125 research outputs found
Challenging behavior in children and adolescents with Dravet syndrome: Exploring the lived experiences of parents
BACKGROUND: Dravet syndrome (DS) is a monogenic syndrome associated with SCN1A mutations in the majority of patients and characterized by devastating epilepsy, that may be life-threatening. Aside from refractory seizures, core symptoms of DS include behavioral difficulties, developmental delay, cognitive impairment, and motor dysfunction. Previous DS research has mainly focused on epileptic seizures and pharmacological management and less on behavioral difficulties. This study aims to explore the lived experience of parents supporting a child with DS, with a focus on behavioral aspects. METHODS: We performed a qualitative study using focus groups and following the consolidated criteria for reporting qualitative research (COREQ) guidelines. We organized three focus groups with parents of children and adults with DS and used a pre-defined topic list of open questions, similar for each focus group to ensure comparability. The focus groups were video recorded, transcribed, and anonymized. Data were analyzed using an iterative coding process where codes were sorted into themes. Differences in coding among the researchers were discussed until a consensus was reached. RESULTS: In total, twenty parents (mothers only) participated in the study. The age of children with DS ranged between 3 to 22 years with a mean age of 11.8 years. A range of behavioral difficulties emerged from the thematic analysis. Overall, the most commonly mentioned behavioral difficulties were aggression, dangerous behavior, impulsivity, hyperactivity, routinized and compulsive habits. Our results showed different behavior per age group, with more externalizing behaviors such as aggression and impulsivity in children aged 3-13 years; and more internalizing behavior such as routinized and compulsive habits in adolescents and young adults (14-22 years). This results in a different kind of support these families need and should be acknowledged when in consult with a healthcare professional. Parents reported that challenging behavior was a source of stress and impacted negatively on their family's quality of life. Parents reported feeling alone in their search for solutions, and many explored options outside the traditional medical context. CONCLUSION: Our results suggest that the challenging behavior associated with DS leads to a huge burden of care. Healthcare professionals working with DS patients may need to develop shared decision-making strategies that take into account challenging behavior
Genotype-phenotype correlations of KIF5A stalk domain variants
The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype
Условия формирования зон скопления метана в углепородном массиве
Розглянуті основні геологічні чинники, які впливають на формування зон скупчення метану у вуглепородному масиві. Виділені, найбільш ефективні показники для середнього катагенеза порід – опосередковані локальні структури, зони тріщинуватості порід, стрижневі ділянки пісковиків (палеопотоки). Для виділених показників виконаний розрахунок дисперсійного аналізу по альтернативній ознаці. На основі розрахунків встановлено вплив кожного фактора на формування зон скупчення метану у вуглепродному масиві.Basic geological factors, which influence on forming of zone of accumulation of methane in coalrock massif, are presented. The most effective indexes for middle katagenesis of rock are determinated - medial local structures, zone of jointing of rock, race areas of sandstones (paleocurrent). For determinated indexes calculation of dispersion on an alternative character is executed. On the basis of calculations influence of every factor on forming of zone of accumulation of methane in a coalrock massif is definited
Changes in empowerment and anxiety of patients and parents during genetic counselling for epilepsy
Genetic testing and counselling are increasingly important in epilepsy care, aiming at finding a diagnosis, understanding aetiology and improving treatment and outcome. The psychological impact of genetic counselling from patients' or parents & rsquo; perspectives is, however, unknown. We studied the counseleereported outcome of genetic counselling before and after genetic testing for epilepsy by evaluating empowerment - a key outcome goal of counselling reflecting cognitive, decisional and behavioural control, emotional regulation and hope - and anxiety. We asked patients or their parents (for those (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Toward responsible clinical n-of-1 strategies for rare diseases
N-of-1 strategies can provide high-quality evidence of treatment efficacy at the individual level and optimize evidence-based selection of off-label treatments for patients with rare diseases. Given their design characteristics, n-of-1 strategies are considered to lay at the intersection between medical research and clinical care. Therefore, whether n-of-1 strategies should be governed by research or care regulations remains a debated issue. Here, we delineate differences between medical research and optimized clinical care, and distinguish the regulations which apply to either. We also set standards for responsible optimized clinical n-of-1 strategies with (off-label) treatments for rare diseases. Implementing clinical n-of-1 strategies as defined here could aid in optimized treatment selection for such diseases
Understanding neurodevelopmental trajectories and behavioral profiles in SCN1A-related epilepsy syndromes
