Publications by authors named "Alex R Paciorkowski"

52 Publications

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

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

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

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

BioVR: a platform for virtual reality assisted biological data integration and visualization.

BMC Bioinformatics 2019 Feb 15;20(1):78. Epub 2019 Feb 15.

Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology, One Lomb Memorial Drive, Rochester, NY, 14623, USA.

Background: Functional characterization of single nucleotide variants (SNVs) involves two steps, the first step is to convert DNA to protein and the second step is to visualize protein sequences with their structures. As massively parallel sequencing has emerged as a leading technology in genomics, resulting in a significant increase in data volume, direct visualization of SNVs together with associated protein sequences/structures in a new user interface (UI) would be a more effective way to assess their potential effects on protein function.

Results: We have developed BioVR, an easy-to-use interactive, virtual reality (VR)-assisted platform for integrated visual analysis of DNA/RNA/protein sequences and protein structures using Unity3D and the C# programming language. It utilizes the cutting-edge Oculus Rift, and Leap Motion hand detection, resulting in intuitive navigation and exploration of various types of biological data. Using Gria2 and its associated gene product as an example, we present this proof-of-concept software to integrate protein and nucleic acid data. For any amino acid or nucleotide of interest in the Gria2 sequence, it can be quickly linked to its corresponding location on Gria2 protein structure and visualized within VR.

Conclusions: Using innovative 3D techniques, we provide a VR-based platform for visualization of DNA/RNA sequences and protein structures in aggregate, which can be extended to view omics data.
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http://dx.doi.org/10.1186/s12859-019-2666-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376704PMC
February 2019

Association of Severe Hydrocephalus With Congenital Zika Syndrome.

JAMA Neurol 2019 02;76(2):203-210

University of Pernambuco, Recife, Pernambuco, Brazil.

Importance: Hydrocephalus is a treatable but potentially fatal complication that has not been previously described in congenital Zika syndrome (CZS).

Objective: To describe the clinical features and imaging findings in 24 patients with congenital Zika syndrome (CZS) who developed hydrocephalus.

Design, Setting, And Participants: This case series included patients with hydrocephalus who were born in October and November 2015 and followed up until mid-2017 in the 2 largest national referral centers for CZS in Brazil. The participants included consecutively enrolled children with a clinical and laboratorial diagnosis of CZS who developed clinical and/or image findings suggestive of hydrocephalus and who were confirmed to experience increased intracranial hypertension during ventriculoperitoneal shunt procedures.

Main Outcomes And Measures: To retrospectively describe clinical and image findings in these 24 patients.

Results: This multicenter cohort included 308 patients with CZS; 24 consecutive children were enrolled in this study. These children were aged between 3 to 18 months, and 13 of 24 (54%) were female. All patients presented with at least 1 positive test result for anti-Zika antibodies in cerebrospinal fluid or serum and had classic signs of CZS. At the time of hydrocephalus diagnosis, only 14 of 24 patients (58%) had symptoms and signs suggestive of hydrocephalus (mainly worsening seizures, vomiting, irritability, and/or sudden increase of head circumference percentile). Two of 24 patients (8%) had no symptoms suggestive of hydrocephalus but were found to have reduced brain volume on repeated imaging. Cerebellar or brainstem hypoplasia on baseline imaging were found in 18 of 23 patients (78%). At the second computed tomographic scan, all patients showed a marked increase of ventricular volume, compatible with communicating hydrocephalus, and reduction of brain tissue that was visibly worse than on baseline imaging for the 23 patients with repeated scans.

Conclusions And Relevance: We present evidence that hydrocephalus is a complication of CZS in at least a proportion of patients. The clinical spectrum of this condition continues to evolve, but given that presenting signs and symptoms of hydrocephalus can be challenging to recognize in CZS, we provisionally recommend that high suspicion and appropriate monitoring for hydrocephalus should be part of the standard care of patients with CZS.
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http://dx.doi.org/10.1001/jamaneurol.2018.3553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439957PMC
February 2019

Phenotypes, genotypes, and the management of paroxysmal movement disorders.

Dev Med Child Neurol 2018 06 30;60(6):559-565. Epub 2018 Mar 30.

Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK.

