Publications by authors named "Constance Smith-Hicks"

24 Publications

  • Page 1 of 1

De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.

Am J Hum Genet 2021 01;108(1):186-193

Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada. Electronic address:

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820722PMC
January 2021

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

Genet Med 2021 Feb 27;23(2):352-362. Epub 2020 Oct 27.

All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK.

Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit.

Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.

Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly.

Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.
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http://dx.doi.org/10.1038/s41436-020-00981-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862067PMC
February 2021

Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder.

Clin Genet 2020 12 12;98(6):571-576. Epub 2020 Oct 12.

Children's Hospital of Philadelphia, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder.
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http://dx.doi.org/10.1111/cge.13851DOI Listing
December 2020

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

New York State Institute for Basic Research in Developmental Disability, NY, Staten Island, USA.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic.

Int J Mol Sci 2019 Oct 15;20(20). Epub 2019 Oct 15.

The Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.

Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies.
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http://dx.doi.org/10.3390/ijms20205098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834180PMC
October 2019

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.

Am J Hum Genet 2019 09 8;105(3):640-657. Epub 2019 Aug 8.

Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731360PMC
September 2019

Caregivers' perception of and experience with variants of uncertain significance from whole exome sequencing for children with undiagnosed conditions.

J Genet Couns 2019 04 24;28(2):304-312. Epub 2019 Jan 24.

Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland.

Despite its promising diagnostic yield, whole exome sequencing (WES) frequently introduces variant(s) of uncertain significance (VUS), which have been speculated to cause parental stress and anxiety. This study aimed to explore the psychosocial impact of receiving a VUS from pediatric WES on caregivers and to identify implications for clinical practice. Fourteen telephone interviews were conducted with parents or legal guardians who received VUS results from their child's WES to assess their understanding of the result, affective responses, perceived impact, and adaptation. Our content analysis showed that most participants had a good understanding of the purpose of the test and the majority of them recalled the result category. Most participants deemed the result had no impact thus far on their perception of their child's condition. However, one participant reported feelings of fear related to the VUS. Most participants experienced a range of emotions from receiving the result. The majority of participants reported that this result did not significantly alter their child's care or their ability to take care of their child, and three participants reported empowerment. Additionally, several participants expressed an interest in research studies and peer support groups dedicated to families with a VUS identified on WES. Our study elicited new information about the psychosocial impact of receiving a VUS from WES. This insight may help to guide pre- and post-WES counseling in the future.
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http://dx.doi.org/10.1002/jgc4.1093DOI Listing
April 2019

De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies.

Am J Hum Genet 2019 02 3;104(2):203-212. Epub 2019 Jan 3.

Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden 01307, Germany.

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369540PMC
February 2019

Neurologic phenotypes associated with / mutations: Expanding the spectrum of disease.

Neurology 2018 11 9;91(22):e2078-e2088. Epub 2018 Nov 9.

