Publications by authors named "Heather E Olson"

25 Publications

  • Page 1 of 1

Generation and characterization of human induced pluripotent stem cells (iPSCs) from three male and three female patients with CDKL5 Deficiency Disorder (CDD).

Stem Cell Res 2021 Mar 5;53:102276. Epub 2021 Mar 5.

Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

CDKL5 Deficiency Disorder (CDD) is a rare X-linked monogenic developmental encephalopathy that is estimated to affect 1:42,000 live births. CDD is caused by pathogenic variants in the CDKL5 gene and is observed in both male and female patients. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from fibroblasts of six unrelated CDD patients-three males and three females. These patients are clinically diagnosed to present with classic CDD phenotypes, including refractory epilepsy and global developmental delay, and are being followed in a longitudinal clinical study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scr.2021.102276DOI Listing
March 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

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

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

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development.

Epilepsia 2019 08 16;60(8):1733-1742. Epub 2019 Jul 16.

Children's Hospital Colorado, Aurora, Colorado.

Objective: The cyclin-dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure-free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones.

Methods: This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit.

Results: Ninety-two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0-11.0). Eighty-one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor-tonic-spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty-three percent of patients experienced a seizure-free period ranging from 1 to >12 months, but only 6% were still seizure-free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia.

Significance: The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098045PMC
August 2019

Severity Assessment in CDKL5 Deficiency Disorder.

Pediatr Neurol 2019 08 27;97:38-42. Epub 2019 Mar 27.

Children's Hospital Colorado and University of Colorado School of Medicine Aurora, Colorado; Department of Pediatrics, Aurora, Colorado; Department of Pharmacology, Aurora, Colorado; Department of Neurology, Aurora, Colorado; Department of Otolaryngology, Aurora, Colorado. Electronic address:

Background: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness.

Methods: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input.

Results: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included.

Conclusions: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2019.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659999PMC
August 2019

Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.

Pediatr Neurol 2019 08 23;97:18-25. Epub 2019 Feb 23.

Children's Hospital Colorado, University of Colorado, School of Medicine, Aurora, Colorado; Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado; Department of Pharmacology, University of Colorado, School of Medicine, Aurora, Colorado; Department of Neurology, University of Colorado, School of Medicine, Aurora, Colorado; Department of Otolaryngology, University of Colorado, School of Medicine, Aurora, Colorado.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2019.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120929PMC
August 2019

Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation.

Brain Sci 2018 Aug 7;8(8). Epub 2018 Aug 7.

Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK.

The gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in , c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci8080145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119949PMC
August 2018

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

Am J Hum Genet 2018 05 12;102(5):995-1007. Epub 2018 Apr 12.

University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986694PMC
May 2018

Neonatal epilepsy genetics.

Semin Fetal Neonatal Med 2018 06 31;23(3):197-203. Epub 2018 Jan 31.

Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy, Boston Children's Hospital, Boston, MA, USA. Electronic address:

Neonatal epilepsy genetics is a rapidly expanding field with recent technological advances in genomics leading to an expanding list of genetic disorders associated with neonatal-onset epilepsy. The genetic causes of neonatal epilepsy can be grouped into the following categories: (i) malformations of cortical development, (ii) genetic-metabolic, (iii) genetic-vascular, (iv) genetic-syndromic, and (v) genetic-cellular. Clinically, epilepsy in the neonate shows phenotypic overlap with pathogenic variants in unrelated genes causing similar clinical presentation (locus heterogeneity) and variants in the same gene leading to a wide clinical spectrum ranging from benign familial neonatal seizures to more severe epileptic encephalopathies (variable expressivity). We suggest a diagnostic approach to obtaining a genetic diagnosis with emphasis on clinical features such as electro-clinical phenotype and magnetic resonance imaging findings. Rapid identification of genetic disorders with targeted treatments should be a clinical priority. Achieving a genetic diagnosis can be challenging in a rapidly changing genetic landscape, but is increasingly possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.siny.2018.01.003DOI Listing
June 2018

Characterization of a novel variant in siblings with Asparagine Synthetase Deficiency.

Mol Genet Metab 2018 03 20;123(3):317-325. Epub 2017 Dec 20.