As a consequence of the genomic revolution, a large number of publications describing paroxysmal movement disorders have been published in the last few years, shedding light on their molecular pathology. Routine gene testing is not necessary to guide treatment for typical forms of paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and episodic ataxia type 1 or 2. It can, however, be helpful in the management of atypical or complex cases, especially for genetic counselling, treatment strategies, and the offer of preimplantation genetic diagnosis. Antiepileptic drugs remain the treatment of choice for PKD and episodic ataxia type 1, benzodiazepines are often useful for PNKD, and episodic ataxia type 2 benefits from acetazolamide regardless of the genetic etiology.

What The Paper Adds: A growing number of genes have been associated with classic and newly described paroxysmal movement disorders. Paroxysmal movement disorders share common mechanisms and clinical features with other neurological paroxysmal phenomena including epilepsy and migraine.
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http://dx.doi.org/10.1111/dmcn.13744DOI Listing
June 2018

Ode to the humble Southern blot in the era of exomes.

Neurol Clin Pract 2018 Feb;8(1):4-5

Departments of Neurology, Pediatrics, Biomedical Genetics, and Neuroscience, Neurogenetics Consultation Service, Hereditary Ataxia Program, Child Neurology, University of Rochester Medical Center, NY.

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http://dx.doi.org/10.1212/CPJ.0000000000000414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839687PMC
February 2018

Genetic Diagnostics for Neurologists.

Continuum (Minneap Minn) 2018 02;24(1, Child Neurology):18-36

Purpose Of Review: This article puts advances in the field of neurogenetics into context and provides a quick review of the broad concepts necessary for current practice in neurology.

Recent Findings: The exponential growth of genetic testing is due to its increased speed and decreasing cost, and it is now a routine part of the clinical care for a number of neurologic patients. In addition, phenotypic pleiotropy (mutations in the same gene causing very disparate phenotypes) and genetic heterogeneity (the same clinical phenotype resulting from mutations in different genes) are now known to exist in a number of conditions, adding an additional layer of complexity for genetic testing in these disorders.

Summary: Although the growing complexity of technical knowledge in the ordering and interpretation of genetic tests makes it necessary for neurologists to consult medical geneticists, limitations in the availability of such professionals often means neurologists will be on the front line dealing with suspected or confirmed neurogenetic conditions. The growing availability of broad genetic testing through chromosomal microarray and next-generation sequencing and the expanded phenotypic spectrum of many conditions has implications for genetic counseling and medical management. This article discusses the various forms of genetic variability and how to test for each of them. It also provides an update on the most common forms of neurologic presentations of genetic disease and a review of testing strategies.
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http://dx.doi.org/10.1212/CON.0000000000000556DOI Listing
February 2018

Expanding the neurodevelopmental phenotype of PURA syndrome.

Am J Med Genet A 2018 01 17;176(1):56-67. Epub 2017 Nov 17.

Department of Neurology, University of Rochester Medical Center, Rochester, New York.

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations.
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http://dx.doi.org/10.1002/ajmg.a.38521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821266PMC
January 2018

CEDNIK: Phenotypic and Molecular Characterization of an Additional Patient and Review of the Literature.

Child Neurol Open 2017 Jan-Dec;4:2329048X17733214. Epub 2017 Oct 8.

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.

Synaptosomal-associated protein 29 (SNAP29) is a t-SNARE protein that is implicated in intracellular vesicle fusion. Mutations in the gene have been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK). In patients with 22q11.2 deletion syndrome, mutations in on the nondeleted chromosome are linked to similar ichthyotic and neurological phenotypes. Here, the authors report a patient with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome who presented with global developmental delay, polymicrogyria, dysgenesis of the corpus callosum, optic nerve dysplasia, gaze apraxia, and dysmorphic features. He has developed ichthyosis and palmoplantar keratoderma as he has grown. Exome sequencing identified a homozygous nonsense mutation in gene designated as c.85C>T (p.Arg29X). The authors compare the findings in the proband with previously reported cases. The previously unreported mutation in this patient and his phenotype add to the characterization of cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome and the accumulating scientific evidence that implicates synaptic protein dysfunction in various neuroectodermal conditions.
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http://dx.doi.org/10.1177/2329048X17733214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638153PMC
October 2017

Congenital Zika syndrome: an epidemic of neurologic disability.

