Publications by authors named "Annapurna Poduri"

157 Publications

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

Epilepsia 2021 Jul 26;62(7):e103-e109. Epub 2021 May 26.

Department of Neuropediatrics, APHP Sorbonne University, Trousseau Hospital, Paris, France.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16931DOI Listing
July 2021

Cerebral visual impairment in CDKL5 deficiency disorder: vision as an outcome measure.

Dev Med Child Neurol 2021 May 24. Epub 2021 May 24.

Department of Neurology, CDKL5 Center of Excellence, Boston Children's Hospital, Boston, MA, USA.

Aim: To characterize the neuro-ophthalmological phenotype of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) and assess visual acuity as a reproducible, quantitative outcome measure.

Method: We retrospectively analyzed clinical data from patients with CDD. Complete neuro-ophthalmological assessments, including visual acuity, were evaluated.

Results: Of 26 patients (22 females, four males; median age 4y, interquartile range 2y 1mo-7y 10mo), cerebral visual impairment (CVI), defined as visual dysfunction in the absence of ocular or anterior visual pathway abnormalities, was diagnosed in all those over 2 years of age. Ophthalmological examinations revealed nystagmus in 10 patients and strabismus in 24 patients. Visual acuity was measured in 24 patients, by preferential looking in all and by sweep visual evoked potential in 13. Visual acuities were lower than age expectations and demonstrated improvement in the first 3 years. Adjusting for age and sex, average preferential looking visual acuity after 2 years of age was higher in patients with intact mobility than in those who were non-mobile.

Interpretation: CVI was observed in patients with CDD. Visual acuity improved over time and correlated with mobility. Visual acuity, as a quantifiable measure of visual function, should be considered as an outcome measure in pre-clinical and clinical studies for CDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14908DOI Listing
May 2021

Genetic Factors Underlying Sudden Infant Death Syndrome.

Appl Clin Genet 2021 15;14:61-76. Epub 2021 Feb 15.

Robert's Program for Sudden Unexpected Death in Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Sudden Infant Death syndrome (SIDS) is a diagnosis of exclusion. Decades of research have made steady gains in understanding plausible mechanisms of terminal events. Current evidence suggests SIDS includes heterogeneous biological conditions, such as metabolic, cardiac, neurologic, respiratory, and infectious conditions. Here we review genetic studies that address each of these areas in SIDS cases and cohorts, providing a broad view of the genetic underpinnings of this devastating phenomenon. The current literature has established a role for monogenic genetic causes of SIDS mortality in a subset of cases. To expand upon our current knowledge of disease-causing genetic variants in SIDS cohorts and their mechanisms, future genetic studies may employ functional assessments of implicated variants, broader genetic tests, and the inclusion of parental genetic data and family history information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/TACG.S239478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894824PMC
February 2021

KCNQ2-DEE: developmental or epileptic encephalopathy?

Ann Clin Transl Neurol 2021 03 22;8(3):666-676. Epub 2021 Feb 22.

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

Objective: KCNQ2-associated developmental and epileptic encephalopathies (DEE) present with seizures and developmental impairments. The relation between seizures and functional impairments in affected children and the relation of a specific genetic variant to seizure control remains unknown.

Methods: Parents of children with documented KCNQ2 variants who participated in a structured, online natural history survey provided information about seizure history, functional mobility, hand use, communication function, and feeding independence. Bivariate analyses were performed with nonparametric methods and logistic regression was used for multivariable analyses.

Results: Thirty-nine children (20, 51% girls, median age 4.5 years, interquartile range (IQR) 1.9-19.3) had a median age of seizure onset of 1 day (IQR 1-3 days). The most common seizure types were bilateral tonic-clonic (N = 72, 28%) and bilateral tonic (N = 13, 33%). Time since last seizure was <6 months (N = 18, 46%), 6-23 months (N = 11, 28%), and ≥24 months (N = 10 26%). Severe functional impairment was reported for mobility (62%), hand grasp (31%), feeding (59%), and communication (77%). Twenty-eight (72%) were impaired in ≥2 domains. There were only weak and inconsistent associations between seizure recency and individual impairments or number of impairments after adjustment for other factors. The functional location of the variants within the K 7.2 protein was not associated with seizure control.

Interpretation: Seizures in KCNQ2-DEE are often well-controlled, but children have severe impairments regardless. With the increased potential for precision therapies targeting the K 7.2 channel or the KCNQ2 gene itself, identifying the most relevant and sensitive clinical endpoints will be critical to ensure successful trials of new therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951099PMC
March 2021

Uridine-responsive epileptic encephalopathy due to inherited variants in CAD: A Tale of Two Siblings.