Department of Biochemistry & Molecular Biology, Genetics Institute, University of Florida College of Medicine, 1200 Newell Drive, FL 32608, USA. Electronic address:

Asparagine Synthetase Deficiency (ASD) is a recently described inborn error of metabolism caused by bi-allelic pathogenic variants in the asparagine synthetase (ASNS) gene. ASD typically presents congenitally with microcephaly and severe, often medically refractory, epilepsy. Development is generally severely affected at birth. Tone is abnormal with axial hypotonia and progressive appendicular spasticity. Hyperekplexia has been reported. Neuroimaging typically demonstrates gyral simplification, abnormal myelination, and progressive cerebral atrophy. The present report describes two siblings from consanguineous parents with a homozygous Arg49Gln variant associated with a milder form of ASD that is characterized by later onset of symptoms. Both siblings had a period of normal development before onset of seizures, and development regression. Primary fibroblast studies of the siblings and their parents document that homozygosity for Arg49Gln blocks cell growth in the absence of extracellular asparagine. Functional studies with these cells suggest no impact of the Arg49Gln variant on basal ASNS mRNA or protein levels, nor on regulation of the gene itself. Molecular modelling of the ASNS protein structure indicates that the Arg49Gln variant lies near the substrate binding site for glutamine. Collectively, the results suggest that the Arg49Gln variant affects the enzymatic function of ASNS. The clinical, cellular, and molecular observations from these siblings expand the known phenotypic spectrum of ASD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2017.12.433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832599PMC
March 2018

Imaging features and prognostic factors in fetal and postnatal torcular dural sinus malformations, part I: review of experience at Boston Children's Hospital.

J Neurointerv Surg 2018 May 30;10(5):467-470. Epub 2017 Sep 30.

Department of Radiology, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: Even for the most common dural sinus malformation (DSM), the torcular DSM (tDSM), generalizable statements about etiology and prognosis are difficult because neurosurgeons/neuroradiologists and obstetrical imagers have focused on different patient age groups, have reported different outcomes, and have offered differing pathophysiologic explanations.

Objective: To examine the imaging features and outcomes of a local cohort of tDSMs across fetal-neonatal life for commonalities.

Methods: Review of imaging and clinical outcome for a local cohort of 12 tDSM patients (9 fetal, 3 postnatal).

Results: All 12 tDSMs had similar imaging characteristics, including enlargement of the torcular and intraluminal thrombus early on, later evolving to peripheral scar tissue after treatment or spontaneous regression. Spontaneous decrease in size of the tDSM was observed in 6 prenatal and 1 postnatal case, and this decrease appeared to be irreversible once it occurred. One of 9 prenatal tDSMs was demonstrated to have arteriovenous fistulae in utero, while 2 of 3 postnatal diagnoses had arteriovenous fisutlae. All 6 prenatal tDSM diagnoses followed to term and all 3 postnatal diagnoses had a grossly normal neurologic outcome after a median of 12 months of age.

Conclusions: Prenatal and postnatal tDSMs have overlapping imaging features suggesting a common etiology, and involution of a tDSM is a key imaging biomarker for a favorable outcome. While there is reason for concern with postnatally diagnosed tDSMs, good outcomes may still be achieved across the fetal-neonatal age spectrum of presentations. These findings are generalized in part II of this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/neurintsurg-2017-013344DOI Listing
May 2018

Imaging features and prognostic factors in fetal and postnatal torcular dural sinus malformations, part II: synthesis of the literature and patient management.

J Neurointerv Surg 2018 May 30;10(5):471-475. Epub 2017 Sep 30.

Department of Radiology, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: Torcular dural sinus malformations (tDSMs) are described as slow flow dural arteriovenous fistulae with frequently poor outcomes in the neuroangiographic literature, but other etiologies have been proposed in the obstetric literature, where outcomes have been more favorable.

Objective: To review tDSMs reported in the literature of multiple specialties for features that support a common etiology, and to identify key prognostic factors, with an emphasis on tDSM trajectory highlighted in part I.

Methods: Analysis of imaging features and clinical outcome for 77 prenatal and 22 postnatal tDSMs reported in 37 papers from the literature.

Results: In addition to large venous lakes, 36% of prenatal and 96% of postnatal tDSMs had evidence of arterialization, where specifically assessed. For fetal cases, where there was an observable natural history, 97% underwent a spontaneous decrease-13% after an initial increase and only 1 case with subsequent enlargement after a decrease. Prenatal cases had 83% survival (62% with a favorable outcome) whereas postnatal cases had 59% survival (29% favorable). In addition to a postnatal diagnosis, unfavorable features included ventriculomegaly, parenchymal injury, arterialization, and need for intervention. Favorable features included decreasing tDSM size, presence of clot, and increasing clot percentage.

Conclusions: Neonatal and fetal tDSMs have overlapping imaging appearances, suggesting a common etiology, where neonatal tDSMs represent those rare fetal tDSMs that do not undergo spontaneous regression and have a propensity for worse outcomes. Decrease in tDSM size is a critical observation when managing a tDSM because it is generally irreversible and associated with a favorable outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/neurintsurg-2017-013343DOI Listing
May 2018

A randomized controlled trial of levodopa in patients with Angelman syndrome.