Arq Neuropsiquiatr 2017 08;75(8):605

University of Rochester Medical Center, Neurogenetics Consultation Service, Departments of Neurology, Pediatrics, Biomedical Genetics, and Neuroscience, New York, USA.

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http://dx.doi.org/10.1590/0004-282X20170104DOI Listing
August 2017

India Allele Finder: a web-based annotation tool for identifying common alleles in next-generation sequencing data of Indian origin.

BMC Res Notes 2017 Jun 27;10(1):233. Epub 2017 Jun 27.

Center for Neurotherapeutics Development, University of Rochester Medical Center, Rochester, NY, USA.

Objective: We built India Allele Finder, an online searchable database and command line tool, that gives researchers access to variant frequencies of Indian Telugu individuals, using publicly available fastq data from the 1000 Genomes Project. Access to appropriate population-based genomic variant annotation can accelerate the interpretation of genomic sequencing data. In particular, exome analysis of individuals of Indian descent will identify population variants not reflected in European exomes, complicating genomic analysis for such individuals.

Results: India Allele Finder offers improved ease-of-use to investigators seeking to identify and annotate sequencing data from Indian populations. We describe the use of India Allele Finder to identify common population variants in a disease quartet whole exome dataset, reducing the number of candidate single nucleotide variants from 84 to 7. India Allele Finder is freely available to investigators to annotate genomic sequencing data from Indian populations. Use of India Allele Finder allows efficient identification of population variants in genomic sequencing data, and is an example of a population-specific annotation tool that simplifies analysis and encourages international collaboration in genomics research.
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http://dx.doi.org/10.1186/s13104-017-2556-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488357PMC
June 2017

PLXNA1 developmental encephalopathy with syndromic features: A case report and review of the literature.

Am J Med Genet A 2017 Jul 2;173(7):1951-1954. Epub 2017 May 2.

Department of Neurology, University of Rochester Medical Center, Rochester, New York.

Developmental encephalopathies constitute a broad and genetically heterogeneous spectrum of disorders associated with global developmental delay, intellectual disability, frequent epilepsy, and other neurofunctional abnormalities. Here, we report a male presenting with infantile onset epilepsy and syndromic features resembling Dubowitz syndrome identified to have a de novo PLXNA1 variant by whole exome sequencing. This constitutes the second report of PLXNA1 sequence variation associated with early onset epilepsy, and the first to expand on the clinical features of this emerging disorder. This reports suggests that nonsynonymous de novo sequence variations in PLXNA1 are associated with a novel human phenotype characterized by intractable early onset epilepsy, intellectual disability, and syndromic features.
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http://dx.doi.org/10.1002/ajmg.a.38236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878136PMC
July 2017

Developing a novel epileptic discharge localization algorithm for electroencephalogram infantile spasms during hypsarrhythmia.

Med Biol Eng Comput 2017 Sep 9;55(9):1659-1668. Epub 2017 Feb 9.

Department of Computer and Electrical Engineering, Florida Atlantic University, 777 Glades Rd, Boca Raton, FL, 33431, USA.

Infantile spasms (ISS) is a devastating epileptic syndrome that affects children under the age of 1 year. The diagnosis of ISS is based on the semiology of the seizure and the electroencephalogram (EEG) background characterized by hypsarrhythmia (HYPS). However, even skilled electrophysiologists may interpret the EEG of children with ISS differently, and commercial software or existing epilepsy detection algorithms are not helpful. Since EEG is a key factor in the diagnosis of ISS, misinterpretation could result in serious consequences including inappropriate treatment. In this paper, we developed a novel algorithm to localize the relevant electrical abnormality known as epileptic discharges (or spikes) to provide a quantitative assessment of ISS in HYPS. The proposed algorithm extracts novel time-frequency features from the EEG signals and localizes the epileptic discharges associated with ISS in HYPS using a support vector machine classifier. We evaluated the proposed method on an EEG dataset with ISS subjects and obtained an average true positive and false negative of 98 and 7%, respectively, which was a significant improvement compared to the results obtained using the clinically available software. The proposed automated method provides a quantitative assessment of ISS in HYPS, which could significantly enhance our knowledge in therapy management of ISS.
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http://dx.doi.org/10.1007/s11517-017-1616-zDOI Listing
September 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.
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http://dx.doi.org/10.1002/ana.24883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366084PMC
March 2017

Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology.

