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Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by â¼25% in the adult-onset cases and by â¼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.
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Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Haploinsuficiencia/genética , Mutación/genética , Proteínas de Unión al ARN/genética , Convulsiones/genética , Adolescente , Adulto , Edad de Inicio , Anciano de 80 o más Años , Animales , Secuencia de Bases , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Evolución Molecular , Femenino , Eliminación de Gen , Células HEK293 , Humanos , Lactante , Masculino , Ratones , Persona de Mediana Edad , Mutación Missense/genética , Neuronas/metabolismo , Neuronas/patología , Linaje , Estabilidad Proteica , Convulsiones/diagnóstico por imagenRESUMEN
AIM: To investigate clinicians' psychosocial experiences navigating interdisciplinary care for children with severe neurological impairment (SNI), for example children with a developmental epileptic encephalopathy; secondarily, to identify preferences for future interventions to support clinicians caring for children with SNI. METHOD: We conducted a qualitative descriptive study with interdisciplinary clinicians by using a purposeful sampling recruitment strategy. Twenty-four participants with expertise caring for children with SNI completed in-depth, semi-structured interviews. We transcribed the interviews, de-identified them, and performed inductive thematic analysis. RESULTS: Thematic analysis elicited interrelated themes. Clinicians experienced immense professional barriers providing patient-centred care across fragmented healthcare contexts. Physical, emotional, and psychological impacts were attributed to inadequate reflective practice training and a paucity of integrated resources to support clinicians over time. Multipronged strategies were prioritized by clinicians, incorporating psychoeducation, interdisciplinary peer mentorship, and psychological resources to build reflective practice skills for clinicians providing complex care in an advancing era of medicine. INTERPRETATION: This study provides novel and in-depth insight into clinicians' experiences navigating care for children with SNI. The results will be used to inform future integrated and multipronged co-developed resources tailored for clinicians, on the basis of their recommendations.
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Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.
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Duplicación Cromosómica , Dosificación de Gen , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Inactivación del Cromosoma X , Adolescente , Australia , Niño , Preescolar , Cara , Femenino , Hemicigoto , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Transportadores de Ácidos Monocarboxílicos/genética , Madres , Mutación Missense , Proteínas del Tejido Nervioso/genética , Linaje , Fenotipo , Simportadores/genética , Ubiquitina-Proteína Ligasas/metabolismo , Adulto JovenRESUMEN
Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.
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Secuencias de Aminoácidos/genética , Variación Genética , Proteínas del Tejido Nervioso/genética , Trastornos Neurocognitivos/etiología , Secuencias Repetitivas de Ácidos Nucleicos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Trastornos Neurocognitivos/clasificación , Trastornos Neurocognitivos/patología , Fenotipo , Pronóstico , SíndromeRESUMEN
This is the third article of a three-part series and addresses how clinicians provide hopefulness meaningfully to families coping with life-limiting and quality of life impairing neurological conditions. The first two articles addressed the enormous challenges faced by carers and also explored the struggles of clinicians trying to provide relief and comfort. Can these families, and those helping clinically, legitimately hope? It is expectation that consolidates desire into a substantial hope that may motivate finding a way forward. Hope must be realistic and directed to something in particular and in someone in particular. Hope and despair are not monolithic but often travel together for both children, families and clinicians. Hope is not denial but a belief that there are positive possibilities. Finding what can be helpfully hoped for and what must be realistically despaired of, is the discerning struggle. Clinicians aim to change what we can and accept what we cannot. Acceptance and grief are arrived at slowly for carers and families. Similarly, clinicians struggle with the hopes of bringing meaningful solace and are supported by trusted colleagues who have shared the same experience. Clinicians strive to respond appropriately and effectively in a dynamic process based on trust, providing presence and compassion when cure is not possible. Clinicians help find the small doable things that foster hope and lessen isolation and abandonment, mindful of the limits of their medical expertise. Surprisingly these modest hopes and faltering acceptances often provide a different form of strength and comfort to sustain a family.
