Medicine (Austin & Northern Health) - Research Publications
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ItemSevere infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45(WILEY, 2018-01)Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.
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ItemSleep problems in Dravet syndrome: a modifiable comorbidity(WILEY, 2018-02)AIM: Many children with severe developmental and epileptic encephalopathies experience significant sleep disturbance, causing major disruption to the family's quality of life. We aimed to determine the frequency and nature of sleep problems in individuals with Dravet syndrome. METHODS: The Sleep Disturbance Scale for Children and a seizure questionnaire were distributed to the parents/guardians of 96 patients with Dravet syndrome. Sixteen patients had two nights of home oximetry. RESULTS: Fifty-seven out of 96 questionnaires were completed. Forty-three out of 57 (75%) individuals had sleep problems. Twenty-five out of 57 (44%) individuals had an abnormal total sleep score, with difficulty initiating and maintaining sleep (22 out of 57, 39%), sleep-wake transition disorders (20 out of 57, 35%), and sleep breathing disorders (19 out of 57, 33%). Twenty-two out of 57 (39%) individuals took medication to assist sleep, predominantly melatonin (n=14). Thirty out of 57 (53%) recently had nocturnal seizures. Overnight oximetry showed 14 out of 16 (88%) had a higher oxygen desaturation index (>3%), and six out of 16 (38%) had higher mean pulse rates than normative values. Home oximetry was normal or inconclusive in all patients. INTERPRETATION: Seventy-five per cent of individuals with Dravet syndrome had sleep problems, highlighting the importance of routinely assessing sleep and initiating appropriate behavioural and pharmacological interventions to improve the patient and family's quality of life. A high oxygen desaturation index and mean pulse rates on pulse oximetry may reflect unrecognized nocturnal seizures. WHAT THIS PAPER ADDS: More than 70% of patients with Dravet syndrome have sleep problems. Difficulty initiating and maintaining sleep was most common, particularly in those older than 20 years. Second most common were sleep-wake transition disorders, affecting more than 50% of those younger than 5 years. Sleep breathing disorders were a frequent problem across all age groups. Oximetry was not diagnostic of sleep-disordered breathing or obvious seizures.
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ItemPerception of impact of Dravet syndrome on children and caregivers in multiple countries: looking beyond seizures(WILEY, 2019-10)AIM: To assess the relevance and generalizability across countries of concepts of the impact of Dravet syndrome beyond seizures, as recognized by families. METHOD: Caregivers of children with Dravet syndrome in four countries (Australia [n=8]; USA, UK, and Italy [all n=4]) participated in 1-hour qualitative telephone interviews, identifying key Dravet syndrome concepts. Interviews were recorded, transcribed, and, where necessary, translated into English for thematic analysis. Conceptual saturation was assessed and findings compared to the previously developed French conceptual disease model. RESULTS: The most common seizure types reported by caregivers were tonic-clonic, absence, or focal-impaired awareness (localized/partial). Fever and physical activity were the most commonly reported triggers. Patient-relevant impacts included impairment in cognition, motor skills, communication, social skills, and behavioural functioning. Caregivers consistently reported negative social, physical, and family impacts. Concepts identified in the interviews showed similarity with the French conceptual model. Minor differences between countries are likely to reflect variations in health care systems. INTERPRETATION: Findings in Italy, Australia, UK, and USA confirm that the key impacts of Dravet syndrome on children and caregivers identified in France are generalizable across countries. Key symptom and impact concepts relevant to children and parents should be targeted as critical outcomes in new therapy evaluations. WHAT THIS PAPER ADDS: Relevance of the impact of Dravet syndrome on children and caregivers was confirmed across countries. Patient and caregiver-relevant Dravet syndrome impacts contribute to poorer health-related quality of life. Indirect seizure impacts were reported to be as important as direct impacts. Country-specific differences in concepts probably reflect differences in health care systems.
