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PURPOSE: We set out to characterize psychogenic non-epileptic seizures (PNES) in individuals with either intellectual disability (ID) or borderline intellectual function (BIF) in comparison to those with normal cognitive function. We aimed to identify differences between the two groups to improve clinical management protocols. METHODS: We conducted a retrospective, observational, single-center study. The medical records of individuals (aged ≥ 14 years) diagnosed with PNES, confirmed through video-electroencephalography (vEEG) at a specialized epilepsy center between January 2008 and December 2021, were reviewed. We restricted our study to individuals who underwent comprehensive neuropsychological evaluations. Furthermore, demographic, clinical, and neuropsychological data with potential prognostic indicators, alongside the reevaluation of vEEG recordings were studied. We compared two study groups based on intelligence quotient (IQ): individuals without ID (IQ≥85; n = 25) and those with either mild ID or BIF (n = 25). RESULTS: No statistically significant clinical differences were observed between the two groups. Individuals with mild ID/BIF didn't show a longer diagnostic delay, and the prescription of inappropriate antiseizure medications (ASMs) was comparable in both cohorts. Most individuals with mild ID/BIF were treated with behavioral psychotherapeutic approaches with similar outcomes in both subgroups. CONCLUSIONS: Individuals with mild ID/BIF and PNES don't differ in clinical management. Demographic and clinical data, as well as semiology, were comparable to those of individuals with normal cognitive function. Cognitive behavioral therapy (CBT) appears to be an effective treatment approach for individuals with and without mild ID/BIF. Further studies are needed to validate and ascertain their possible applicability in individuals with moderate/severe ID.
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Background: Sleep is disturbed in Rett syndrome (RTT), a rare and progressive neurodevelopmental disorder primarily affecting female patients (prevalence 7.1/100,000 female patients) linked to pathogenic variations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Autonomic nervous system dysfunction with a predominance of the sympathetic nervous system (SNS) over the parasympathetic nervous system (PSNS) is reported in RTT, along with exercise fatigue and increased sudden death risk. The aim of the present study was to test the feasibility of a continuous 24 h non-invasive home monitoring of the biological vitals (biovitals) by an innovative wearable sensor device in pediatric and adolescent/adult RTT patients. Methods: A total of 10 female patients (mean age 18.3 ± 9.4 years, range 4.7-35.5 years) with typical RTT and MECP2 pathogenic variations were enrolled. Clinical severity was assessed by validated scales. Heart rate (HR), respiratory rate (RR), and skin temperature (SkT) were monitored by the YouCare Wearable Medical Device (Accyourate Group SpA, L'Aquila, Italy). The average percentage of maximum HR (HRmax%) was calculated. Heart rate variability (HRV) was expressed by consolidated time-domain and frequency-domain parameters. The HR/LF (low frequency) ratio, indicating SNS activation under dynamic exercise, was calculated. Simultaneous continuous measurement of indoor air quality variables was performed and the patients' contributions to the surrounding water vapor partial pressure [PH2O (pt)] and carbon dioxide [PCO2 (pt)] were indirectly estimated. Results: Of the 6,559.79 h of biovital recordings, 5051.03 h (77%) were valid for data interpretation. Sleep and wake hours were 9.0 ± 1.1 h and 14.9 ± 1.1 h, respectively. HRmax % [median: 71.86% (interquartile range 61.03-82%)] and HR/LF [median: 3.75 (interquartile range 3.19-5.05)] were elevated, independent from the wake-sleep cycle. The majority of HRV time- and frequency-domain parameters were significantly higher in the pediatric patients (p ≤ 0.031). The HRV HR/LF ratio was associated with phenotype severity, disease progression, clinical sleep disorder, subclinical hypoxia, and electroencephalographic observations of multifocal epileptic activity and general background slowing. Conclusion: Our findings indicate the feasibility of a continuous 24-h non-invasive home monitoring of biovital parameters in RTT. Moreover, for the first time, HRmax% and the HR/LF ratio were identified as potential objective markers of fatigue, illness severity, and disease progression.
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PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.