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Enfermedades del Sistema Nervioso , Calidad de Vida , Adaptación Psicológica , Niño , Esperanza , Humanos , Enfermedades del Sistema Nervioso/terapia , Padres , Enfermedades RarasRESUMEN
This is the second of a three-part series that explores different aspects of uncertainty, certainty and hope in the context of providing clinical care for children with rare and life-limiting neurological disorders. When caring for families impacted by an overwhelming complex disorder in a child, complicated by threatening uncertainties and potentially more threatening certainties, clinicians utilise skills drawn from differing fields to make the load of information, and the emotional impact more manageable. The first article in this series addressed how clinicians might manage the 'accumulation of uncertainties' and to provide compassionate care not only to their patients, and their families, but also to themselves. This second paper delves into the less helpful aspects of 'certainty', including the associated losses and griefs endured by parents responding to threatening fears associated with their child's condition. In the extreme, disconnection and psychological isolation borne by parents can lead to a sense of hopelessness and desperation. Facing unwelcome certainties - clinicians and parents together - forms the basis of future trust and hope. Clinicians who share the field of trust with families and show commitment to helping parents, even when cure remains elusive, build a sense of hope. This is the sort of hopefulness that clinicians need to have and to offer as they share the journey with families. In this series, we seek to harness a shared approach to face unwelcome certainties and to kindle a sense of hope that is both credible and meaningful to the parents, family and clinician.
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Enfermedades del Sistema Nervioso , Padres , Niño , Familia , Esperanza , Humanos , Enfermedades del Sistema Nervioso/terapia , Padres/psicología , Enfermedades Raras , IncertidumbreRESUMEN
This is the first of three articles exploring the aspects of clinical care for children with rare neurological disorders including uncertainties old and new. The disruptive technologies of genomic sequencing and advanced therapeutics such as gene-based therapies offer parents of children with severe but rare neurological conditions for the first-time unprecedented opportunities for 'precision medicine'. At the same time, the realities of limited genomic diagnostic yields and not infrequent detection of variants of uncertain significance, lack of natural history study data and management guidelines for individually rare neurogenetic conditions, means that high pre-genomic test expectations are all too often replaced by an accumulation of new uncertainties. This can add to the chronic traumatic stress experienced by many families but may also have under-recognised impacts for their clinicians, contributing to 'burn-out' and attendant negative psychosocial impacts. This first article aims to address how clinicians might manage the accumulation of uncertainties to be more helpful to patients and their families. Moreover, it seeks to address how clinicians can move forward providing compassionate care to their patients and a little more consideration for themselves.
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Enfermedades del Sistema Nervioso , Padres , Niño , Humanos , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/terapia , Padres/psicología , Enfermedades Raras/terapia , IncertidumbreRESUMEN
PURPOSE: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. METHODS: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. RESULTS: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. CONCLUSION: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Humanos , Proteínas de la Membrana , Linaje , Convulsiones , VirulenciaRESUMEN
AIM: Parents and carers of children with developmental and epileptic encephalopathies (DEEs) experience high rates of mental health disorders including depression and posttraumatic stress disorder. Physical activity is an evidence-based strategy which may help to improve the wellbeing of this population. METHOD: We delivered a 4-week physical activity group program via a private Facebook group for carers of children with DEEs and their nominated support person. The facilitators provided education and motivation on different weekly topics (e.g. goal setting, overcoming barriers to exercise) and encouraged social support between participants. All participants were provided with a physical activity tracker (Fitbit). The primary outcome was feasibility and secondary outcomes included psychological distress, quality of life, physical activity levels, and PTSD symptoms. RESULTS: N=20 (parents and support partners) were recruited. All participants remained in the program for the full duration and 85% completed the post assessment questionnaires. High acceptability was observed in the qualitative interviews and exploratory analysis of pre-post outcomes found significant improvements in psychological distress and quality of life (ps < 0.01), while changes in physical activity levels and PTSD symptoms were non-significant. CONCLUSION: A mental health informed physical activity program delivered via Facebook is feasible for carers of children with DEEs and may help improve wellbeing.
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Encefalopatías , Cuidadores , Niño , Ejercicio Físico , Estudios de Factibilidad , Humanos , Salud Mental , Calidad de VidaRESUMEN
The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat-Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.