Ann Clin Transl Neurol 2021 03 26;8(3):716-722. Epub 2021 Jan 26.

Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.

We report two siblings with intractable epilepsy, developmental regression, and progressive cerebellar atrophy due to biallelic variants in the gene CAD. For the affected girl, uridine started at age 5 resulted in dramatic improvements in seizure control and development, cessation of cerebellar atrophy, and resolution of hematological abnormalities. Her older brother had a more severe course and only modest response to uridine started at 14 years old. Treatment of this progressive condition via uridine supplementation provides an example of precision diagnosis and treatment using clear outcome measures and biomarkers to monitor efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951104PMC
March 2021

A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.

Genet Med 2021 05 20;23(5):900-908. Epub 2021 Jan 20.

Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.

Purpose: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation.

Methods: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts.

Results: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding.

Conclusion: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-01071-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105169PMC
May 2021

Biallelic variants in cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration.

J Med Genet 2021 Jan 4. Epub 2021 Jan 4.

Medical Genetics Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Next-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.

Methods: Here, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).

Results: We identified five patients from four unrelated families with homozygous variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from -4 SD to -8 SD), profound psychomotor delay, hypertonic-dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.

Conclusion: Our findings support the role of biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2020-107430DOI Listing
January 2021

Characterization of the GABRB2-Associated Neurodevelopmental Disorders.

Ann Neurol 2021 03 24;89(3):573-586. Epub 2020 Dec 24.

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA.

Objective: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2, coding for the γ-aminobutyric acid type A (GABA ) receptor subunit β2.

Methods: We recruited and systematically evaluated 25 individuals with variants in GABRB2, 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system.

Results: Our cohort of 25 individuals from 22 families with variants in GABRB2 demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty-eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease-associated variants cluster in the extracellular N-terminus and transmembrane domains 1-3, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA-evoked anionic currents.

Interpretation: GABRB2-related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABA receptor-encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying GABRB2-associated neurodevelopmental disorders. ANN NEUROL 2021;89:573-586.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25985DOI Listing
March 2021

Experiencing Positive Health, as a Family, While Living With a Rare Complex Disease: Bringing Participatory Medicine Through Collaborative Decision Making Into the Real World.

J Particip Med 2020 Jun 22;12(2):e17602. Epub 2020 Jun 22.

Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

Physician-patient collaboration was recognized as a critical core of participatory medicine more than a century ago. However, the subsequent focus on scientific research to enable cures and increased dominance of physicians in health care subordinated patients to a passive role. This paternalistic model weakened in the past 50 years-as women, minorities, and the disabled achieved greater rights, and as incurable chronic diseases and unrelieved pain disorders became more prevalent-promoting a more equitable role for physicians and patients. By 2000, a shared decision-making model became the pinnacle for clinical decisions, despite a dearth of data on health outcomes, or the model's reliance on single patient or solo practitioner studies, or evidence that no single model could fit all clinical situations. We report about a young woman with intractable epilepsy due to a congenital brain malformation whose family and medical specialists used a collaborative decision-making approach. This model positioned the health professionals as supporters of the proactive family, and enabled them all to explore and co-create knowledge beyond the clinical realm. Together, they involved other members of the community in the decisions, while harnessing diverse relationships to allow all family members to achieve positive levels of health, despite the resistance of the seizures to medical treatment and the incurable nature of the underlying disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/17602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434078PMC
June 2020

Polymicrogyria is Associated With Pathogenic Variants in PTEN.

Ann Neurol 2020 12 8;88(6):1153-1164. Epub 2020 Oct 8.

Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Objective: Congenital structural brain malformations have been described in patients with pathogenic phosphatase and tensin homologue (PTEN) variants, but the frequency of cortical malformations in patients with PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation.

Methods: We systematically searched a local radiology database for patients with PTEN variants who had available brain magnetic resonance imaging (MRI). The MRI scans were reviewed systematically for cortical abnormalities. We reviewed electroencephalogram (EEG) data and evaluated the electronic medical record for evidence of epilepsy and developmental delay.

Results: In total, we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4-17 years). Twelve among these 22 patients (54%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of global developmental delay (GDD), intellectual disability (ID), and motor delay in individuals with cortical abnormalities, although cohort size limited statistical significance.

