Publications by authors named "Amy Schneider"

56 Publications

Somatic IDH1 variant (p.R132C) in an adult male with Maffucci syndrome.

Cold Spring Harb Mol Case Stud 2021 Sep 29. Epub 2021 Sep 29.

Epilepsy Research Centre, Department of Medicine (Austin Hospital), University of Melbourne, Heidelberg, Victoria, Australia.

Maffucci Syndrome is a rare, highly variable somatic mosaic condition and well-known cancer related gain-of-function variants in either the IDH1 or IDH2 genes have been found in the affected tissues of most reported patients. Features include benign enchondroma and spindle cell hemangioma, with a recognized increased risk of various malignancies. Fewer than 200 cases have been reported, therefore accurate estimates of malignancy risk are difficult to quantify and recommended surveillance guidelines are not available. The same gain-of-function IDH1 and IDH2 variants are also implicated in a variety of other benign and malignant tumors. An adult male presented with several soft palpable lesions on the right upper limb. Imaging and histopathology raised the possibility of Maffucci syndrome. DNA was extracted from peripheral blood lymphocytes and tissue surgically resected from a spindle-cell hemangioma. Sanger sequencing and Droplet-digital PCR analysis of the IDH1 gene was performed. We identified a somatic mosaic c.394C>T (p.R132C) variant in exon 5 of IDH1, in DNA derived from hemangioma tissue at ~ 17% mutant allele frequency. This variant was absent in DNA derived from blood. This variant has been identified in the affected tissue of most reported patients with Maffucci syndrome Although the patient has a potentially targetable variant, and there is a recognized risk of malignant transformation in this condition, a decision was made not to intervene with an IDH1 inhibitor. The reasons and prospects for therapy in this condition are discussed.
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http://dx.doi.org/10.1101/mcs.a006127DOI Listing
September 2021

Defining Dravet syndrome: An essential pre-requisite for precision medicine trials.

Epilepsia 2021 Sep 2;62(9):2205-2217. Epub 2021 Aug 2.

Department of Medicine, Austin Health, Epilepsy Research Centre, University of Melbourne, Heidelberg, Vic., Australia.

Objective: The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials.

Methods: Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome.

Results: Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5-20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ≥30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months-25.4 years) and 15.5 months (range 4 months-8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%.

Significance: An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.
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http://dx.doi.org/10.1111/epi.17015DOI Listing
September 2021

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.

Ann Neurol 2021 Aug 13;90(2):274-284. Epub 2021 Jul 13.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia.

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 <2 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.
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http://dx.doi.org/10.1002/ana.26147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324566PMC
August 2021

Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain.

Brain Commun 2021 21;3(1):fcaa235. Epub 2021 Jan 21.

Department of Medicine (Austin Health), University of Melbourne, Melbourne, Victoria 3084, Australia.

Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours. Here, we asked if cerebrospinal fluid liquid biopsy can be used to detect somatic mosaicism in non-malignant brain diseases. First, we reliably quantified cerebrospinal fluid cell-free DNA in 28 patients with focal epilepsy and 28 controls using droplet digital PCR. Then, in three patients we identified somatic mutations in cerebrospinal fluid: in one patient with subcortical band heterotopia the p. Lys64* variant at 9.4% frequency; in a second patient with focal cortical dysplasia the p. Phe581His*6 variant at 7.8% frequency; and in a third patient with ganglioglioma the p. Val600Glu variant at 3.2% frequency. To determine if cerebrospinal fluid cell-free DNA was brain-derived, whole-genome bisulphite sequencing was performed and brain-specific DNA methylation patterns were found to be significantly enriched ( = 0.03). Our proof of principle study shows that cerebrospinal fluid liquid biopsy is valuable in investigating mosaic neurological disorders where brain tissue is unavailable.
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http://dx.doi.org/10.1093/braincomms/fcaa235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954394PMC
January 2021

The severe epilepsy syndromes of infancy: A population-based study.

Epilepsia 2021 02 21;62(2):358-370. Epub 2021 Jan 21.

Department of Neurology, Royal Children's Hospital, Melbourne, Vic, Australia.

Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.

Methods: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.

Results: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased.

Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
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http://dx.doi.org/10.1111/epi.16810DOI Listing
February 2021

Contribution of rare genetic variants to drug response in absence epilepsy.

Epilepsy Res 2021 Feb 4;170:106537. Epub 2021 Jan 4.

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC, 3084, Australia; Department of Neurology, Royal Children's Hospital, The University of Melbourne, 50 Flemington Rd, Parkville, VIC, 3052, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville, VIC, 3052, Australia; Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.

Objective: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive.

Methods: We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA.

Results: Sixty-two patients were included; 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43; 0.43-27.65; p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82; 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups; these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy.

Significance: We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger sample is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106537DOI Listing
February 2021

The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

J Neurol Sci 2021 01 3;420:117260. Epub 2020 Dec 3.

Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia; Australian Genomics Health Alliance, Melbourne, Australia.

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.
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http://dx.doi.org/10.1016/j.jns.2020.117260DOI Listing
January 2021

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability.

Epilepsia 2021 01 6;62(1):e13-e21. Epub 2020 Dec 6.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
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http://dx.doi.org/10.1111/epi.16784DOI Listing
January 2021

A Novel Pharmacodynamic Biomarker and Mechanistic Modeling Facilitate the Development of Tovetumab, a Monoclonal Antibody Directed Against Platelet-Derived Growth Factor Receptor Alpha, for Cancer Therapy.

AAPS J 2020 11 18;23(1). Epub 2020 Nov 18.

Clinical and Quantitative Pharmacology, BioPharmaceuticals Research and Development, AstraZeneca, 121 Oyster Point Blvd., South San Francisco, California, 94080, USA.

Tovetumab (MEDI-575) is a fully human IgG2κ monoclonal antibody that specifically binds to human platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor signal transduction by PDGF ligands. The affinity of tovetumab determined using surface plasmon resonance technology and flow cytometry demonstrated comparable binding affinity for human and monkey PDGFRα. In single and repeat-dose monkey pharmacokinetic-pharmacodynamic (PK-PD) studies, tovetumab administration resulted in dose-dependent elevation of circulating levels of PDGF-AA, a member of the PDGF ligand family, due to displacement of PDGF-AA from PDGFRα by tovetumab and subsequent blockade of PDGFRα-mediated PDGF-AA degradation. As such, PDGF-AA accumulation is an indirect measurement of receptor occupancy and is a novel PD biomarker for tovetumab. The nonlinear PK of tovetumab and dose-dependent increase in circulating PDGF-AA profiles were well described by a novel mechanistic model, in which tovetumab and PDGF-AA compete for the binding to PDGFRα. To facilitate translational simulation, the internalization half-lives of PDGF-AA and tovetumab upon binding to PDGFRα were determined using confocal imaging to be 14 ± 4 min and 30 ± 8 min, respectively. By incorporating PDGFRα internalization kinetics, the model not only predicted the target receptor occupancy by tovetumab, but also the biologically active agonistic ligand-receptor complex. This work described a novel PD biomarker approach applicable for anti-receptor therapeutics and the first mechanistic model to delineate the in vivo tri-molecular system of a drug, its target receptor, and a competing endogenous ligand, which collectively have been used for optimal dose recommendation supporting clinical development of tovetumab.
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http://dx.doi.org/10.1208/s12248-020-00523-3DOI Listing
November 2020

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

Genet Med 2021 02 4;23(2):363-373. Epub 2020 Nov 4.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.

Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.

Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.

Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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http://dx.doi.org/10.1038/s41436-020-00988-9DOI Listing
February 2021

Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.

Am J Hum Genet 2020 11 14;107(5):977-988. Epub 2020 Oct 14.

Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.

PRKACA and PRKACB code for two catalytic subunits (Cα and Cβ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cβ subunits of PKA during human development.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675002PMC
November 2020

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

Epilepsia 2020 11 21;61(11):2461-2473. Epub 2020 Sep 21.

Reference Center for Rare Developmental Abnormalities CLAD-Ouest, Rennes University Hospital Center, Rennes, France.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.

Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature.

Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants.

Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
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http://dx.doi.org/10.1111/epi.16679DOI Listing
November 2020

Cognitive, behavioral, and social functioning in children and adults with Dravet syndrome.

Epilepsy Behav 2020 11 25;112:107319. Epub 2020 Aug 25.

Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Road, Parkville, 3052, Melbourne, Australia; Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Australia; Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Australia. Electronic address:

Aim: The objective of the study was to delineate the cognitive, behavioral, psychological, and social functioning of individuals with Dravet syndrome.

Method: Cognitive, behavioral, and social functioning were assessed in patients with Dravet syndrome by comprehensive, age-appropriate standardized neuropsychological testing. Primary caregivers completed standardized measures regarding participants' behavior, psychological status, adaptive functioning, and social skills, including their involvement with intervention services.

Results: The cohort comprised 45 patients, aged 2-30 years. Intellectual functioning ranged from average intellect to profound intellectual disability, with a decrease in cognitive and adaptive functioning with age. Only 6 children were able to complete the entire neuropsychological battery and showed a range of cognitive profiles. Five of 6 participants scored within the average range on Affect Recognition and 5/6 on Motor Free Visual Perception tests. Twenty-one (58%) participants had deficits in social skills and 18/27 (67%) in social communication, with 10 participants, who did not yet have a diagnosis of autism spectrum disorder (ASD), screening positive for social communication deficits. Behavioral problems were frequently reported, with attention problems in 24 (65%) and atypicality in 25 (70%). Despite this, parents reported that psychological services were the least utilized health interventions.

Conclusions: Cognitive functioning varies markedly in individuals with Dravet syndrome, with some patients demonstrating global impairment while others have a discordant neuropsychological profile. Behavioral, psychological, social problems, and ASD are common. Social deficits should be reviewed to identify those who warrant ASD assessment. Early identification of behavioral and psychological disorders and targeted use of psychological intervention are essential components of holistic care in Dravet syndrome.
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http://dx.doi.org/10.1016/j.yebeh.2020.107319DOI Listing
November 2020

Familial adult myoclonic epilepsy type 1 SAMD12 TTTCA repeat expansion arose 17,000 years ago and is present in Sri Lankan and Indian families.

Eur J Hum Genet 2020 07 16;28(7):973-978. Epub 2020 Mar 16.

Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.

Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12 on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12 in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be ~670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12 TTTCA expansion.
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http://dx.doi.org/10.1038/s41431-020-0606-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316749PMC
July 2020

Development and implementation of an electrolyte replacement protocol in the outpatient oncology infusion centers of a large academic healthcare system.

J Oncol Pharm Pract 2020 Dec 4;26(8):1871-1877. Epub 2020 Mar 4.

Department of Medical Oncology/Hematology, Houston Methodist Hospital, Houston, TX, USA.

Background: Patients receiving chemotherapy frequently experience electrolyte imbalances. Electrolyte replacement is, therefore, a necessity as patients may experience life-threatening symptoms. The objective of this study was to evaluate the occurrence of low serum potassium and magnesium, and identify the rate of replacement for patients with low serum potassium and magnesium levels. Based on our findings, we developed and implemented a nursing-driven electrolyte replacement protocol.

Methods: Preimplementation phase - A retrospective review for serum potassium and magnesium values obtained during infusion clinic visit between 1 August and 31 October 2016 was conducted. Implementation phase - A nursing-driven electrolyte replacement protocol with medication order "smart-set" and order selection intelligence within EPIC Beacon was developed and implemented in May 2017. Postimplementation phase - The postimplementation phase data were collected from 1 August to 30 November 2017 using a similar approach as the preimplementation phase.

Results: Preimplementation phase - During the preimplementation phase of the study, a total of 1495 serum potassium levels and 1193 serum magnesium levels were obtained. Among the 152 patients who needed potassium replacement, 34% ( = 52) were replaced and among the 118 serum magnesium levels that needed replacement, 30% ( = 35) were replaced. Postimplementation phase - 3979 serum potassium and 2707 magnesium levels were obtained. Among the 170 patients who needed potassium replacement, 75% ( = 127) were replaced. Among the 142 patients who needed magnesium replacement, 73% ( = 104) were replaced.

Conclusion: A 121% increase in potassium replacement and a 143% increase in magnesium replacement were identified after implementing this protocol.
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http://dx.doi.org/10.1177/1078155220907671DOI Listing
December 2020

BRAT1 encephalopathy: a recessive cause of epilepsy of infancy with migrating focal seizures.