Eur J Hum Genet 2017 02 14;25(2):216-221. Epub 2016 Dec 14.

Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

SIK1 syndrome is a newly described developmental epilepsy disorder caused by heterozygous mutations in the salt-inducible kinase SIK1. To better understand the pathophysiology of SIK1 syndrome, we studied the effects of SIK1 pathogenic sequence variations in human neurons. Primary human fetal cortical neurons were transfected with a lentiviral vector to overexpress wild-type and mutant SIK1 protein. We evaluated the transcriptional activity of known downstream gene targets in neurons expressing mutant SIK1 compared with wild type. We then assayed neuronal morphology by measuring neurite length, number and branching. Truncating SIK1 sequence variations were associated with abnormal MEF2C transcriptional activity and decreased MEF2C protein levels. Epilepsy-causing SIK1 sequence variations were associated with significantly decreased expression of ARC (activity-regulated cytoskeletal-associated) and other synaptic activity response element genes. Assay of mRNA levels for other MEF2C target genes NR4A1 (Nur77) and NRG1, found significantly, decreased the expression of these genes as well. The missense p.(Pro287Thr) SIK1 sequence variation was associated with abnormal neuronal morphology, with significant decreases in mean neurite length, mean number of neurites and a significant increase in proximal branches compared with wild type. Epilepsy-causing SIK1 sequence variations resulted in abnormalities in the MEF2C-ARC pathway of neuronal development and synapse activity response. This work provides the first insights into the mechanisms of pathogenesis in SIK1 syndrome, and extends the ARX-MEF2C pathway in the pathogenesis of developmental epilepsy.
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http://dx.doi.org/10.1038/ejhg.2016.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5255945PMC
February 2017

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

Genet Med 2017 06 10;19(6):691-700. Epub 2016 Nov 10.

Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.

Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.

Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.

Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.
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http://dx.doi.org/10.1038/gim.2016.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438871PMC
June 2017

Phenotype Differentiation of FOXG1 and MECP2 Disorders: A New Method for Characterization of Developmental Encephalopathies.

J Pediatr 2016 Nov 15;178:233-240.e10. Epub 2016 Sep 15.

Department of Neurology, University of Rochester Medical Center, Rochester, NY; Departments of Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY; Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY. Electronic address:

Objective: To differentiate developmental encephalopathies by creating a novel quantitative phenotyping tool.

Study Design: We created the Developmental Encephalopathy Inventory (DEI) to differentiate disorders with complex multisystem neurodevelopmental symptoms. We then used the DEI to study the phenotype features of 20 subjects with FOXG1 disorder and 11 subjects with MECP2 disorder.

Results: The DEI identified core domains of fine motor and expressive language that were severely impaired in both disorders. Individuals with FOXG1 disorder were overall more severely impaired. Subjects with FOXG1 disorder were less able to walk, had worse fine motor skills, more disability in receptive language and reciprocity, and had more disordered sleep than did subjects with MECP2 disorder (P <.05). Covariance, cluster, and principal component analysis confirmed a relationship between impaired awareness, reciprocity, and language in both disorders. In addition, abnormal ambulation was a first principal component for FOXG1 but not for MECP2 disorder, suggesting that impaired ambulation is a strong differentiating factor clinically between the 2 disorders.

Conclusions: We have developed a novel quantitative developmental assessment tool for developmental encephalopathies and propose this tool as a method to identify and illustrate core common and differential domains of disability in these complex disorders. These findings demonstrate clear phenotype differences between FOXG1 and MECP2 disorders.
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http://dx.doi.org/10.1016/j.jpeds.2016.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873956PMC
November 2016

Automatic localization of epileptic spikes in eegs of children with infantile spasms.