Interpretation: Malformations of cortical development, PMG in particular, represent an under-recognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the previously reported high risk of epilepsy in patients with PMG. ANN NEUROL 2020;88:1153-1164.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877488PMC
December 2020

Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.

Am J Hum Genet 2020 10 26;107(4):683-697. Epub 2020 Aug 26.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536581PMC
October 2020

Children's rare disease cohorts: an integrative research and clinical genomics initiative.

NPJ Genom Med 2020 6;5:29. Epub 2020 Jul 6.

Computational Health Informatics Program, Boston Children's Hospital, Boston, MA 02115 USA.

While genomic data is frequently collected under distinct research protocols and disparate clinical and research regimes, there is a benefit in streamlining sequencing strategies to create harmonized databases, particularly in the area of pediatric rare disease. Research hospitals seeking to implement unified genomics workflows for research and clinical practice face numerous challenges, as they need to address the unique requirements and goals of the distinct environments and many stakeholders, including clinicians, researchers and sequencing providers. Here, we present outcomes of the first phase of the Children's Rare Disease Cohorts initiative (CRDC) that was completed at Boston Children's Hospital (BCH). We have developed a broadly sharable database of 2441 exomes from 15 pediatric rare disease cohorts, with major contributions from early onset epilepsy and early onset inflammatory bowel disease. All sequencing data is integrated and combined with phenotypic and research data in a genomics learning system (GLS). Phenotypes were both manually annotated and pulled automatically from patient medical records. Deployment of a genomically-ordered relational database allowed us to provide a modular and robust platform for centralized storage and analysis of research and clinical data, currently totaling 8516 exomes and 112 genomes. The GLS integrates analytical systems, including machine learning algorithms for automated variant classification and prioritization, as well as phenotype extraction via natural language processing (NLP) of clinical notes. This GLS is extensible to additional analytic systems and growing research and clinical collections of genomic and other types of data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-020-0137-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338382PMC
July 2020

A de novo BRPF1 variant in a case of Sudden Unexplained Death in Childhood.

Eur J Med Genet 2020 Sep 8;63(9):104002. Epub 2020 Jul 8.

Robert's Program for Sudden Unexpected Death in Pediatrics, Boston Children's Hospital, USA; Department of Pediatrics, Harvard Medical School, USA; Division of General Pediatrics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. Electronic address:

Sudden Unexplained Death in Childhood (SUDC), the death of a child that remains unexplained after a complete autopsy and investigation, is a rare and poorly understood entity. This case report describes a 3-year-old boy with history of language delay and ptosis, who died suddenly in his sleep without known cause. A pathogenic de novo frameshift mutation in BRPF1, a gene which has been associated with the syndrome of Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), was identified during a post-mortem evaluation. The finding of a pathogenic variant in BRPF1, which has not previously been associated with sudden death, in an SUDC case has implications for this child's family and contributes to the broader field of SUDC research. This case demonstrates the utility of post-mortem genetic testing in SUDC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2020.104002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469702PMC
September 2020

Gene tests in adults with epilepsy and intellectual disability.

Nat Rev Neurol 2020 Oct;16(10):527-528

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41582-020-0388-5DOI Listing
October 2020

Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice.

Brain 2020 07;143(7):2039-2057

Institute for Genomic Medicine, Columbia University, New York, NY, USA.

NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363493PMC
July 2020

The role of sodium channels in sudden unexpected death in pediatrics.

Mol Genet Genomic Med 2020 08 25;8(8):e1309. Epub 2020 May 25.

Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes.

Methods: To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines.

Results: In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data.

Conclusion: We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434613PMC
August 2020

Posterior-onset Rasmussen's encephalitis with ipsilateral cerebellar atrophy and uveitis resistant to rituximab.

Epilepsy Behav Rep 2020 21;14:100360. Epub 2020 Mar 21.

Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.