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Deficiência Intelectual , Fenótipo , Humanos , Adulto , Deficiência Intelectual/genética , Deficiência Intelectual/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Haploinsuficiência/genética , Convulsões/genética , Convulsões/epidemiologia , Médicos , Adolescente , Fácies , Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Anormalidades DentáriasRESUMO
BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.
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Encefalopatias , Transtornos Cromossômicos , Polimicrogiria , Masculino , Feminino , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/genética , Neuroimagem , Encéfalo/diagnóstico por imagem , Cromossomos Humanos Par 12 , Estudos Observacionais como AssuntoRESUMO
CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. Patients with CDD frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in individuals with CDD (n = 17) and their healthy relatives (n = 17). Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. In particular, at genus level, CDD microbial communities were characterized by an increase in the relative abundance of Clostridium_AQ, Eggerthella, Streptococcus, and Erysipelatoclostridium, and by a decrease in Eubacterium, Dorea, Odoribacter, Intestinomonas, and Gemmiger, pointing toward a dysbiotic profile. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features and ambulation capacity. Enrichment in Lachnoclostridium and Enterobacteriaceae was observed in the microbiota of patients with more severe GI symptoms, while Clostridiaceae, Peptostreptococcaceae, Coriobacteriaceae, Erysipelotrichaceae, Christensenellaceae, and Ruminococcaceae were enriched in patients experiencing daily epileptic seizures. Our findings suggest a potential connection between CDD, microbiota and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in subjects with CDD. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of patients with CDD.
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Síndromes Epilépticas , Microbioma Gastrointestinal , Síndrome de Rett , Espasmos Infantis , Humanos , Microbioma Gastrointestinal/fisiologia , Síndrome de Rett/genética , Convulsões , Proteínas Serina-Treonina QuinasesRESUMO
Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.
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Defeitos Congênitos da Glicosilação , Sequenciamento do Exoma , Humanos , Masculino , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Lactente , alfa-Glucosidases/genética , Mutação/genética , Espasmos Infantis/genética , Espasmos Infantis/diagnóstico , Epilepsia/genética , Epilepsia/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/diagnósticoRESUMO
Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.
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Glicosilfosfatidilinositóis , Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Estudos Retrospectivos , Lactente , Adulto , Glicosilfosfatidilinositóis/deficiência , Glicosilfosfatidilinositóis/genética , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/genética , Adulto Jovem , Defeitos Congênitos da Glicosilação/genética , Fenótipo , Convulsões/genéticaRESUMO
Myoclonus classically presents as a brief (10-50 ms duration), non-rhythmic jerk movement. The etiology could vary considerably ranging from self-limited to chronic or even progressive disorders, the latter falling into encephalopathic pictures that need a prompt diagnosis. Beyond the etiological classification, others evaluate myoclonus' body distribution (i.e., clinical classification) or the location of the generator (i.e., neurophysiological classification); particularly, knowing the anatomical source of myoclonus gives inputs on the observable clinical patterns, such as EMG bursts duration or EEG correlate, and guides the therapeutic choices. Among all the chronic disorders, myoclonus often presents itself as a manifestation of epilepsy. In this context, myoclonus has many facets. Myoclonus occurs as one, or the only, seizure manifestation while it can also present as a peculiar type of movement disorder; moreover, its electroclinical features within specific genetically determined epileptic syndromes have seldom been investigated. In this review, following a meeting of recognized experts, we provide an up-to-date overview of the neurophysiology and nosology surrounding myoclonus. Through the dedicated exploration of epileptic syndromes, coupled with pragmatic guidance, we aim to furnish clinicians and researchers alike with practical advice for heightened diagnostic management and refined treatment strategies. PLAIN LANGUAGE SUMMARY: In this work, we described myoclonus, a movement characterized by brief, shock-like jerks. Myoclonus could be present in different diseases and its correct diagnosis helps treatment.
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Epilepsia , Síndromes Epilépticas , Transtornos dos Movimentos , Mioclonia , Humanos , Mioclonia/diagnóstico , Mioclonia/terapia , Mioclonia/etiologia , Diagnóstico Diferencial , Epilepsia/complicações , Síndromes Epilépticas/complicaçõesRESUMO
The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children's Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.