Background: Tubulin mutations are a cause of neuronal migrational disorders referred to as tubuli... more Background: Tubulin mutations are a cause of neuronal migrational disorders referred to as tubulinopathies. Mutations in tubulin genes can have a severe impact on microtubule function and result in heterogeneous clinical presentations. Current understanding of the clinical spectrum of tubulinopathies is predominantly based on research in fetal tissue and earlychildhood cases. Methods: Testing of candidate genes followed by whole-exome sequencing was performed in an adult woman with a neurodevelopmental, hyperkinetic movement disorder, to identify the underlying genetic cause. Bioinformatic modeling and a systematic review of literature was conducted to investigate genotype-phenotype correlations. Results: The patient was found to carry a heterozygous, de novo c.722G>A, p.R241H mutation in a conserved domain of TUBB2B, encoding the β-isoform of tubulin. In silico analysis indicated that this mutation was pathogenic. On neuroimaging, the patient had asymmetric pachygyria and dysmorphic basal ganglia. Her neurological examination demonstrated mild cognitive impairment, myoclonus-dystonia, and skeletal anomalies. Conclusions: Here, we report the unique phenotype of an adult TUBB2B mutation carrier. This case illustrates a relatively mild phenotype compared to previously described fetal and early childhood cases. This highlights
Introduction-Complex motor stereotypies in children are repetitive, rhythmic movements that have ... more Introduction-Complex motor stereotypies in children are repetitive, rhythmic movements that have a predictable pattern and location, seem purposeful, but serve no obvious function, tend to be prolonged, and stop with distraction, e.g., arm/hand flapping, waving. They occur in both "primary" (otherwise typically developing) and secondary conditions. These movements are best defined as habitual behaviors and therefore pathophysiologically hypothesized to reside in premotor to posterior putamen circuits. This study sought to clarify the underlying neurobiological abnormality in children with primary complex motor stereotypies using structural neuroimaging, emphasizing brain regions hypothesized to underlie these atypical behaviors. Methods-High-resolution anatomical MRI images, acquired at 3.0T, were analyzed in children ages 8-12 years (20 with primary complex motor stereotypies, 20 typically developing). Frontal lobe sub-regions and striatal structures were delineated for analysis. Results-Significant reductions (p=0.045) in the stereotypies group were identified in total putamen volume, but not caudate, nucleus accumbens or frontal sub-regions. There were no group differences in total cerebral volume.
Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thi... more Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thirteen children with high grade astrocytomas. These included four of seven children with hemispheral tumors and two of six children with malignant brainstem gliomas. Leptomeningeal spread was diagnosed by the clinical picture and CSF profile. Meningeal spread occurred an average of 5 months (range 0-16) after initial diagnosis of tumor was made. Several patients responded well to local radiation and/or chemotherapy. Mean survival after evidence of meningeal spread was 7 months (range 2 16) with one patient still alive. Meningeal spread of malignant childhood astrocytomas appears to be common and should be sought for in these patients as local radiation is beneficial. Serious consideration should be given to a controlled trial of prophylactic craniospinal radiation in thee tumors. The role of chemotherapy also requires further study.
In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12... more In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12 week randomised (allocation concealed*), blinded (unclear)*, controlled trial. 12 neurological and psychiatric outpatient clinics in Belgium, the Netherlands, and South Africa.
Background: The COVID-19 pandemic uniquely affects patients with neurologic and developmental dis... more Background: The COVID-19 pandemic uniquely affects patients with neurologic and developmental disabilities at the Kennedy Krieger Institute. These patients are at increased risk of co-morbidities, increasing their risk of contracting COVID-19. Disruptions in their home and school routines, and restrictions accessing crucial healthcare services has had a significant impact. Methods: A Pandemic Intake questionnaire regarding COVID-19 related medical concerns of guardians of patients was distributed using Qualtrics. Data from May-December 2020 were merged with demographic information of patients from 10 clinics (Center for Autism and Related Disorders (CARD), Neurology, Epigenetics, Neurogenetics, Center for Development and TYPE
Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving m... more Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesio...