Dev Med Child Neurol 2020 09 23;62(9):1096-1099. Epub 2019 Dec 23.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.

Epilepsy of infancy with migrating focal seizures (EIMFS), one of the most severe developmental and epileptic encephalopathy syndromes, is characterized by seizures that migrate from one hemisphere to the other. EIMFS is genetically heterogeneous with 33 genes. We report five patients with EIMFS caused by recessive BRAT1 variants, identified via next generation sequencing. Recessive pathogenic variants in BRAT1 cause the rigidity and multifocal seizure syndrome, lethal neonatal with hypertonia, microcephaly, and intractable multifocal seizures. The epileptology of BRAT1 encephalopathy has not been well described. All five patients were profoundly impaired with seizure onset in the first week of life and focal seizure migration between hemispheres. We show that BRAT1 is an important recessive cause of EIMFS with onset in the first week of life, profound impairment, and early death. Early recognition of this genetic aetiology will inform management and reproductive counselling.
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http://dx.doi.org/10.1111/dmcn.14428DOI Listing
September 2020

SCN1A Variants in vaccine-related febrile seizures: A prospective study.

Ann Neurol 2020 02 12;87(2):281-288. Epub 2019 Dec 12.

Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.

Objective: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls.

Methods: We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals.

Results: We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81).

Interpretation: Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.
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http://dx.doi.org/10.1002/ana.25650DOI Listing
February 2020

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.

Nat Commun 2019 10 29;10(1):4920. Epub 2019 Oct 29.

Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185, Rome, Italy.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
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http://dx.doi.org/10.1038/s41467-019-12671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820779PMC
October 2019

Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature.

Hum Mutat 2020 01 4;41(1):69-80. Epub 2019 Oct 4.

Departments of Neurology and Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of K 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.
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http://dx.doi.org/10.1002/humu.23915DOI Listing
January 2020

Incidence of chemotherapy-induced peripheral neuropathy within 12 weeks of starting neurotoxic chemotherapy for multiple myeloma or lymphoma: a prospective, single-center, observational study.

Support Care Cancer 2020 Apr 29;28(4):1901-1912. Epub 2019 Jul 29.

Department of Medicine, Houston Methodist Hospital, Houston, TX, USA.

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) may necessitate chemotherapy dose reduction, delay, or discontinuation. This pilot study tested feasibility of patient enrollment, CIPN screening, and data collection in cancer patients for a future clinical study that will assess the safety and efficacy of an intervention that may prevent CIPN.

Methods: This prospective, observational, single-center, pilot study included adults with newly diagnosed lymphoma or multiple myeloma receiving neurotoxic chemotherapy. Patients were enrolled between September 2016 and February 2017. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire was completed by patients at 3 time points: baseline, week 6, and week 12. The primary outcome was change in the neurotoxicity score between these time points.

Results: Of 33 patients approached for consent, 28 (85%) provided consent and were enrolled. The FACT/GOG-Ntx questionnaire was completed by 28 (100%) at baseline, 25 (89%) at week 6, and 24 (86%) at week 12. Average (standard deviation) neurotoxicity scores were 36.5 (6.6) at baseline, 34.0 (8.3) at week 6, and 30.6 (7.6) at week 12. Neurotoxicity scores changed from baseline by - 2.7 points (95% CI - 5.5 to 0.1; p = 0.061) at week 6 and - 6.0 points (95% CI - 5.6 to - 0.8; p = 0.012) at week 12. Clinically meaningful declines (decrease of > 10% from baseline) in neurotoxicity score were detected in 36% (9 of 25) at week 6 and in 67% (16 of 24) at week 12.

Conclusion: Sixty-seven percent of patients experienced clinically significant CIPN within 12 weeks of starting chemotherapy. Feasibility metrics for enrollment, consent, CIPN assessment, and follow-up were met.
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http://dx.doi.org/10.1007/s00520-019-05006-6DOI Listing
April 2020

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

Nat Commun 2019 07 12;10(1):3094. Epub 2019 Jul 12.

Pediatric Neurology Unit, Safra Children's Hospital, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 526121, Ramat Gan, Israel.