Am J Med Genet A 2018 05 25;176(5):1099-1107. Epub 2017 Sep 25.

Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital; Harvard Medical School, Boston, Massachusetts.

Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin-dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867193PMC
May 2018

Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients.

Epilepsia 2017 08 12;58(8):1415-1422. Epub 2017 Jun 12.

Telethon Kids Institute, University of Western Australia, West Perth, Western Australia, Australia.

Objective: Pathogenic variants involving the CDKL5 gene result in a severe epileptic encephalopathy, often later presenting with features similar to Rett syndrome. Cardinal features of epilepsy in the CDKL5 disorder include early onset at a median age of 6 weeks and poor response to antiepileptic drugs. The ketogenic diet (KD) was first introduced in the 1920s as a treatment option for refractory epilepsy in children. This study investigated use of the KD in the CDKL5 disorder and its influences on seizures.

Methods: The International CDKL5 Disorder Database, established in 2012, collects information on individuals with the CDKL5 disorder. Families have provided information regarding seizure characteristics, use, and side effects of the KD treatment. Descriptive statistics and time to event analyses were performed. Clinical vignettes were also provided on patients attending Boston Children's Hospital.

Results: Data regarding KD use were available for 204 individuals with a pathogenic CDKL5 variant. Median age of inclusion in the database was 4.8 years (range = 0.3-33.9 years), with median age of 6 weeks (range = 1 day-65 weeks) at seizure onset. History of KD use was reported for 51% (104 of 204) of individuals, with a median duration of use of 17 months (95% confidence interval = 9-24). Changes in seizure activity after commencing KD were reported for two-thirds (69 of 104), with improvements in 88% (61 of 69). Nearly one-third (31.7%) experienced side effects during the diet. At ascertainment, only one-third (32%) remained on the diet, with lack of long-term efficacy as the main reason for diet cessation (51%, 36 of 70).

Significance: Benefits of KD in the CDKL5 disorder are in keeping with previous trials on refractory epilepsies. However, poor long-term efficacy remains as a significant barrier. In view of its side effect profile, KD administration should be supervised by a pediatric neurologist and specialist dietician.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.13813DOI Listing
August 2017

Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression.

Ann Neurol 2017 Mar 14;81(3):419-429. Epub 2017 Feb 14.

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

Objective: We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations.

Methods: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, electroencephalography, and magnetic resonance imaging. We confirmed burst suppression in 28 of 33 patients. Research-based exome sequencing was performed for patients without a previously identified molecular diagnosis from clinical evaluation or a research-based epilepsy gene panel.

Results: In 17 of 28 (61%) patients with confirmed early burst suppression, we identified variants predicted to be pathogenic in KCNQ2 (n = 10), STXBP1 (n = 2), SCN2A (n = 2), PNPO (n = 1), PIGA (n = 1), and SEPSECS (n = 1). In 3 of 5 (60%) patients without confirmed early burst suppression, we identified variants predicted to be pathogenic in STXBP1 (n = 2) and SCN2A (n = 1). The patient with the homozygous PNPO variant had a low cerebrospinal fluid pyridoxal-5-phosphate level. Otherwise, no early laboratory or clinical features distinguished the cases associated with pathogenic variants in specific genes from each other or from those with no prior genetic cause identified.

Interpretation: We characterize the genetic landscape of epileptic encephalopathy with burst suppression, without brain malformations, and demonstrate feasibility of genetic diagnosis with clinically available testing in >60% of our cohort, with KCNQ2 implicated in one-third. This electroclinical syndrome is associated with pathogenic variation in SEPSECS. Ann Neurol 2017;81:419-429.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.24883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366084PMC
March 2017

A Model Program for Translational Medicine in Epilepsy Genetics.

J Child Neurol 2017 03 6;32(4):429-436. Epub 2017 Jan 6.

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

Recent technological advances in gene sequencing have led to a rapid increase in gene discovery in epilepsy. However, the ability to assess pathogenicity of variants, provide functional analysis, and develop targeted therapies has not kept pace with rapid advances in sequencing technology. Thus, although clinical genetic testing may lead to a specific molecular diagnosis for some patients, test results often lead to more questions than answers. As the field begins to focus on therapeutic applications of genetic diagnoses using precision medicine, developing processes that offer more than equivocal test results is essential. The success of precision medicine in epilepsy relies on establishing a correct genetic diagnosis, analyzing functional consequences of genetic variants, screening potential therapeutics in the preclinical laboratory setting, and initiating targeted therapy trials for patients. The authors describe the structure of a comprehensive, pediatric Epilepsy Genetics Program that can serve as a model for translational medicine in epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0883073816685654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625332PMC
March 2017

BRAT1 mutations present with a spectrum of clinical severity.