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Linfocitos T CD8-positivos/inmunología , Enfermedad de Hirschsprung/inmunología , Discapacidad Intelectual/inmunología , Microcefalia/inmunología , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/inmunología , Animales , Estudios de Casos y Controles , Niño , Preescolar , Facies , Femenino , Perfilación de la Expresión Génica , Haploinsuficiencia , Enfermedad de Hirschsprung/genética , Humanos , Inmunidad Celular , Memoria Inmunológica/genética , Discapacidad Intelectual/genética , Activación de Linfocitos/genética , Masculino , Ratones , Ratones Noqueados , Microcefalia/genética , Mutación , Subgrupos de Linfocitos T/inmunología , Adulto Joven , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/deficiencia , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genéticaRESUMEN
The Clinical Immunogenomics Research Consortium Australasia (CIRCA) crowdsources expertise in medicine, genomics, data science, and fundamental biology to diagnose and treat patients with rare inborn errors of immunity. This distributed network model operates free of geographic borders and allows rapid progression through the full research/translation/clinical management pipeline, from initial gene variant discovery, through functional validation, and on to precision mechanism-based treatment of patients throughout Australia and New Zealand. The model is scalable and applicable to other rare diseases where clinical experience and scientific know-how are limited, and enables efficient delivery of genomics for all.
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Atención a la Salud/métodos , Modelos Económicos , Enfermedades de Inmunodeficiencia Primaria/genética , Australasia/epidemiología , Redes Comunitarias , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunogenética , Medicina de Precisión , Enfermedades de Inmunodeficiencia Primaria/epidemiología , Investigación Biomédica TraslacionalRESUMEN
We report an individual who presented with severe neurodevelopmental delay and an intractable infantile-onset seizure disorder. Exome sequencing identified a homozygous single nucleotide change that abolishes a splice donor site in the ARV1 gene (c.294 + 1G > A homozygous). This variant completely prevented splicing in minigene assays, and resulted in exon skipping and an in-frame deletion of 40 amino acids in primary human fibroblasts (NP_073623.1: p.(Lys59_Asn98del). The p.(Lys59_Asn98del) and previously reported p.(Gly189Arg) ARV1 variants were evaluated for protein expression and function. The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature. In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells. Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood. Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy.
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Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Espasmos Infantiles/genética , Exones/genética , Femenino , Genotipo , Humanos , Lactante , Mutación , Linaje , Fenotipo , Sitios de Empalme de ARN/genética , Espasmos Infantiles/fisiopatologíaRESUMEN
Asparagine Synthetase Deficiency is a recently described cause of profound intellectual disability, marked progressive cerebral atrophy and variable seizure disorder. To date there has been limited functional data explaining the underlying pathophysiology. We report a new case with compound heterozygous mutations in the ASNS gene (NM_183356.3:c. [866G>C]; [1010C>T]). Both variants alter evolutionarily conserved amino acids and were predicted to be pathogenic based on in silico protein modelling that suggests disruption of the critical ATP binding site of the ASNS enzyme. In patient fibroblasts, ASNS expression as well as protein and mRNA stability are not affected by these variants. However, there is markedly reduced proliferation of patient fibroblasts when cultured in asparagine-limited growth medium, compared to parental and wild type fibroblasts. Restricting asparagine replicates the physiology within the blood-brain-barrier, with limited transfer of dietary derived asparagine, resulting in reliance of neuronal cells on intracellular asparagine synthesis by the ASNS enzyme. These functional studies offer insight into the underlying pathophysiology of the dramatic progressive cerebral atrophy associated with Asparagine Synthetase Deficiency.