Pathogenic variants in EEF1A2, a gene encoding a eukaryotic translation elongation factor, have b... more Pathogenic variants in EEF1A2, a gene encoding a eukaryotic translation elongation factor, have been previously reported in pediatric cases of epileptic encephalopathy and intellectual disability. We report a case of a 17-year-old male with a prior history of epilepsy, autism, intellectual disability, and the abrupt onset of choreo-athetotic movements. The patient was diagnosed with an EEF1A2 variant by whole exome sequencing. His movement disorder responded dramatically to treatment with tetrabenazine. To the best of our knowledge, this is the first report of successful treatment of a hyperkinetic movement disorder in the setting of EEF1A2 mutation. A trial with tetrabenazine should be considered in cases with significant choreoathetosis.
BACKGROUND: Complex motor stereotypies (CMS) typically begin before age three years and include r... more BACKGROUND: Complex motor stereotypies (CMS) typically begin before age three years and include rhythmic, repetitive, fixed movements that last for seconds to minutes and can be interrupted with distraction. OBJECTIVE: We evaluated the effectiveness of a home-based, parent-provided therapy accompanied by scheduled telephone calls with a therapist, in fiveto seven-year old children with primary CMS. METHODS: Eligible families received an instructional digital versatile disk (DVD) written instructions, and scheduled telephone contacts with a therapist at baseline (DVD receipt), one, three, and eight weeks later. At each call, parents completed outcome measures and received feedback. Outcome scales Stereotypy Severity Scale (SSS) Motor and Impairment scales and a Stereotypy Linear Analogue Scale (SLAS) were also completed via the Iinternet (REDCap)-at screening, one and two months post-baseline call. At study conclusion, participants were divided into an intent-to-treat (ITT; had at least one call) or a lost-to-follow-up (LTF) group. RESULTS: Thirty-eight children (mean = 5 years § 11 months) were enrolled. The LTF group (n = 14) had significantly higher scores than the ITT (n = 24) group on all attention-deficit/hyperactivity disorder ratings (P < 0.01), but not stereotypy severity. Primary outcome scores, acquired by telephone and REDCap, showed a significant reduction in SSS Motor and Impairment scores between the initial and the last completed evaluation (P 0.001). Calculated change ratios were SSS Motor ¡0.23/¡0.30 (cal/REDCap); SSS Impairment ¡0.31/¡0.32; and SLAS ¡0.54 (REDCap). Clinical improvement was further supported by results from a parent improvement scale and end of study questionnaires. CONCLUSIONS: Home-based, parent-administered behavioral therapy supplemented by telephone contact with a therapist is effective in reducing complex motor stereotypies in children.
Developmental Medicine & Child Neurology, 2016
AimPrimary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movem... more AimPrimary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movements in young people with typical development. This study evaluated the efficacy of an instructional DVD as a home‐based, parent‐administered, behavioral therapy for primary CMS.MethodEighty‐one children with primary CMS were enrolled. Primary outcome measures included the Stereotypy Severity Scale (SSS) – Motor and Impairment scores, and Stereotypy Linear Analog Scale (SLAS). Mean CMS onset was 13.4 months (SD 13.1). Eligibility required observed CMS. Psychiatric disorders were not exclusionary and a stable medication regimen was required. Intellectual disability, neurological disorder, autism spectrum disorder, and tics were exclusionary. Initial assessments were completed via REDCap before receipt of the DVD. Fifty‐four of the 81 children (34 male, 20 female; mean age 8y 2mo, SD 1.42, range 7–14y) completed assessments at 1, 2, or 3 months after receiving the DVD.ResultsReductions (ba...
AJNR. American journal of neuroradiology, Jan 5, 2015
Complex motor stereotypies are rhythmic, repetitive, fixed, purposeful but purposeless movements ... more Complex motor stereotypies are rhythmic, repetitive, fixed, purposeful but purposeless movements that stop with distraction. They can occur in otherwise normal healthy children (primary stereotypies) as well in those with autism spectrum disorders (secondary stereotypies). The underlying neurobiologic basis for these movements is unknown but is thought to involve cortical-striatal-thalamo-cortical pathways. To further clarify potential neurochemical alterations, gamma-aminobutyric acid (GABA), glutamate, glutamine, N-acetylaspartate, and choline levels were measured in 4 frontostriatal regions by using (1)H MRS at 7T. A total of 18 children with primary complex motor stereotypies and 24 typically developing controls, ages 5-10 years, completed MR spectroscopy at 7T. Single voxel STEAM acquisitions from the anterior cingulate cortex, premotor cortex, dorsolateral prefrontal cortex, and striatum were obtained, and metabolites were quantified with respect to Cr by using LCModel. The 7T...