Am J Med Genet A 2016 09 9;170(9):2265-73. Epub 2016 Jun 9.

Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland.

Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, are associated with a severe phenotype known as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL; OMIM # 614498), characterized by intractable seizures, hypertonia, autonomic instability, and early death. We expand the phenotypic spectrum of BRAT1 related disorders by reporting on four individuals with various BRAT1 mutations resulting in clinical severity that is either mild or moderate compared to the severe phenotype seen in RMFSL. Representing mild severity are three individuals (Patients 1-3), who are girls (including two sisters, Patients 1-2) between 4 and 10 years old, with subtle dysmorphisms, intellectual disability, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; additionally, Patient 3 has well-controlled epilepsy and microcephaly. Representing moderate severity is a 15-month-old boy (Patient 4) with severe global developmental delay, refractory epilepsy, microcephaly, spasticity, hyperkinetic movements, dysautonomia, and chronic lung disease. In contrast to RMFSL, his seizure onset occurred later at 4 months of age, and he is still alive. All four of the individuals have compound heterozygous BRAT1 mutations discovered via whole exome sequencing: c.638dupA (p.Val214Glyfs*189); c.803+1G>C (splice site mutation) in Patients 1-2; c.638dupA (p.Val214Glyfs*189); c.419T>C (p.Leu140Pro) in Patient 3; and c.171delG (p.Glu57Aspfs*7); c.419T>C (p.Leu140Pro) in Patient 4. Only the c.638dupA (p.Val214Glyfs*189) mutation has been previously reported in association with RMFSL. These patients illustrate that, compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later-onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532882PMC
September 2016

SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures.

Neurology 2015 Sep 19;85(11):958-66. Epub 2015 Aug 19.

From the Departments of Neurology (K.B.H., M.T.M., V.R.-C., J.L.F., A.S.H., I.E.S.) and Radiology (S.M.), The Royal Children's Hospital, Melbourne; Department of Paediatrics (K.B.H., M.T.M., S.M., A.S.H., I.E.S.), The University of Melbourne; Murdoch Childrens Research Institute (K.B.H., M.T.M., J.L.F., A.S.H.), Melbourne; Epilepsy Research Centre (J.M.M., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Division of Genetic Medicine (G.L.C., H.C.M.), Department of Paediatrics, University of Washington, Seattle; Epilepsy Genetics Program (D.T., H.E.O., A.P.), Department of Neurology, Harvard Medical School, Boston Children's Hospital, MA; TY Nelson Department of Neurology and Neurosurgery (R.W.), The Children's Hospital at Westmead, Sydney; Department of Neurology (D.C.), Women's and Children's Hospital, Adelaide; Neurosciences Children's Health Queensland (S.C.), Lady Cilento Children's Hospital, Brisbane; and Florey Institute of Neuroscience and Mental Health (S.M., A.S.H., I.E.S.), Melbourne, Australia.

Objective: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy.

Methods: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping.

Results: Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1-4 in 8, week 2-6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one.

Conclusions: Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile-onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000001926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567464PMC
September 2015

The genetics of the epilepsies.

Curr Neurol Neurosci Rep 2015 Jul;15(7):39

Division of Epilepsy, Department of Neurology, Boston Children's Hospital, and Harvard Medical School, Fegan 9, 300 Longwood Ave, Boston, MA, 02115, USA,

While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a diverse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype-phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11910-015-0559-8DOI Listing
July 2015

Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.

Am J Med Genet A 2015 Sep 25;167A(9):2017-25. Epub 2015 Apr 25.

Epilepsy Genetics Program, Division of Epilepsy & Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.

Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722031PMC
September 2015

Genetic forms of epilepsies and other paroxysmal disorders.

Semin Neurol 2014 Jul 5;34(3):266-79. Epub 2014 Sep 5.