Annu Int Conf IEEE Eng Med Biol Soc 2015 ;2015:6194-7

A novel methodology is proposed for identifying epileptiform discharges associated with individuals exhibiting Infantile Spasms (ISS) also known as West Syndrome, which is characterized by electroencephalogram (EEG) recordings exhibiting hypsarrythmia (HYPS). The approach to identify these discharges consists of three stages: first - construct the time-frequency domain (TFD) of the EEG recording using matching pursuit TFD (MP-TFD), second - decompose the TFD matrix into two submatrices (W, H) using non-negative matrix factorization (NMF), and third - use the decomposed spectral and temporal vectors to locate the epileptiform discharges, referred to as spikes, during intervals of HYPS. The method was applied to an EEG dataset of five individuals and the identification of spike locations was compared with those which were visually identified by the epileptologists and those obtained using commercially available clinical analysis software. The MP-TFD method resulted in average true positive and false negative percentages of 86% and 14%, respectively, which represents a significant improvement over the clinical software, which achieved average true positive and false negative percentages of 4% and 96%, respectively.
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http://dx.doi.org/10.1109/EMBC.2015.7319807DOI Listing
September 2016

Familial recurrences of FOXG1-related disorder: Evidence for mosaicism.

Am J Med Genet A 2015 Dec 14;167A(12):3096-102. Epub 2015 Sep 14.

Department of Neurology, University of Rochester Medical Center, Rochester, New York.

FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities. The recurrence risk for de novo mutations in FOXG1-related disorders is assumed to be low. Here, we describe three unrelated sets of full siblings with mutations in FOXG1 (c.515_577del63, c.460dupG, and c.572T > G), representing familial recurrence of the disorder. In one family, we have documented maternal somatic mosaicism for the FOXG1 mutation, and all of the families presumably represent parental gonadal (or germline) mosaicism. To our knowledge, mosaicism has not been previously reported in FOXG1-related disorders. Therefore, this report provides evidence that germline mosaicism for FOXG1 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with FOXG1-related disorders.
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http://dx.doi.org/10.1002/ajmg.a.37353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715619PMC
December 2015

Autism spectrum disorder and epilepsy: Disorders with a shared biology.

Epilepsy Behav 2015 Jun 19;47:191-201. Epub 2015 Apr 19.

Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA; Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA; Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA. Electronic address:

There is an increasing recognition of clinical overlap in patients presenting with epilepsy and autism spectrum disorder (ASD), and a great deal of new information regarding the genetic causes of both disorders is available. Several biological pathways appear to be involved in both disease processes, including gene transcription regulation, cellular growth, synaptic channel function, and maintenance of synaptic structure. We review several genetic disorders where ASD and epilepsy frequently co-occur, and we discuss the screening tools available for practicing neurologists and epileptologists to help determine which patients should be referred for formal ASD diagnostic evaluation. Finally, we make recommendations regarding the workflow of genetic diagnostic testing available for children with both ASD and epilepsy. This article is part of a Special Issue entitled "Autism and Epilepsy".
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http://dx.doi.org/10.1016/j.yebeh.2015.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475437PMC
June 2015

De novo mutations in SIK1 cause a spectrum of developmental epilepsies.

Am J Hum Genet 2015 Apr;96(4):682-90

Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA; Departments of Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address:

Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy.
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http://dx.doi.org/10.1016/j.ajhg.2015.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385182PMC
April 2015

Characteristic Features of the Interictal EEG Background in 2 Patients With Malignant Migrating Partial Epilepsy in Infancy.

J Clin Neurophysiol 2015 Aug;32(4):e23-9

*Department of Neurology, University of Rochester Medical Center, Rochester, New York, U.S.A.; †Strong Epilepsy Center, University of Rochester Medical Center, Rochester, New York, U.S.A.; and ‡Departments of Pediatrics and Biomedical Genetics, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A.

Purpose: To describe chronological electrographic features of the interictal EEG background observed in two patients with malignant migrating partial epilepsy in infancy from neonatal to early infantile period.

Methods: EEGs of two patients who fulfilled diagnostic criteria for malignant migrating partial epilepsy in infancy were acquired over the period of 6 months to monitor treatment efficacy and characterize seizures and other paroxysmal events.

Results: Both patients followed a similar sequential pattern. A distinctive evolution from a dysmature term neonatal EEG pattern to an asynchronous suppression burst pattern was observed before the interictal background becoming continuous.