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Asparagina/metabolismo , Aspartatoamoníaco Ligasa/deficiencia , Aspartatoamoníaco Ligasa/genética , Proliferación Celular , Mutación , Adenosina Trifosfato/metabolismo , Aspartatoamoníaco Ligasa/química , Aspartatoamoníaco Ligasa/metabolismo , Sitios de Unión , Células Cultivadas , Simulación por Computador , Medios de Cultivo/química , Exoma , Femenino , Fibroblastos/patología , Humanos , Discapacidad Intelectual/etiología , Discapacidad Intelectual/genética , Masculino , Análisis de Secuencia de ADNRESUMEN
AIMS: The updated 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines include changes to HER2 in-situ hybridization (ISH) interpretation criteria. We conducted a retrospective review of a consecutive cohort of primary breast carcinomas to assess the impact of updated guidelines on HER2 classification and laboratory resource utilization, and to characterize the pathobiology of HER2 equivocal tumours. METHODS AND RESULTS: A total of 904 dual-probe HER2/chromosome enumeration probe (CEP17) FISH tests on invasive breast carcinomas were studied. Eighty-five (9.4%) cases had a classification change with the updated guidelines; 66 (7.3%) went from HER2-negative to -equivocal, 15 cases (1.7%) were reclassified as HER2-positive and four cases from HER2-equivocal to -negative. A subset of primary breast cancers, reported initially as HER2-negative but -equivocal by 2013 guidelines, was identified. Traditional pathological factors of this subset were compared to HER2-negative and -positive control cases. The three HER2 groups demonstrated statistically significant differences with respect to prognostic factors, including tumour size, grade and nodal involvement. CONCLUSIONS: The updated HER2 testing guidelines will result in the reclassification of approximately 9.4% of primary breast cancers with uncertainty regarding the clinical impact of this reclassification in the majority of cases. Resource utilization will increase as a result of the recommendation for retesting.
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Neoplasias de la Mama/diagnóstico , Guías de Práctica Clínica como Asunto , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Oncología Médica/normas , Técnicas de Amplificación de Ácido Nucleico , Receptor ErbB-2/genéticaRESUMEN
OBJECTIVES: To determine: i) seizure recurrence; ii) developmental disability; iii) co-morbidities and risk factors in self-limited familial neonatal and/or infantile epilepsy (SeLFE) in a multigenerational study. METHODS: Families were retrospectively recruited from epilepsy databases (2021-2022) in 2 paediatric hospitals, Sydney, Australia. Eligible families had 2 first degree relatives with seizures and underwent genetic testing. Demographics/clinical data were collected from interviews and medical records. Vineland Adaptive Behaviour Scales-Third Edition measured adaptive function. RESULTS: Fifteen families participated. Fourteen had a genetic diagnosis (93%): 11 pathogenic; PRRT2 (n=4), KCNQ2 (n=3), SCN2A (n=4), 3 likely pathogenic; KCNQ2 (n=1), SCN8A (n=2). Seizures affected 73 individuals (ages 1-76 years); 30 children and 20 adults had in-depth phenotyping. Ten of 50 individuals (20%) had seizure recurrence, aged 8-65 years. Median time from last neonatal/infantile seizure was 11.8/12.8 years. Predictors of recurrence were high seizure number (p=0.05) and longer treatment duration (p=0.03). Seven children had global developmental delay (GDD): mild (n=4), moderate (n=1) and severe (n=2). Vineland-3 identified 3 had low-average and 3 had mild-moderately impaired functioning. The majority (82%) were average. GDD was associated with older age at last seizure (p=0.03), longer epilepsy duration (p=0.02), and higher number of anti-seizure medications (p=0.05). Four children had speech delay, 5 (10%) had Autism Spectrum Disorder. Paroxysmal kinesiogenic dyskinesia (n=5) occurred in 4 families and hemiplegic migraine (n=8) in 3 families. CONCLUSIONS: Individuals with SeLFE have a small risk of recurrent seizures (20%) and neurodevelopmental disability. Significant predictors are higher seizure number and longer epilepsy duration. Developmental surveillance is imperative.