Auto antibodies found in the mothers of children with autistic disorder (MCAD) when passively tra... more Auto antibodies found in the mothers of children with autistic disorder (MCAD) when passively transferred to pregnant mice cause behavioral alterations in juvenile and adult offspring. The goal of this study was to identify whether intraperitoneal injection of MCAD-IgG during gestation affected postnatal cell proliferation and survival in P7 offspring. Pooled MCAD-IgG or IgG from mothers of unaffected children (MUC) or phosphate-buffered saline was injected daily into C57BL/J6 pregnant dams (gestational days E13-E18). MCAD-IgG exposure significantly increased cell proliferation in the subventricular and subgranular zones. In contrast, BrdU-labeled cells on P1 and surviving until P7 (P1-generated cells) showed reduced cell densities in layers 2-4 of frontal and parietal cortices of MCAD mice compared to those in MUC and PBS-injected mice. In conclusion, significant increases in cell proliferation at P7 and reduced densities of P1-generated cells distinguish in utero exposure to MCAD ...
From the Departmentaof Ophthalmology (MI. Lasker), Neurology (DIE. Zee. Hain, and Singer), and Ps... more From the Departmentaof Ophthalmology (MI. Lasker), Neurology (DIE. Zee. Hain, and Singer), and Psychiatry (Dr. Folstein),
Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thi... more Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thirteen children with high grade astrocytomas. These included four of seven children with hemispheral tumors and two of six children with malignant brainstem gliomas. Leptomeningeal spread was diagnosed by the clinical picture and CSF profile. Meningeal spread occurred an average of 5 months (range 0-16) after initial diagnosis of tumor was made. Several patients responded well to local radiation and/or chemotherapy. Mean survival after evidence of meningeal spread was 7 months (range 2 16) with one patient still alive. Meningeal spread of malignant childhood astrocytomas appears to be common and should be sought for in these patients as local radiation is beneficial. Serious consideration should be given to a controlled trial of prophylactic craniospinal radiation in thee tumors. The role of chemotherapy also requires further study.
Although typically described in autistic, mentally retarded, and sensory-deprived individuals, mo... more Although typically described in autistic, mentally retarded, and sensory-deprived individuals, motor stereotypies also occur in normal children. In this preliminary report, the behavior modification techniques of habit reversal and differential reinforcement of other behavior were evaluated as a therapeutic modality for the suppression of stereotypic movements in nonautistic subjects. Twelve children, ages 6 to 14 years, with physiologic stereotypies were treated using a standardized treatment protocol. Clinical outcomes were based on differences between assessments obtained at baseline and on telephone follow-up. Evaluation scales included measures of the frequency, intensity, interference, and number of stereotypies (Stereotypy Severity Scale motor portion and Stereotypy Linear Analog Scale) and assessment of global function (Child Global Assessment Scale and Stereotypy Severity Scale global portion). The results were correlated with the child's level of motivation and the num...
Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbal... more Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR.We identified distinct multiexonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism.The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.
In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12... more In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12 week randomised (allocation concealed*), blinded (unclear)*, controlled trial. 12 neurological and psychiatric outpatient clinics in Belgium, the Netherlands, and South Africa.
We will present a comparison of serum antineuronal antibody profiles in children with OCD-only (n... more We will present a comparison of serum antineuronal antibody profiles in children with OCD-only (n=13), PANDAS + OCD (n=20), CTD + OCD (n=23), and age-matched controls (n=29). Detection methods used to evaluate anti-brain antibodies included immunohistochemistry (striatum), ELISA (BA 9/10, BA 11, caudate, and cingulate gyrus), and Western immunoblotting (BA 9/10, BA 11, caudate, and cingulate gyrus). Immunublotting was further used to assess the presence and concentration of putative antigens identified in post-streptococcal patients, i.e., *-and *-enolase, aldolase C, pyruvate kinase M1 and tubulin. Anti-lysoganglioside GM1 activity was measured by competitive inhibition.