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 Ca-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.
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http://dx.doi.org/10.1038/s41467-019-10910-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626132PMC
July 2019

Double somatic mosaicism in a child with Dravet syndrome.

Neurol Genet 2019 Jun 19;5(3):e333. Epub 2019 Apr 19.

Division of Genetic Medicine (A.M.M., A.S.B., H.C.M.), Department of Pediatrics, University of Washington, Seattle, WA; Department of Paediatrics and Child Health (C.K.), University of Otago, Wellington, New Zealand; Department of Medicine (A.L.S., I.E.S.), Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Australia; The Florey Institute and Murdoch Children's Research Institute (I.E.S.), Parkville, Australia; Department of Neurology (I.E.S.), Royal Children's Hospital, Parkville, Australia; and Department of Paediatrics and Child Health (L.G.S.), University of Otago, Wellington, New Zealand.

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http://dx.doi.org/10.1212/NXG.0000000000000333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481227PMC
June 2019

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

Am J Hum Genet 2019 05 11;104(5):948-956. Epub 2019 Apr 11.

Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Ca2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Ca2.2 in normal human neurodevelopment.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507039PMC
May 2019

Perception of impact of Dravet syndrome on children and caregivers in multiple countries: looking beyond seizures.

Dev Med Child Neurol 2019 10 4;61(10):1229-1236. Epub 2019 Mar 4.

PCO, Adelphi Values Ltd, Bollington, UK.

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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http://dx.doi.org/10.1111/dmcn.14186DOI Listing
October 2019

Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies.

Am J Hum Genet 2018 12;103(6):1022-1029

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address:

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs. This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons, including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly. Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288405PMC
December 2018

Evaluation of the prescribing patterns, adverse effects, and drug interactions of oral chemotherapy agents in an outpatient cancer center.

J Oncol Pharm Pract 2019 Oct 31;25(7):1564-1569. Epub 2018 Aug 31.

1 Houston Methodist Hospital, Houston, TX, USA.

Purpose: Although oral chemotherapy offers advantages over intravenous chemotherapy, it creates a unique set of challenges. Potential barriers include treatment complexity, patient responsibility for medication adherence and monitoring, reduced healthcare contact, and increased financial burden. The purpose of this study is to estimate the prevalence of drug-related problems among a sample of patients treated with oral chemotherapy agents.

Methods: A single-center, retrospective chart review was conducted on patients prescribed oral chemotherapy at our institution between 1 January 2017 and 31 August 2017. The primary endpoint was the incidence of drug-related toxicities within 90 days of starting treatment. Secondary endpoints included incidence of drug-drug interactions, proportion of patients receiving medication education by a clinical pharmacist, and quantification of issues related to medication access.

Results: Charts of 100 patients were reviewed. Median time to oral chemotherapy receipt by the patient from the day the order was written was eight days. Prior to initiating therapy, 27% of patients received education by a clinical pharmacist. Toxicity checks were conducted by the provider at 30, 60, and 90 days for 80%, 65%, and 48% of patients, respectively. Treatment-related toxicities secondary to oral chemotherapy were reported by 79% of patients, with 55% classified as severe. Potential drug interactions were in 55% of the patients.

Conclusion: Data from this study have highlighted avenues for pharmacists to make an impact on patients newly started on oral chemotherapy. Opportunities exist to increase patient education, ensure appropriate follow-up, and assess adherence while preventing and managing treatment-related toxicities.
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http://dx.doi.org/10.1177/1078155218798150DOI Listing
October 2019

A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy.

Epilepsia 2018 06 11;59(6):1177-1187. Epub 2018 May 11.

Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia.

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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http://dx.doi.org/10.1111/epi.14087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990455PMC
June 2018

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

Ann Neurol 2018 05 30;83(5):926-934. Epub 2018 Apr 30.

Department of Medical Genetics, Lyon University Hospital and GENDEV team CNRS UMR 5292, INSERM U1028, CRNL, and University Claude Bernard Lyon 1, GHE, Lyon, France.

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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http://dx.doi.org/10.1002/ana.25222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021218PMC
May 2018

Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.

Epilepsia 2018 01 24;59(1):e5-e13. Epub 2017 Nov 24.

Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.

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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http://dx.doi.org/10.1111/epi.13957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760358PMC
January 2018
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