Conclusions: Physicians providing care to infants with intractable epilepsy and burst suppression EEG pattern should be alert to the possibility of malignant migrating partial epilepsy in infancy. An earlier diagnosis of malignant migrating partial epilepsy in infancy would help to guide diagnostic workup including genetic testing.
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http://dx.doi.org/10.1097/WNP.0000000000000178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527937PMC
August 2015

Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly.

Epilepsia 2015 Mar 5;56(3):422-30. Epub 2015 Feb 5.

Departments of Neurology, Pediatrics, and Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, U.S.A; Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A.

Objective: Mutations of ATP1A3 have been associated with rapid onset dystonia-parkinsonism and more recently with alternating hemiplegia of childhood. Here we report one child with catastrophic early life epilepsy and shortened survival, and another with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental disability. Novel heterozygous mutations (p.Gly358Val and p.Ile363Asn) were identified in ATP1A3 in these children.

Methods: Subjects underwent next-generation sequencing under a research protocol. Clinical data were collected retrospectively. The biochemical effects of the mutations on ATP1A3 protein function were investigated. Postmortem neuropathologic specimens from control and affected subjects were studied.

Results: The mutations localized to the P domain of the Na,K-ATPase α3 protein, and resulted in significant reduction of Na,K-ATPase activity in vitro. We demonstrate in both control human brain tissue and that from the subject with the p.Gly358Val mutation that ATP1A3 immunofluorescence is prominently associated with interneurons in the cortex, which may provide some insight into the pathogenesis of the disease.

Significance: The findings indicate these mutations cause severe phenotypes of ATP1A3-related disorder spectrum that include catastrophic early life epilepsy, episodic apnea, and postnatal microcephaly.
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http://dx.doi.org/10.1111/epi.12914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363281PMC
March 2015

An integrative computational approach for prioritization of genomic variants.

PLoS One 2014 15;9(12):e114903. Epub 2014 Dec 15.

Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Computation Institute, University of Chicago/Argonne National Laboratory, Chicago, Illinois, United States of America.

An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidate genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. The study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114903PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266634PMC
November 2015

Comparison of insertion/deletion calling algorithms on human next-generation sequencing data.

BMC Res Notes 2014 Dec 1;7:864. Epub 2014 Dec 1.

Center for Neural Development and Disease, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, USA.

Background: Insertions/deletions (indels) are the second most common type of genomic variant and the most common type of structural variant. Identification of indels in next generation sequencing data is a challenge, and algorithms commonly used for indel detection have not been compared on a research cohort of human subject genomic data. Guidelines for the optimal detection of biologically significant indels are limited. We analyzed three sets of human next generation sequencing data (48 samples of a 200 gene target exon sequencing, 45 samples of whole exome sequencing, and 2 samples of whole genome sequencing) using three algorithms for indel detection (Pindel, Genome Analysis Tool Kit's UnifiedGenotyper and HaplotypeCaller).

Results: We observed variation in indel calls across the three algorithms. The intersection of the three tools comprised only 5.70% of targeted exon, 19.52% of whole exome, and 14.25% of whole genome indel calls. The majority of the discordant indels were of lower read depth and likely to be false positives. When software parameters were kept consistent across the three targets, HaplotypeCaller produced the most reliable results. Pindel results did not validate well without adjustments to parameters to account for varied read depth and number of samples per run. Adjustments to Pindel's M (minimum support for event) parameter improved both concordance and validation rates. Pindel was able to identify large deletions that surpassed the length capabilities of the GATK algorithms.

Conclusions: Despite the observed variability in indel identification, we discerned strengths among the individual algorithms on specific data sets. This allowed us to suggest best practices for indel calling. Pindel's low validation rate of indel calls made in targeted exon sequencing suggests that HaplotypeCaller is better suited for short indels and multi-sample runs in targets with very high read depth. Pindel allows for optimization of minimum support for events and is best used for detection of larger indels at lower read depths.
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http://dx.doi.org/10.1186/1756-0500-7-864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265454PMC
December 2014

Introduction: Brain malformations.

Am J Med Genet C Semin Med Genet 2014 Jun 22;166C(2):117-23. Epub 2014 May 22.