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

Genetic mechanisms explain the pathophysiology of many forms of epilepsy and other paroxysmal disorders, such as alternating hemiplegia of childhood, familial hemiplegic migraine, and paroxysmal dyskinesias. Epilepsy is a key feature of well-defined genetic syndromes including tuberous sclerosis complex, Rett syndrome, Angelman syndrome, and others. There is an increasing number of single-gene causes or susceptibility factors associated with several epilepsy syndromes, including the early-onset epileptic encephalopathies, benign neonatal/infantile seizures, progressive myoclonus epilepsies, genetic generalized and benign focal epilepsies, epileptic aphasias, and familial focal epilepsies. Molecular mechanisms are diverse, and a single gene can be associated with a broad range of phenotypes. Additional features, such as dysmorphisms, head size, movement disorders, and family history may provide clues to a genetic diagnosis. Genetic testing can impact medical care and counseling. We discuss genetic mechanisms of epilepsy and other paroxysmal disorders, tools and indications for genetic testing, known genotype-phenotype associations, the importance of genetic counseling, and a look toward the future of epilepsy genetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0034-1386765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834292PMC
July 2014

Clinical application and evaluation of the Bien diagnostic criteria for Rasmussen encephalitis.

Epilepsia 2013 Oct 23;54(10):1753-60. Epub 2013 Aug 23.

Division of Epilepsy, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, U.S.A; Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: The 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures, clinical deficits, electroencephalography (EEG), neuroimaging, and pathology (Brain, 128, 2005, 451). We applied these criteria to patients evaluated for RE and epilepsy surgery controls to determine the sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) using pathology as the gold standard.

Methods: We identified patients evaluated for RE based on medical records from 1993 to 2011. Fifty-two control patients with refractory epilepsy, unilateral magnetic resonance imaging (MRI) changes, and biopsies were selected from an epilepsy surgery database from matching years. Patients meeting all three of group A and/or two of three group B criteria were classified as meeting full criteria (positive). Patients not meeting full criteria were classified as negative. When available, pathology findings were re-reviewed with neuropathologists, and MRI imaging was re-reviewed with a neuroradiologist.

Key Findings: RE was considered in the differential diagnosis for 82 patients, of whom 35 had biopsies. Twenty patients met full criteria (positive) without another explanation, including seven for whom biopsy was required to meet criteria and one in whom another etiology was identified. Two patients met full criteria but had another explanation. Thirty-five met partial criteria (negative), of whom 14 had another etiology identified. Twenty-five met no criteria (negative). The diagnostic criteria had a sensitivity of 81% with four false negatives (criteria-negative, biopsy-positive) when compared to pathology as a gold standard. Five false positives (criteria positive, biopsy negative) had identifiable alternate diagnoses.

Significance: The 2005 Bien clinical diagnostic criteria for RE have reasonably high sensitivity and specificity and good clinical-pathologic correlation in most cases. We suggest modification of the criteria to allow inclusion of cases with well-described but less common features. Specifically we suggest making the diagnosis in the absence of epilepsia partialis continua (EPC) or clear progression of focal cortical deficits or MRI findings if biopsy is positive and two of the A criteria are met (B3 plus two of three A criteria). This would improve the sensitivity of the criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.12334DOI Listing
October 2013

Neural stem cell- and Schwann cell-loaded biodegradable polymer scaffolds support axonal regeneration in the transected spinal cord.

Tissue Eng Part A 2009 Jul;15(7):1797-805

Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Biodegradable polymer scaffolds provide an excellent approach to quantifying critical factors necessary for restoration of function after a transection spinal cord injury. Neural stem cells (NSCs) and Schwann cells (SCs) support axonal regeneration. This study examines the compatibility of NSCs and SCs with the poly-lactic-co-glycolic acid polymer scaffold and quantitatively assesses their potential to promote regeneration after a spinal cord transection injury in rats. NSCs were cultured as neurospheres and characterized by immunostaining for nestin (NSCs), glial fibrillary acidic protein (GFAP) (astrocytes), betaIII-tubulin (immature neurons), oligodendrocyte-4 (immature oligodendrocytes), and myelin oligodendrocyte (mature oligodendrocytes), while SCs were characterized by immunostaining for S-100. Rats with transection injuries received scaffold implants containing NSCs (n=17), SCs (n=17), and no cells (control) (n=8). The degree of axonal regeneration was determined by counting neurofilament-stained axons through the scaffold channels 1 month after transplantation. Serial sectioning through the scaffold channels in NSC- and SC-treated groups revealed the presence of nestin, neurofilament, S-100, and betaIII tubulin-positive cells. GFAP-positive cells were only seen at the spinal cord-scaffold border. There were significantly more axons in the NSC- and SC- treated groups compared to the control group. In conclusion, biodegradable scaffolds with aligned columns seeded with NSCs or SCs facilitate regeneration across the transected spinal cord. Further, these multichannel biodegradable polymer scaffolds effectively serve as platforms for quantitative analysis of axonal regeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ten.tea.2008.0364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792101PMC
July 2009