From the Department of Clinical and Experimental Epilepsy (S.Z., Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.) and Division of Neuropathology (Z.M., M.T.), UCL Institute of Neurology, London, UK; Clinic of Neurology (S.Z.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy; Department of Pediatric Neurology and Neurological Rehabilitation (C.S., T.H., P.W., G.J.K.) and Neurosurgery Clinic and Clinic for Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth; Department of Pediatrics (C.S., M.S.), Children's Hospital Augsburg, Germany; UCL Great Ormond Street Institute of Child Health (J.R.N., K.V., S.M.V., J.H.C.), London, UK; Paediatric Neurology and Neurogenetics Unit and Laboratories (D.M., R.G.), A. Meyer Children's Hospital, University of Florence, Italy; Chalfont Centre for Epilepsy (Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.), Chalfont-St-Peter, Buckinghamshire, UK; CeGaT-Center for Genomics and Transcriptomics (A.P., S. Biskup), Tübingen, Germany; Neurogenetics Unit (M.L.), Department of Medical Genetics, Hospital de São João, Porto, Portugal; Department of Pediatrics and Adolescent Medicine (J.G.), University Medical Center Göttingen; Hospital for Children and Adolescents (A.M.), University Clinic Leipzig, Germany; Freiburg Medical Laboratory (M.J.), Dubai; The Danish Epilepsy Centre (R.S.M., E.G.), Dianalund; Institute for Regional Health Services (R.S.M., E.G.), University of Southern Denmark, Odense; Department of Clinical Genetics (B.S.K.), Odense University Hospital; Hans Christian Andersen Children's Hospital (L.K.H.), Odense, Denmark; Pediatric Neurology and Muscular Diseases Unit (M.S.V., P.S.), Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa "G. Gaslini" Institute, Italy; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Department of Neurology (S.D., C.L.S.-H.), Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD; Center for Genomic Medicine (N.H.-F.), Tohoku University; Department of Pediatrics (N.H.-F.), Tohoku University School of Medicine, Sendai, Japan; Department of Pediatrics (T.T., R.L.) and Institute of Clinical Medicine (K.O.), University of Tartu; Children's Clinic (T.T., R.L.), Department of Radiology (P.I.), and Department of Clinical Genetics, United Laboratories (K.O.), Tartu University Hospital, Estonia; Ludwig-Maximilians-University Munich (I.K.); Department of Pediatric Neurology (A.H.), Clinic Traunstein; Children's Hospital (M.K.), Dr. Horst Schmidt Klinik, Wiesbaden; Altona Children's Hospital (J.H.), Hamburg; Department of Pediatrics (C. Makowski), Technische Universität München, Germany; Department of Clinical Genetics (S.G.), Royal North Shore Hospital, St Leonards; John Hunter Children's Hospital (G.M.S.), New Lambton Heights, New South Wales, Australia; Department of Neurology (R.T.), University Hospital of Wales; Institute of Psychological Medicine and Clinical Neurosciences (R.H.T.), Cardiff University; Division of Neuroradiology (C. Micallef), National Hospital for Neurology and Neurosurgery, London; Department of Brain Repair & Rehabilitation (D.J.W.), Stroke Research Centre, UCL Institute of Neurology, London, UK; Paracelsus Medical University (G.J.K.), Salzburg, Austria; and IRCCS Stella Maris Foundation (R.G.), Pisa, Italy.

Objective: To characterize the neurologic phenotypes associated with mutations and to seek genotype-phenotype correlation.

Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with mutations.

Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across and a clear genotype-phenotype correlation did not emerge.

Conclusion: mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.
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http://dx.doi.org/10.1212/WNL.0000000000006567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239PMC
November 2018

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

Am J Hum Genet 2018 11;103(5):752-768

Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA.

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218805PMC
November 2018

De Novo HECW2 Mutation Associated With Epilepsy, Developmental Decline, and Intellectual Disability: Case Report and Review of Literature.

Pediatr Neurol 2018 08 4;85:76-78. Epub 2018 Apr 4.

Division of Pediatric Neurology, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2018.03.005DOI Listing
August 2018

A PIGH mutation leading to GPI deficiency is associated with developmental delay and autism.

Hum Mutat 2018 06 26;39(6):827-829. Epub 2018 Apr 26.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.

We identified an individual with a homozygous missense variant (p.Ser103Pro) in a conserved residue of the glycosylphosphatidylinositol (GPI) biosynthesis gene PIGH. This gene encodes an essential component of the phosphatidylinositol N-acetylglucosaminyltransferase complex, in the first step of the biosynthesis of GPI, a glycolipid anchor added to more than one hundred human proteins, several being critical for embryogenesis and neurological functions. The affected individual had hypotonia, moderate developmental delay, and autism. Unlike other reported individuals with GPI deficiency, the proband did not have epilepsy; however, he did have two episodes of febrile seizures. He had normal alkaline phosphatase and no brachytelephalangy. Upon analysis of the surface expression of GPI-anchored proteins on granulocytes, he was demonstrated to have GPI deficiency. This suggests that PIGH mutations may cause a syndrome with developmental delay and autism, but without an epileptic encephalopathy, and should increase the awareness of the potentially deleterious nature of biallelic variants in this gene.
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http://dx.doi.org/10.1002/humu.23426DOI Listing
June 2018

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

Am J Med Genet A 2018 04 13;176(4):925-935. Epub 2018 Feb 13.

Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, Maine.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.
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http://dx.doi.org/10.1002/ajmg.a.38630DOI Listing
April 2018

Monogenic disorders that mimic the phenotype of Rett syndrome.

Neurogenetics 2018 01 10;19(1):41-47. Epub 2018 Jan 10.

Hugo W. Moser Research Institute at Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD, 21205, USA.