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Trastorno del Espectro Autista , Epilepsia Benigna Neonatal , Epilepsia , Síndromes Epilépticos , Niño , Recién Nacido , Adulto , Humanos , Epilepsia Benigna Neonatal/genética , Estudios Retrospectivos , Mutación , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Australia/epidemiología , Epilepsia/epidemiología , Epilepsia/genética , Convulsiones/epidemiología , Convulsiones/genéticaAsunto(s)
Inmunodeficiencia Variable Común/complicaciones , Inmunosupresores/uso terapéutico , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Sirolimus/uso terapéutico , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/etiología , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/tratamiento farmacológico , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunofenotipificación , Inmunosupresores/farmacología , Linfocitos/metabolismo , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Sirolimus/farmacología , Evaluación de Síntomas , Trombocitopenia/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Caregivers of a child with a Developmental and Epileptic Encephalopathy (DEE) often report challenges accessing relevant and understandable information regarding their child's condition. We developed GenE Compass, an information linker service where caregivers are invited to submit questions and receive high-quality, personalised reports. We conducted a pilot evaluation to determine the feasibility and acceptability of GenE Compass. METHODS: We invited eligible caregivers to complete a baseline questionnaire (Q1) prior to receiving three months access to submit an unlimited number of questions to GenE Compass. We then invited caregivers to complete a follow-up questionnaire (Q2) and optional interview. Caregivers also had the opportunity to share report-specific feedback at the time of receiving each report. RESULTS: Seventy-two caregivers completed Q1, of which 41 submitted at least one question (range = 1-7). We received a total of 76 questions. The median turnaround time was 12 working days for our information linker (range = 1-28). Thirty-seven caregivers completed Q2, of whom 32 submitted at least one question (87 %). Overall, caregivers were highly satisfied with GenE Compass and their reports, and indicated that they would use it in the future if they had another question. Caregivers' qualitative data from Q1 and interviews highlighted the ongoing need for an information linker service like GenE Compass due to a lack of understandable information and limited resources, and the benefit in reducing burden of constant information searching. CONCLUSION: Our study shows that GenE Compass is feasible with the appropriate allocation of resources and highly acceptable to caregivers who have a child with a DEE.
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Encefalopatías , Cuidadores , Niño , Humanos , Encuestas y CuestionariosRESUMEN
Objective: To understand parents' of children with developmental and epileptic encephalopathies needs and preferences for psychological resources. Methods: Using a person-based approach, a multidisciplinary panel of clinician and researchers (n = 9) hosted a priority-setting workshop to 1) understand parents' needs and preferences for psychological resources and 2) to develop 'guiding principles' to inform a future suite of psychological resources. The multidisciplinary panel analysed the parent priority-setting workshop data, using a combination of thematic and lexical analysis. Results: Thematic analysis identified six key domains wherein parents (n = 8) prioritised a need for psychological resources to support adaptation to their child's genetic DEE diagnosis. Lexical analysis revealed that connection to diagnosis-specific resources provided a pathway to promote enhanced psychological adaptation, by reducing social isolation and reorienting parents towards feelings of hope. Combination of both analyses generated six thematic informed 'guiding principles'. Conclusion: Codesigned psychological resources may help parents to cope with the unique and complex interplay of stressors associated with their child's DEE diagnosis and treatment. Our 'guiding principles' will be translated to inform a future suite of tailored psychological resources. Innovation: This study demonstrates an innovative codesign approach to inform tailored psychological resources for families of children with rare genetic conditions.
RESUMEN
Developmental and epileptic encephalopathies (DEEs) are chronic and life-threatening conditions, frequently with a genetic basis and infantile-onset. Caregivers often experience enduring distress adapting to their child's diagnosis and report a deficit of accessible psychological supports. We aimed to pilot a novel, empirically-driven suite of audio-visual positive psychology resources tailored for caregivers of children with a DEE, called 'Finding a Way'. METHODS: We recruited caregivers through two paediatric hospital databases, and we also shared an invitation to the online questionnaire via genetic epilepsy advocacy organisations. The online questionnaire included a combination of validated, purpose-designed, and open-ended questions to assess the acceptability, relevance, and emotional impact of the resources among caregivers. RESULTS: 167 caregivers from 18 countries reviewed the resources, with 56 caregivers completing over 85% of the evaluation. Caregivers rated the resources as highly acceptable and relevant to their experiences. In both the quantitative and qualitative data, caregivers reported that the resources normalised their emotional experiences and provided helpful suggestions about managing their personal relationships, seeking support and accepting help from others. Frequently reported emotional responses after viewing the resources included feeling "comforted", "hopeful", "connected" and "reassured". Suggestions for improvement included, expanding the suite of resources and embedding the resources with links to specialised psychological services. CONCLUSION: 'Finding a Way' is a novel codesigned suite of audio-visual positive psychology resources tailored for caregivers of children with DEEs. Our results suggest that 'Finding a Way' is acceptable to caregivers and may contribute towards enhanced emotional adaptation and coping.