado do TratamentoRESUMO
OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.
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Epilepsia/diagnóstico , Epilepsia/genética , Sequenciamento do Exoma/métodos , Exoma/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Epilepsia/epidemiologia , Feminino , Testes Genéticos/métodos , Humanos , Deficiência Intelectual/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Epilepsy is both a disease of the brain and the mind. Here, we present the second of two papers with extended summaries of selected presentations of the Third International Congress on Epilepsy, Brain and Mind (April 3-5, 2014; Brno, Czech Republic). Humanistic, biologic, and therapeutic aspects of epilepsy, particularly those related to the mind, were discussed. The extended summaries provide current overviews of epilepsy, cognitive impairment, and treatment, including brain functional connectivity and functional organization; juvenile myoclonic epilepsy; cognitive problems in newly diagnosed epilepsy; SUDEP including studies on prevention and involvement of the serotoninergic system; aggression and antiepileptic drugs; body, mind, and brain, including pain, orientation, the "self-location", Gourmand syndrome, and obesity; euphoria, obsessions, and compulsions; and circumstantiality and psychiatric comorbidities.
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Encéfalo/patologia , Congressos como Assunto , Epilepsia/diagnóstico , Internacionalidade , Relações Metafísicas Mente-Corpo , Agressão/psicologia , Anticonvulsivantes/uso terapêutico , Encéfalo/fisiopatologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Comportamento Compulsivo/diagnóstico , Comportamento Compulsivo/tratamento farmacológico , Comportamento Compulsivo/psicologia , Congressos como Assunto/tendências , República Tcheca , Morte Súbita/prevenção & controle , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Humanos , Epilepsia Mioclônica Juvenil/diagnóstico , Epilepsia Mioclônica Juvenil/tratamento farmacológico , Epilepsia Mioclônica Juvenil/psicologia , Dor/diagnóstico , Dor/tratamento farmacológico , Dor/psicologiaRESUMO
Gastrointestinal and urological symptoms are frequently reported by people with myotonic dystrophy type 1 (DM1) but have remained understudied. In a cross-sectional study, frequency, nature, treatment and impact of gastrointestinal and urological symptoms in children with DM1 aged 5-18 years were assessed. We included 58 children (30 males, 28 females) with a mean age of 13 years; 74.1 % reported at least one gastrointestinal symptom. Abdominal pain was the most frequently reported symptom (51.7 %), followed by dysphagia (41.8 %), diarrhoea (36.2 %), encopresis (36.0 %), constipation (32.7 %), bloating and flatulence (both 25.9 %). The most frequently reported urological symptoms were difficulty with toilet training (59.3 %), urinary incontinence (22.0 %), enuresis nocturna (10.3 %) and voiding (23.5 % hesitancy, 4.8 % intermittency and 13.8 % dysuria). The majority considered urological and gastrointestinal symptoms to have a negative influence on their daily life; 22.4 % of parents reported severe influence on daily family life (shame, social restrictions, school absence and concerns for their children's future). Considering the high prevalence of urological and gastrointestinal symptoms in children with DM1 and their influence on daily life it is key to correctly recognize, diagnose and treat these symptoms. We recommend screening for gastrointestinal and urological symptoms in the standard of care for children with DM1.
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Transtornos de Deglutição , Distrofia Miotônica , Humanos , Masculino , Criança , Feminino , Adolescente , Distrofia Miotônica/complicações , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/epidemiologia , Estudos Transversais , Prevalência , Qualidade de VidaRESUMO
Brody disease is a rare autosomal recessive myopathy, caused by pathogenic variants in the ATP2A1 gene. It is characterized by an exercise-induced delay in muscle relaxation, often reported as muscle stiffness. Children may manifest with an abnormal gait and difficulty running. Delayed relaxation is commonly undetected, resulting in a long diagnostic delay. Almost all published cases so far were adults with childhood onset and adult diagnosis. With diagnostic next-generation sequencing, an increasing number of patients are diagnosed in childhood. We describe the clinical and genetic features of 9 children from 6 families with Brody disease. All presented with exercise-induced delayed relaxation, reported as difficulty running and performing sports. Muscle strength and mass was normal, and several children even had an athletic appearance. However, the walking and running patterns were abnormal. The diagnostic delay ranged between 2 and 7 years. Uniformly, a wide range of other disorders were considered before genetic testing was performed, revealing pathogenic genetic variants in ATP2A1. To conclude, this case series is expected to improve clinical recognition and timely diagnosis of Brody disease in children. We propose that ATP2A1 should be added to gene panels for congenital myopathies, developmental and movement disorders, and muscle channelopathies.
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Transtornos dos Movimentos , Doenças Musculares , Miotonia Congênita , Adulto , Criança , Humanos , Diagnóstico Tardio , Mutação/genética , Doenças Musculares/genética , MarchaAssuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Proteínas de Transporte de Monossacarídeos/deficiência , Acidente Vascular Cerebral/diagnóstico , Criança , Pré-Escolar , Diagnóstico Diferencial , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos RetrospectivosRESUMO
PURPOSE: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. METHODS: Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired. KEY FINDINGS: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. SIGNIFICANCE: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.
Assuntos
Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Epilepsia do Lobo Frontal/epidemiologia , Epilepsia do Lobo Frontal/fisiopatologia , Lobo Frontal/fisiologia , Rede Nervosa/fisiologia , Adolescente , Criança , Transtornos Cognitivos/psicologia , Estudos de Coortes , Epilepsia do Lobo Frontal/psicologia , Feminino , Humanos , Masculino , Vias Neurais/fisiologia , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologia , Sistema de RegistrosRESUMO
BACKGROUND: Acute flaccid paralysis (AFP) is characterized by rapidly progressive limb weakness with low muscle tone. It has a broad differential diagnosis, which includes acute flaccid myelitis (AFM), a rare polio-like condition that mainly affects young children. Differentiation between AFM and other causes of AFP may be difficult, particularly at onset of disease. Here, we evaluate the diagnostic criteria for AFM and compare AFM to other causes of acute weakness in children, aiming to identify differentiating clinical and diagnostic features. METHODS: The diagnostic criteria for AFM were applied to a cohort of children with acute onset of limb weakness. An initial classification based on positive diagnostic criteria was compared to the final classification, based on application of features suggestive for an alternative diagnosis and discussion with expert neurologists. Cases classified as definite, probable, or possible AFM or uncertain, were compared to cases with an alternative diagnosis. RESULTS: Of 141 patients, seven out of nine patients initially classified as definite AFM, retained this label after further classification. For probable AFM, this was 3/11, for possible AFM 3/14 and for uncertain 11/43. Patients initially classified as probable or possible AFM were most commonly diagnosed with transverse myelitis (16/25). If the initial classification was uncertain, Guillain-Barré syndrome was the most common diagnosis (31/43). Clinical and diagnostic features not included in the diagnostic criteria, were often used for the final classification. CONCLUSION: The current diagnostic criteria for AFM usually perform well, but additional features are sometimes required to distinguish AFM from other conditions.