This issue of the American Journal of Medical Genetics Seminar Series Part C is dedicated to congenital brain malformations with a special focus on the molecular mechanisms underlying this fascinating, and often complex, group of developmental brain disorders. As with most genetic disorders, the past few years have witnessed a dramatic leap in our understanding of the molecular basis of these malformations that include both constitutional and post-zygotic (or mosaic) genetic aberrations. This is best exemplified by the recent identification of mutations within components of the PI3K-AKT-mTOR pathway in hemimegalencephaly and megalencephaly syndromes, and the rapidly increased identification of mutations within the tubulin family in a broad range of cortical and non-cortical brain malformations. These discoveries, particularly of the emerging "tubulinopathies" spectrum, have not only expanded our knowledge of these disorders but challenge our existing, and perhaps overly simplistic, classification of these malformations based on the primary neuronal stage at which the abnormality occurs. It is our hope that this series will facilitate a deeper understanding of these malformations beyond their clinical and neuroimaging features and syndromic associations to their molecular and pathway underpinnings. We believe this knowledge will most certainly be instrumental as we move into the era of delineating genotype-phenotype correlations and, ultimately, pathway-based therapies.
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http://dx.doi.org/10.1002/ajmg.c.31404DOI Listing
June 2014

Genetic disorders associated with postnatal microcephaly.

Am J Med Genet C Semin Med Genet 2014 Jun 16;166C(2):140-55. Epub 2014 May 16.

Several genetic disorders are characterized by normal head size at birth, followed by deceleration in head growth resulting in postnatal microcephaly. Among these are classic disorders such as Angelman syndrome and MECP2-related disorder (formerly Rett syndrome), as well as more recently described clinical entities associated with mutations in CASK, CDKL5, CREBBP, and EP300 (Rubinstein-Taybi syndrome), FOXG1, SLC9A6 (Christianson syndrome), and TCF4 (Pitt-Hopkins syndrome). These disorders can be identified clinically by phenotyping across multiple neurodevelopmental and neurobehavioral realms, and enough data are available to recognize these postnatal microcephaly disorders as separate diagnostic entities in their own right. A second diagnostic grouping, comprised of Warburg MICRO syndrome, Cockayne syndrome, and Cerebral-oculo-facial skeletal syndrome, share similar features of somatic growth failure, ophthalmologic, and dysmorphologic features. Many postnatal microcephaly syndromes are caused by mutations in genes important in the regulation of gene expression in the developing forebrain and hindbrain, although important synaptic structural genes also play a role. This is an emerging group of disorders with a fascinating combination of brain malformations, specific epilepsies, movement disorders, and other complex neurobehavioral abnormalities.
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http://dx.doi.org/10.1002/ajmg.c.31400DOI Listing
June 2014

Epilepsy and outcome in FOXG1-related disorders.

Epilepsia 2014 Aug 16;55(8):1292-300. Epub 2014 May 16.

Department of Neurology, University of Rochester Medical Center, Rochester, New York, U.S.A.

Objective: FOXG1-related disorders are associated with severe intellectual disability, absent speech with autistic features, and epilepsy. Children with deletions or intragenic mutations of FOXG1 also have postnatal microcephaly, morphologic abnormalities of the corpus callosum, and choreiform movements. Duplications of 14q12 often present with infantile spasms, and have subsequent intellectual disability with autistic features. Long-term epilepsy outcome and response to treatment have not been studied systematically in a well-described cohort of subjects with FOXG1-related disorders. We report on the epilepsy features and developmental outcome of 23 new subjects with deletions or intragenic mutations of FOXG1, and 7 subjects with duplications.

Methods: Subjects had either chromosomal microarray or FOXG1 gene sequencing performed as part of routine clinical care. Development and epilepsy follow-up data were collected from medical records from treating neurologists and through telephone parental interviews using standardized questionnaires.

Results: Epilepsy was diagnosed in 87% of the subjects with FOXG1-related disorders. The mean age of epilepsy diagnosis in FOXG1 duplications was significantly younger than those with deletions/intragenic mutations (p = 0.0002). All of the duplication FOXG1 children with infantile spasms responded to hormonal therapy, and only one required long-term antiepileptic therapy. In contrast, more children with deletions/intragenic mutations required antiepileptic drugs on follow-up (p < 0.0005). All subjects with FOXG1-related disorders had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or intractability of seizures. All had impaired verbal language and social contact, and three duplication subjects were formally diagnosed with autism. Subjects with deletion/intragenic mutations, however, had significantly worse ambulation (p = 0.04) and functional hand use (p < 0.0005).