Rasmussen encephalitis (RE) is a disorder characterized by drug-resistant seizures and progressive unihemispheric atrophy, hemiparesis, and varying degrees of cognitive decline. The pathophysiology of RE remains elusive, with hypotheses suggesting underlying autoimmune- and T cell-mediated processes. In this case report, we describe a single patient's clinical course from the first day of presentation until definitive treatment for atypical Rasmussen encephalitis at a tertiary care pediatric center. The patient exhibited several atypical features of Rasmussen encephalitis, including a posterior predominance of initial seizure onset with the development of severe choreoathetosis and ipsilateral cerebellar atrophy. He subsequently developed coexistent autoimmune disorders in the form of psoriasis and uveitis, and underwent multiple forms of immunotherapy with limited benefit. This patient shows an association of RE with other autoimmune conditions supporting an autoimmune mechanism of disease while exhibiting several atypical features of RE. Rarely, occipital lobe seizures have been documented as the presenting semiology of this syndrome. This case highlights the need to be mindful of atypical features that may delay hemispherectomy, which remains the definitive treatment. It also suggests that children may be predisposed to the development of autoimmune disorders in later stages of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebr.2020.100360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184158PMC
March 2020

Epigenetics explained: a topic "primer" for the epilepsy community by the ILAE Genetics/Epigenetics Task Force.

Epileptic Disord 2020 Apr;22(2):127-141

Department of Physiology & Medical Physics and FutureNeuro SFI Research Centre Royal College of Surgeons in Ireland, Dublin, Ireland.

Epigenetics refers broadly to processes that influence medium to long-term gene expression by changing the readability and accessibility of the genetic code. The Neurobiology Commission of the International League Against Epilepsy (ILAE) recently convened a Task Force to explore and disseminate advances in epigenetics to better understand their role and intersection with genetics and the neurobiology of epilepsies and their co-morbidities, and to accelerate translation of these findings into the development of better therapies. Here, we provide a topic primer on epigenetics, explaining the key processes and findings to date in experimental and human epilepsy. We review the growing list of genes with epigenetic functions that have been linked with epilepsy in humans. We consider potential practical applications, including using epigenetic signals as biomarkers for tissue- and biofluid-based diagnostics and the prospects for developing epigenetic-based treatments for epilepsy. We include a glossary of terms, FAQs and other supports to facilitate a broad understanding of the topic for the non-expert. Last, we review the limitations, research gaps and the next challenges. In summary, epigenetic processes represent important mechanisms controlling the activity of genes, providing opportunities for insight into disease mechanisms, biomarkers and novel therapies for epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2020.1143DOI Listing
April 2020

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders.

Genome Med 2020 03 17;12(1):28. Epub 2020 Mar 17.

Stanley Center for Psychiatric Research, The Broad Institute of Harvard and M.I.T, Cambridge, MA, USA.

Background: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs.

Methods: Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families.

Results: We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint.

Conclusion: This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00725-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079346PMC
March 2020

Mortality in infantile spasms: A hospital-based study.

Epilepsia 2020 04 5;61(4):702-713. Epub 2020 Mar 5.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.

Objective: To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). We describe the overall goals of care for those who died.

Methods: This is a retrospective chart review of IS patients born between 2000 and 2011. We examined potential risk factors for mortality, including etiology, neurologic impairment, medication use, persistence of epileptic spasms, and comorbid systemic involvement (requirement for G-tube feedings, respiratory interventions). For patients who died, we describe cause of death and resuscitation status or end-of-life care measures.

Results: We identified 150 IS patients with median follow-up of 12 years. During the study period, 25 (17%) patients died, 13 before 5 years of age. Univariate analysis demonstrated that developmental delay, identifiable etiology, hormonal use for IS, persistence of epileptic spasms, polypharmacy with antiseizure medications, refractory epilepsy, respiratory system comorbidity, and the need for a G-tube were significant risk factors for mortality. In a multivariate analysis, mortality was predicted by persistence of epileptic spasms (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 1.11-16.67, P = .035) and significant respiratory system comorbidity (OR = 12.75, 95% CI = 2.88-56.32, P = .001). Mortality was epilepsy-related in one-third of patients who died with sudden unexpected death in epilepsy (SUDEP), accounting for 88% of epilepsy-related deaths. Most deaths before age 5 years were related to respiratory failure, and SUDEP was less common (17%) whereas SUDEP was more common (45%) with deaths after 5 years. For the majority (67%) of patients with early mortality, an end-of-life care plan was in place (based on documentation of resuscitation status, comfort measures, or decision not to escalate medical care).

Significance: Mortality at our single-center IS cohort was 17%, and persistence of epileptic spasms and comorbid respiratory system disorders were the most important determinants of mortality. Early deaths were related to neurological impairments/comorbidities. SUDEP was more common in children who died after 5 years of age than in those who died younger than 5 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16468DOI Listing
April 2020

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice.

Epilepsia 2020 03 23;61(3):387-399. Epub 2020 Feb 23.

Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.

Objective: Voltage-gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain-expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN-related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone.