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ItemA population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy(WILEY, 2018-06)OBJECTIVE: The severe epilepsies of infancy (SEI) are a devastating group of disorders that pose a major care and economic burden on society; early diagnosis is critical for optimal management. This study sought to determine the incidence and etiologies of SEI, and model the yield and cost-effectiveness of early genetic testing. METHODS: A population-based study was undertaken of the incidence, etiologies, and cost-effectiveness of a whole exome sequencing-based gene panel (targeted WES) in infants with SEI born during 2011-2013, identified through electroencephalography (EEG) and neonatal databases. SEI was defined as seizure onset before age 18 months, frequent seizures, epileptiform EEG, and failure of ≥2 antiepileptic drugs. Medical records, investigations, MRIs, and EEGs were analyzed, and genetic testing was performed if no etiology was identified. Economic modeling was performed to determine yield and cost-effectiveness of investigation of infants with unknown etiology at epilepsy onset, incorporating targeted WES at different stages of the diagnostic pathway. RESULTS: Of 114 infants with SEI (incidence = 54/100 000 live births/y), the etiology was determined in 76 (67%): acquired brain injuries (n = 14), focal cortical dysplasias (n = 14), other brain malformations (n = 17), channelopathies (n = 11), chromosomal (n = 9), metabolic (n = 6), and other genetic (n = 5) disorders. Modeling showed that incorporating targeted WES increased diagnostic yield compared to investigation without targeted WES (48/86 vs 39/86). Early targeted WES had lower total cost ($677 081 U.S. dollars [USD] vs $738 136 USD) than late targeted WES. A pathway with early targeted WES and limited metabolic testing yielded 7 additional diagnoses compared to investigation without targeted WES (46/86 vs 39/86), with lower total cost ($455 597 USD vs $661 103 USD), lower cost per diagnosis ($9904 USD vs $16 951 USD), and a dominant cost-effectiveness ratio. SIGNIFICANCE: Severe epilepsies occur in 1 in 2000 infants, with the etiology identified in two-thirds, most commonly malformative. Early use of targeted WES yields more diagnoses at lower cost. Early genetic diagnosis will enable timely administration of precision medicines, once developed, with the potential to improve long-term outcome.
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ItemThe epilepsy phenotypic spectrum associated with a recurrent CUX2 variant(WILEY, 2018-05)OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.
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ItemCHD2 variants are a risk factor for photosensitivity in epilepsy(OXFORD UNIV PRESS, 2015-05-01)Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.
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ItemSeizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase(PUBLIC LIBRARY SCIENCE, 2015-03)Epilepsy is a common disabling disease with complex, multifactorial genetic and environmental etiology. The small fraction of epilepsies subject to Mendelian inheritance offers key insight into epilepsy disease mechanisms; and pathologies brought on by mutations in a single gene can point the way to generalizable therapeutic strategies. Mutations in the PRICKLE genes can cause seizures in humans, zebrafish, mice, and flies, suggesting the seizure-suppression pathway is evolutionarily conserved. This pathway has never been targeted for novel anti-seizure treatments. Here, the mammalian PRICKLE-interactome was defined, identifying prickle-interacting proteins that localize to synapses and a novel interacting partner, USP9X, a substrate-specific de-ubiquitinase. PRICKLE and USP9X interact through their carboxy-termini; and USP9X de-ubiquitinates PRICKLE, protecting it from proteasomal degradation. In forebrain neurons of mice, USP9X deficiency reduced levels of Prickle2 protein. Genetic analysis suggests the same pathway regulates Prickle-mediated seizures. The seizure phenotype was suppressed in prickle mutant flies by the small-molecule USP9X inhibitor, Degrasyn/WP1130, or by reducing the dose of fat facets a USP9X orthologue. USP9X mutations were identified by resequencing a cohort of patients with epileptic encephalopathy, one patient harbored a de novo missense mutation and another a novel coding mutation. Both USP9X variants were outside the PRICKLE-interacting domain. These findings demonstrate that USP9X inhibition can suppress prickle-mediated seizure activity, and that USP9X variants may predispose to seizures. These studies point to a new target for anti-seizure therapy and illustrate the translational power of studying diseases in species across the evolutionary spectrum.
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ItemEpileptic spasms are a feature of DEPDC5 mTORopathy(LIPPINCOTT WILLIAMS & WILKINS, 2015-08)OBJECTIVE: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms. METHODS: We performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants. RESULTS: We identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. CONCLUSIONS: While recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies.
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ItemDouble somatic mosaicism in a child with Dravet syndrome(LIPPINCOTT WILLIAMS & WILKINS, 2019-06)
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ItemAMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders(NATURE PORTFOLIO, 2019-07-12)AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.