Significance: Epilepsy and developmental outcome characteristics allow clinicians to distinguish among the FOXG1-related disorders. Further genotype-phenotype studies of FOXG1 may help to elucidate why children develop different forms of developmental epilepsy.
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http://dx.doi.org/10.1111/epi.12648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265461PMC
August 2014

Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism.

Hum Genet 2014 Aug 20;133(8):1023-39. Epub 2014 Apr 20.

Division of Genetic Medicine, Department of Pediatrics, Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.

Defects in centrosome, centrosomal-associated and spindle-associated proteins are the most frequent cause of primary microcephaly (PM) and microcephalic primordial dwarfism (MPD) syndromes in humans. Mitotic progression and segregation defects, microtubule spindle abnormalities and impaired DNA damage-induced G2-M cell cycle checkpoint proficiency have been documented in cell lines from these patients. This suggests that impaired mitotic entry, progression and exit strongly contribute to PM and MPD. Considering the vast protein networks involved in coordinating this cell cycle stage, the list of potential target genes that could underlie novel developmental disorders is large. One such complex network, with a direct microtubule-mediated physical connection to the centrosome, is the kinetochore. This centromeric-associated structure nucleates microtubule attachments onto mitotic chromosomes. Here, we described novel compound heterozygous variants in CENPE in two siblings who exhibit a profound MPD associated with developmental delay, simplified gyri and other isolated abnormalities. CENPE encodes centromere-associated protein E (CENP-E), a core kinetochore component functioning to mediate chromosome congression initially of misaligned chromosomes and in subsequent spindle microtubule capture during mitosis. Firstly, we present a comprehensive clinical description of these patients. Then, using patient cells we document abnormalities in spindle microtubule organization, mitotic progression and segregation, before modeling the cellular pathogenicity of these variants in an independent cell system. Our cellular analysis shows that a pathogenic defect in CENP-E, a kinetochore-core protein, largely phenocopies PCNT-mutated microcephalic osteodysplastic primordial dwarfism-type II patient cells. PCNT encodes a centrosome-associated protein. These results highlight a common underlying pathomechanism. Our findings provide the first evidence for a kinetochore-based route to MPD in humans.
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http://dx.doi.org/10.1007/s00439-014-1443-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415612PMC
August 2014

De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy.

Am J Hum Genet 2014 Apr;94(4):634-41

Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, WA 98101, USA; Departments of Pediatrics and Neurology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Tubulins, and microtubule polymers into which they incorporate, play critical mechanical roles in neuronal function during cell proliferation, neuronal migration, and postmigrational development: the three major overlapping events of mammalian cerebral cortex development. A number of neuronally expressed tubulin genes are associated with a spectrum of disorders affecting cerebral cortex formation. Such "tubulinopathies" include lissencephaly/pachygyria, polymicrogyria-like malformations, and simplified gyral patterns, in addition to characteristic extracortical features, such as corpus callosal, basal ganglia, and cerebellar abnormalities. Epilepsy is a common finding in these related disorders. Here we describe two unrelated individuals with infantile-onset epilepsy and abnormalities of brain morphology, harboring de novo variants that affect adjacent amino acids in a beta-tubulin gene TUBB2A. Located in a highly conserved loop, we demonstrate impaired tubulin and microtubule function resulting from each variant in vitro and by using in silico predictive modeling. We propose that the affected functional loop directly associates with the alpha-tubulin-bound guanosine triphosphate (GTP) molecule, impairing the intradimer interface and correct formation of the alpha/beta-tubulin heterodimer. This study associates mutations in TUBB2A with the spectrum of "tubulinopathy" phenotypes. As a consequence, genetic variations affecting all beta-tubulin genes expressed at high levels in the brain (TUBB2B, TUBB3, TUBB, TUBB4A, and TUBB2A) have been linked with malformations of cortical development.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980418PMC
April 2014