Background: Tubulin mutations are a cause of neuronal migrational disorders referred to as tubuli... more Background: Tubulin mutations are a cause of neuronal migrational disorders referred to as tubulinopathies. Mutations in tubulin genes can have a severe impact on microtubule function and result in heterogeneous clinical presentations. Current understanding of the clinical spectrum of tubulinopathies is predominantly based on research in fetal tissue and earlychildhood cases. Methods: Testing of candidate genes followed by whole-exome sequencing was performed in an adult woman with a neurodevelopmental, hyperkinetic movement disorder, to identify the underlying genetic cause. Bioinformatic modeling and a systematic review of literature was conducted to investigate genotype-phenotype correlations. Results: The patient was found to carry a heterozygous, de novo c.722G>A, p.R241H mutation in a conserved domain of TUBB2B, encoding the β-isoform of tubulin. In silico analysis indicated that this mutation was pathogenic. On neuroimaging, the patient had asymmetric pachygyria and dysmorphic basal ganglia. Her neurological examination demonstrated mild cognitive impairment, myoclonus-dystonia, and skeletal anomalies. Conclusions: Here, we report the unique phenotype of an adult TUBB2B mutation carrier. This case illustrates a relatively mild phenotype compared to previously described fetal and early childhood cases. This highlights
Introduction-Complex motor stereotypies in children are repetitive, rhythmic movements that have ... more Introduction-Complex motor stereotypies in children are repetitive, rhythmic movements that have a predictable pattern and location, seem purposeful, but serve no obvious function, tend to be prolonged, and stop with distraction, e.g., arm/hand flapping, waving. They occur in both "primary" (otherwise typically developing) and secondary conditions. These movements are best defined as habitual behaviors and therefore pathophysiologically hypothesized to reside in premotor to posterior putamen circuits. This study sought to clarify the underlying neurobiological abnormality in children with primary complex motor stereotypies using structural neuroimaging, emphasizing brain regions hypothesized to underlie these atypical behaviors. Methods-High-resolution anatomical MRI images, acquired at 3.0T, were analyzed in children ages 8-12 years (20 with primary complex motor stereotypies, 20 typically developing). Frontal lobe sub-regions and striatal structures were delineated for analysis. Results-Significant reductions (p=0.045) in the stereotypies group were identified in total putamen volume, but not caudate, nucleus accumbens or frontal sub-regions. There were no group differences in total cerebral volume.
Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thi... more Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thirteen children with high grade astrocytomas. These included four of seven children with hemispheral tumors and two of six children with malignant brainstem gliomas. Leptomeningeal spread was diagnosed by the clinical picture and CSF profile. Meningeal spread occurred an average of 5 months (range 0-16) after initial diagnosis of tumor was made. Several patients responded well to local radiation and/or chemotherapy. Mean survival after evidence of meningeal spread was 7 months (range 2 16) with one patient still alive. Meningeal spread of malignant childhood astrocytomas appears to be common and should be sought for in these patients as local radiation is beneficial. Serious consideration should be given to a controlled trial of prophylactic craniospinal radiation in thee tumors. The role of chemotherapy also requires further study.
In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12... more In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12 week randomised (allocation concealed*), blinded (unclear)*, controlled trial. 12 neurological and psychiatric outpatient clinics in Belgium, the Netherlands, and South Africa.
Background: The COVID-19 pandemic uniquely affects patients with neurologic and developmental dis... more Background: The COVID-19 pandemic uniquely affects patients with neurologic and developmental disabilities at the Kennedy Krieger Institute. These patients are at increased risk of co-morbidities, increasing their risk of contracting COVID-19. Disruptions in their home and school routines, and restrictions accessing crucial healthcare services has had a significant impact. Methods: A Pandemic Intake questionnaire regarding COVID-19 related medical concerns of guardians of patients was distributed using Qualtrics. Data from May-December 2020 were merged with demographic information of patients from 10 clinics (Center for Autism and Related Disorders (CARD), Neurology, Epigenetics, Neurogenetics, Center for Development and TYPE
Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving m... more Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesio...