Rett syndrome (RTT) is caused by mutations in methyl-CpG-binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. We performed a retrospective chart review on n = 319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment, (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results, and (3) ultimately arrived at a diagnosis other than RTT with WES. n = 7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These seven patients collectively possessed pathogenic variants in six different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n = 2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT-associated features included the following: loss of hand or language skills (n = 3; IQSEC2, KCNB1 x 2); disrupted sleep (n = 4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n = 5; FOXG1, KNCB1 x 2, MEIS2, TCF4); bruxism (n = 3; KCNB1 x 2; TCF4); and hypotonia (n = 7). Clinically based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.
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http://dx.doi.org/10.1007/s10048-017-0535-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156085PMC
January 2018

Randomized open-label trial of dextromethorphan in Rett syndrome.

Neurology 2017 Oct 20;89(16):1684-1690. Epub 2017 Sep 20.

From the Departments of Neurology (C.L.S.-H., S.G., J.B.E., M.V.J., S.N.), Psychological and Brain Science (J.B.E.), Pediatrics (L.K., R.K.), Psychiatry (E.T.), and Psychology (R.V.), and the Neurogenetics Department (G.B.), Kennedy Krieger Institute, Johns Hopkins University School of Medicine (N.B.); Investigational Drug Service, Department of Pharmacy (M.H.), Johns Hopkins Hospital; and Johns Hopkins Bloomberg School of Public Health (A.S., G.Y.), Johns Hopkins Biostatistics Center, Baltimore, MD.

Objective: To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome.

Methods: We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist-Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity.

Results: Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale.

Conclusions: Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome.

Classification Of Evidence: This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.
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http://dx.doi.org/10.1212/WNL.0000000000004515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644464PMC
October 2017

Evaluation of QTc in Rett syndrome: Correlation with age, severity, and genotype.

Am J Med Genet A 2017 Jun 10;173(6):1495-1501. Epub 2017 Apr 10.

Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.

Rett syndrome (RTT) is caused by MECP2 mutations, resulting in various neurological symptoms. Prolonged corrected QT interval (QTc) is also reported and is a speculated cause of sudden death in RTT. The purpose of this study was to correlate QTc in RTT patients with age, clinical severity, and genotype. 100 RTT patients (98 females, 2 males) with MECP2 mutations underwent baseline neurological evaluation (KKI-RTT Severity Scale) and QTc measurement (standard 12 lead electrocardiogram) as part of our prospective natural history study. Mean QTc of the cohort was 422.6 msec, which did not exceed the normal values for age. 7/100 patients (7%) had QTc prolongation (>450 msec). There was a trend for increasing QTc with age and clinical severity (P = 0.09). No patients with R106C, R106W, R133C, R168*, R270*, R294*, R306C, R306H, and R306P mutations demonstrated QTc prolongation. There was a relatively high proportion of QTc prolongation in patients with R255* mutations (2/8, 25%) and large deletions (1/4, 25%). The overall presence of QTc prolongation did not correlate with mutation category (P = 0.52). Our findings demonstrate that in RTT, the prevalence of QTc prolongation is lower than previously reported. Hence, all RTT patients warrant baseline ECG; if QTc is prolonged, then cardiac followup is warranted. If initial QTc is normal, then annual ECGs, particularly in younger patients, may not be necessary. However, larger sample sizes are needed to solidify the association between QTc and age and clinical severity. The biological and clinical significance of mild QTc prolongation above the normative data remains undetermined.
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http://dx.doi.org/10.1002/ajmg.a.38191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444992PMC
June 2017

Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome Assayed by Arc Expression.

Front Neural Circuits 2017 3;11. Epub 2017 Feb 3.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineBaltimore, MD, USA; Department of Neurology, Johns Hopkins University School of MedicineBaltimore, MD, USA.