Background: A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families. This study describes the profile and course of the behavioral phenotype in patients with SCN1A-related epilepsy syndromes, explores correlations between behavioral difficulties and potential risk factors. Methods: Data were collected from questionnaires, medical records, and semi-structured interviews. Behavior difficulties were measured using the Adult/Child Behavior Checklist (C/ABCL) and Adult self-report (ASR). Other questionnaires included the Pediatric Quality of Life Inventory (PedsQL), the Functional Mobility Scale (FMS) and the Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP). To determine differences in behavioral difficulties longitudinally, paired T-tests were used. Pearson correlation and Spearman rank test were used in correlation analyses and multivariable regression analyses were employed to identify potential risk factors. Results: A cohort of 147 participants, including 107 participants with DS and 40 with genetic epilepsy with febrile seizures plus (GEFS + ), was evaluated. Forty-six DS participants (43.0 %) and three GEFS + participants (7.5 %) showed behavioral problems in the clinical range on the A/CBCL total problems scale. The behavioral profile in DS exists out of withdrawn behavior, aggressive behavior, and attention problems. In DS patients, sleep disturbances (β = 1.15, p < 0.001) and a lower age (β = -0.21, p = 0.001) were significantly associated with behavioral difficulties. Between 2015 and 2022, behavioral difficulties significantly decreased with age (t = -2.24, CI = -6.10 – −0.15, p = 0.04) in DS participants aging from adolescence into adulthood. A decrease in intellectual functioning (β = 3.37, p = 0.02) and using less antiseizure medications in 2022 than in 2015, (β = -1.96, p = 0.04), were identified as possible risk factors for developing (more) behavioral difficulties. Conclusions: These findings suggest that, in addition to epilepsy, behavioral difficulties are a core feature of the DS phenotype. Behavioral problems require personalized management and treatment strategies. Further research is needed to identify effective interventions
Epilepsy is an important feature of KBG syndrome associated with poorer developmental outcome
OBJECTIVE: To describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype-phenotype correlation. METHODS: We collected data of patients with ANKRD11 variants by contacting University Medical Centers in the Netherlands, an international network of collaborating clinicians, and study groups who previously published about KBG syndrome. All patients with a likely pathogenic or pathogenic ANKRD11 variant were included in our patient cohort and categorized into an 'epilepsy group' or 'non-epilepsy group'. Additionally, we included previously reported patients with (likely) pathogenic ANKRD11 variants and epilepsy from the literature. RESULTS: We included 75 patients with KBG syndrome of whom 26 had epilepsy. Those with epilepsy more often had moderate to severe intellectual disability (42.3% vs 9.1% , RR 4.6 (95% CI 1.7-13.1)). Seizure onset in patients with KBG syndrome occurred at a median age of four years (range 12 months - 20 years) and the majority had generalized onset seizures (57.7%)with tonic-clonic seizures being most common (23.1%). The epilepsy type was mostly classified as generalized (42.9%) or combined generalized and focal (42.9%), not fulfilling criteria of an electroclinical syndrome diagnosis. Half of the epilepsy patients (50.0%) were seizure free on anti-seizure medication (ASM) for at least one year at the time of last assessment, but 26.9% of patients had drug-resistant epilepsy (failure of ≥ 2 ASM). No genotype-phenotype correlation could be identified for the presence of epilepsy or epilepsy characteristics. SIGNIFICANCE: Epilepsy in KBG syndrome most often presents as a generalized or combined focal and generalized type. No distinctive epilepsy syndrome could be identified. Patients with KBG syndrome and epilepsy had a significant poorer neurodevelopmental outcome compared to those without epilepsy. Clinicians should consider KBG syndrome as a causal etiology of epilepsy and be aware of the poorer neurodevelopmental outcome in individuals with epilepsy
Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease - Case series and review
We describe the shared clinical, biochemical, radiological and myopathological characteristics of four patients with distal spinal muscular atrophy (dSMA) caused by vaccinia-related kinase 1 (VRK1) variants and provide a review of the literature on phenotype-genotype correlations in VRK1-related disease. The clinical phenotype was characterized by adult-onset dSMA with predominant calf muscle involvement and mildly elevated serum creatinine kinase (CK) levels. Muscle imaging showed predominant atrophy and fatty replacement of calf muscles. We identified the novel compound heterozygous variants c.607C>T (p.Arg203Trp) and c.858G>T (p.Met286Ile) in two siblings with adult-onset dSMA. Additionally, two unrelated patients both carried the known c.583T>G (p.Leu195Val) VRK1 variant, with either c.197C>G (p.Ala66Gly) or c.701A>G (p.Asn234Ser) as a second variant. We conclude that compound heterozygous VRK1 variants cause distal spinal muscular atrophy with predominant posterior leg muscle involvement
Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy
Objective: The MAST family of microtubule-associated serine–threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at \u3c2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. Interpretation: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274–284
The Association between Intracranial Calcifications and Symptoms in Patients with Primary Familial Brain Calcification
(1) Background: Primary Familial Brain Calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcifications of the basal ganglia and other intracranial areas. Many patients experience symptoms of motor dysfunction and cognitive disorders. The aim of this study was to investigate the association between the amount and location of intracranial calcifications with these symptoms. (2) Methods: Patients with suspected PFBC referred to our outpatient clinic underwent a clinical work-up. Intracranial calcifications were visualized on Computed Tomography (CT), and a Total Calcification Score (TCS) was constructed. Logistic and linear regression models were performed. (3) Results: Fifty patients with PFBC were included in this study (median age 64.0 years, 50% women). Of the forty-one symptomatic patients (82.0%), 78.8% showed motor dysfunction, and 70.7% showed cognitive disorders. In multivariate analysis, the TCS was associated with bradykinesia/hypokinesia (OR 1.07, 95%-CI 1.02-1.12, p < 0.01), gait ataxia (OR 1.06, 95%-CI 1.00-1.12, p = 0.04), increased fall risk (OR 1.04, 95%-CI 1.00-1.08, p = 0.03), and attention/processing speed disorders (OR 1.06, 95%-CI 1.01-1.12, p = 0.02). Calcifications of the lentiform nucleus and subcortical white matter were associated with motor and cognitive disorders. (4) Conclusions: cognitive and motor symptoms are common among patients with PFBC, and there is an association between intracranial calcifications and these symptoms
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