Methods: We analyzed genotype-phenotype correlations in large SCN-patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders.

Results: Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy-associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain-of-function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed.

Significance: Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16438DOI Listing
March 2020

Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequence of Seizures and Their Treatment Across the Life Span.

Epilepsy Curr 2020 Jan-Feb;20(1_suppl):31S-39S. Epub 2020 Jan 23.

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Epilepsy represents a complex spectrum disorder, with patients sharing seizures as a common symptom and manifesting a broad array of additional clinical phenotypes. To understand this disorder and treat individuals who live with epilepsy, it is important not only to identify pathogenic mechanisms underlying epilepsy but also to understand their relationships with other health-related factors. Benchmarks Area IV focuses on the impact of seizures and their treatment on quality of life, development, cognitive function, and other aspects and comorbidities that often affect individuals with epilepsy. Included in this review is a discussion on sudden unexpected death in epilepsy and other causes of mortality, a major area of research focus with still many unanswered questions. We also draw attention to special populations, such as individuals with nonepileptic seizures and pregnant women and their offspring. In this study, we review the progress made in these areas since the 2016 review of the Benchmarks Area IV and discuss challenges and opportunities for future study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1535759719895277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031803PMC
January 2020

Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects.

Epilepsy Curr 2020 Jan-Feb;20(1_suppl):23S-30S. Epub 2020 Jan 22.

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy-one-third of patients-emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1535759719895279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031805PMC
January 2020

Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions.

Epilepsy Curr 2020 Jan-Feb;20(1_suppl):5S-13S. Epub 2020 Jan 22.

Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

The 2014 NINDS Benchmarks for Epilepsy Research included area I: Understand the causes of the epilepsies and epilepsy-related neurologic, psychiatric, and somatic conditions. In preparation for the 2020 Curing Epilepsies Conference, where the Benchmarks will be revised, this review will cover scientific progress toward that Benchmark, with emphasize on studies since 2016.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1535759719895280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031801PMC
January 2020

Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort.

Epilepsia 2020 02 19;61(2):249-258. Epub 2020 Jan 19.

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.

Objective: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

Methods: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

Results: Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%).

Significance: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404709PMC
February 2020

Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression.

Epilepsy Curr 2020 Jan-Feb;20(1_suppl):14S-22S. Epub 2020 Jan 15.

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Area II of the 2014 Epilepsy Research Benchmarks aims to establish goals for preventing the development and progression of epilepsy. In this review, we will highlight key advances in Area II since the last summary of research progress and opportunities was published in 2016. We also highlight areas of investigation that began to develop before 2016 and in which additional progress has been made more recently.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1535759719895274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031802PMC
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14428DOI Listing
September 2020

Duplication 2p16 is associated with perisylvian polymicrogyria.

Am J Med Genet A 2019 12 29;179(12):2343-2356. Epub 2019 Oct 29.

Department of Pediatrics (Genetics) and Neurology, University of Washington, and Seattle Children's Research Institute, Seattle, Washington.

Polymicrogyria (PMG) is a heterogeneous brain malformation that may result from prenatal vascular disruption or infection, or from numerous genetic causes that still remain difficult to identify. We identified three unrelated patients with polymicrogyria and duplications of chromosome 2p, defined the smallest region of overlap, and performed gene pathway analysis using Cytoscape. The smallest region of overlap in all three children involved 2p16.1-p16.3. All three children have bilateral perisylvian polymicrogyria (BPP), intrauterine and postnatal growth deficiency, similar dysmorphic features, and poor feeding. Two of the three children had documented intellectual disability. Gene pathway analysis suggested a number of developmentally relevant genes and gene clusters that were over-represented in the critical region. We narrowed a rare locus for polymicrogyria to a region of 2p16.1-p16.3 that contains 33-34 genes, 23 of which are expressed in cerebral cortex during human fetal development. Using pathway analysis, we showed that several of the duplicated genes contribute to neurodevelopmental pathways including morphogen, cytokine, hormonal and growth factor signaling, regulation of cell cycle progression, cell morphogenesis, axonal guidance, and neuronal migration. These findings strengthen the evidence for a novel locus associated with polymicrogyria on 2p16.1-p16.3, and comprise the first step in defining the underlying genetic etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61342DOI Listing
December 2019

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.

Ann Neurol 2019 12;86(6):821-831

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

Objective: Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort.

Methods: Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study.

Results: We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months.

Interpretation: We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821-831.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423163PMC
December 2019
-->