Down syndrome (DS) is the leading chromosomal cause of intellectual disability, yet the neural substrates of learning and memory deficits remain poorly understood. Here, we interrogate neural networks linked to learning and memory in a well-characterized model of DS, the Ts65Dn mouse. We report that Ts65Dn mice exhibit exploratory behavior that is not different from littermate wild-type (WT) controls yet behavioral activation of Arc mRNA transcription in pyramidal neurons of the CA1 region of the hippocampus is altered in Ts65Dn mice. In WT mice, a 5 min period of exploration of a novel environment resulted in Arc mRNA transcription in 39% of CA1 neurons. By contrast, the same period of exploration resulted in only ~20% of CA1 neurons transcribing Arc mRNA in Ts65Dn mice indicating increased sparsity of the behaviorally induced ensemble. Like WT mice the CA1 pyramidal neurons of Ts65Dn mice reactivated Arc transcription during a second exposure to the same environment 20 min after the first experience, but the size of the reactivated ensemble was only ~60% of that in WT mice. After repeated daily exposures there was a further decline in the size of the reactivated ensemble in Ts65Dn and a disruption of reactivation. Together these data demonstrate reduction in the size of the behaviorally induced network that expresses Arc in Ts65Dn mice and disruption of the long-term stability of the ensemble. We propose that these deficits in network formation and stability contribute to cognitive symptoms in DS.
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http://dx.doi.org/10.3389/fncir.2017.00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289947PMC
October 2017

Neuroimaging Abnormalities in a Child With Infantile Spasms on High-Dose Vigabatrin.

Pediatr Neurol 2017 Feb 13;67:109-110. Epub 2016 Oct 13.

Division of Pediatric Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland.

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http://dx.doi.org/10.1016/j.pediatrneurol.2016.10.004DOI Listing
February 2017

GABAergic dysfunction in pediatric neuro-developmental disorders.

Front Cell Neurosci 2013 Dec 19;7:269. Epub 2013 Dec 19.

Neurology, Kennedy Krieger Institute Baltimore, MD, USA ; Neurology, Johns Hopkins School of Medicine Baltimore, MD, USA.

The GABAergic system is central to the development and functional maturation of the nervous system. Emerging evidence support the role of GABAergic dysfunction in neuro-developmental disorders. This review presents the molecules and mechanisms that underlie GABA system dysfunction in several neuro-developmental disorders presenting in childhood. The impact on synaptic plasticity, neuronal circuit function and behavior, followed by targeted treatment strategies are discussed.
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http://dx.doi.org/10.3389/fncel.2013.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867664PMC
December 2013

Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks.

Neuron 2011 Feb;69(3):437-44

Institute for Cell Engineering, Neuroregeneration Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Thus, Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation.
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http://dx.doi.org/10.1016/j.neuron.2011.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056341PMC
February 2011

SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells.

Nat Neurosci 2010 Sep 8;13(9):1082-9. Epub 2010 Aug 8.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc-/- cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc-/-, SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.
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http://dx.doi.org/10.1038/nn.2611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003596PMC
September 2010

Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD.

Neuron 2008 Jul;59(1):70-83

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 20205, USA.

Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca(2+)/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.
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http://dx.doi.org/10.1016/j.neuron.2008.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743934PMC
July 2008

A double blind randomized placebo control trial of levetiracetam in Tourette syndrome.

Mov Disord 2007 Sep;22(12):1764-70

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

The objective of this study was to investigate the effectiveness of levetiracetam for the treatment of tics in children with Tourette syndrome (TS). Levetiracetam, an atypical anticonvulsant, has been suggested in open-label protocols to be an effective tic-suppressing agent in individuals with TS. A double blind, randomized, placebo-controlled, cross-over trial was performed to investigate this medication in children with moderate to moderately-severe tics. Subjects received, in a randomized sequence, 4-weeks of levetiracetam (maximum dose 30 mg/kg/day) or placebo, with a 2-week intervening washout period between cycles. Primary outcome measures included two separate scales from the Yale Global Tic Severity Scale; the Total Tic score and the Total overall score. Measures were assessed at baseline, prior to randomization, on Day 28 (end of Phase 1), on Day 42 (baseline for second phase) and on Day 70 (end of Phase 2). Twenty-two subjects (21 boys and 1 girl) with TS, mean age 12.2 +/- 2.3 years, range 8 to 16 years, participated. A mild reduction in tics occurred during both the levetiracetam and placebo treatment phases. There was no significant difference between treatments and no evidence of sequence or cross-over effects. In conclusion, Levetiracetam is not more beneficial than placebo in suppressing tics in children with TS.
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http://dx.doi.org/10.1002/mds.21615DOI Listing
September 2007

Case 9: pregnant? Who's pregnant? Memory loss in a young woman.

MedGenMed 2005 May 26;7(2):59. Epub 2005 May 26.

Department of Pediatric Neurology, Johns Hopkins Hospital, Baltimore, Maryland, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1681593PMC
May 2005