Pathogenic variants in EEF1A2, a gene encoding a eukaryotic translation elongation factor, have b... more Pathogenic variants in EEF1A2, a gene encoding a eukaryotic translation elongation factor, have been previously reported in pediatric cases of epileptic encephalopathy and intellectual disability. We report a case of a 17-year-old male with a prior history of epilepsy, autism, intellectual disability, and the abrupt onset of choreo-athetotic movements. The patient was diagnosed with an EEF1A2 variant by whole exome sequencing. His movement disorder responded dramatically to treatment with tetrabenazine. To the best of our knowledge, this is the first report of successful treatment of a hyperkinetic movement disorder in the setting of EEF1A2 mutation. A trial with tetrabenazine should be considered in cases with significant choreoathetosis.
BACKGROUND: Complex motor stereotypies (CMS) typically begin before age three years and include r... more BACKGROUND: Complex motor stereotypies (CMS) typically begin before age three years and include rhythmic, repetitive, fixed movements that last for seconds to minutes and can be interrupted with distraction. OBJECTIVE: We evaluated the effectiveness of a home-based, parent-provided therapy accompanied by scheduled telephone calls with a therapist, in fiveto seven-year old children with primary CMS. METHODS: Eligible families received an instructional digital versatile disk (DVD) written instructions, and scheduled telephone contacts with a therapist at baseline (DVD receipt), one, three, and eight weeks later. At each call, parents completed outcome measures and received feedback. Outcome scales Stereotypy Severity Scale (SSS) Motor and Impairment scales and a Stereotypy Linear Analogue Scale (SLAS) were also completed via the Iinternet (REDCap)-at screening, one and two months post-baseline call. At study conclusion, participants were divided into an intent-to-treat (ITT; had at least one call) or a lost-to-follow-up (LTF) group. RESULTS: Thirty-eight children (mean = 5 years § 11 months) were enrolled. The LTF group (n = 14) had significantly higher scores than the ITT (n = 24) group on all attention-deficit/hyperactivity disorder ratings (P < 0.01), but not stereotypy severity. Primary outcome scores, acquired by telephone and REDCap, showed a significant reduction in SSS Motor and Impairment scores between the initial and the last completed evaluation (P 0.001). Calculated change ratios were SSS Motor ¡0.23/¡0.30 (cal/REDCap); SSS Impairment ¡0.31/¡0.32; and SLAS ¡0.54 (REDCap). Clinical improvement was further supported by results from a parent improvement scale and end of study questionnaires. CONCLUSIONS: Home-based, parent-administered behavioral therapy supplemented by telephone contact with a therapist is effective in reducing complex motor stereotypies in children.
Developmental Medicine & Child Neurology, 2016
AimPrimary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movem... more AimPrimary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movements in young people with typical development. This study evaluated the efficacy of an instructional DVD as a home‐based, parent‐administered, behavioral therapy for primary CMS.MethodEighty‐one children with primary CMS were enrolled. Primary outcome measures included the Stereotypy Severity Scale (SSS) – Motor and Impairment scores, and Stereotypy Linear Analog Scale (SLAS). Mean CMS onset was 13.4 months (SD 13.1). Eligibility required observed CMS. Psychiatric disorders were not exclusionary and a stable medication regimen was required. Intellectual disability, neurological disorder, autism spectrum disorder, and tics were exclusionary. Initial assessments were completed via REDCap before receipt of the DVD. Fifty‐four of the 81 children (34 male, 20 female; mean age 8y 2mo, SD 1.42, range 7–14y) completed assessments at 1, 2, or 3 months after receiving the DVD.ResultsReductions (ba...
AJNR. American journal of neuroradiology, Jan 5, 2015
Complex motor stereotypies are rhythmic, repetitive, fixed, purposeful but purposeless movements ... more Complex motor stereotypies are rhythmic, repetitive, fixed, purposeful but purposeless movements that stop with distraction. They can occur in otherwise normal healthy children (primary stereotypies) as well in those with autism spectrum disorders (secondary stereotypies). The underlying neurobiologic basis for these movements is unknown but is thought to involve cortical-striatal-thalamo-cortical pathways. To further clarify potential neurochemical alterations, gamma-aminobutyric acid (GABA), glutamate, glutamine, N-acetylaspartate, and choline levels were measured in 4 frontostriatal regions by using (1)H MRS at 7T. A total of 18 children with primary complex motor stereotypies and 24 typically developing controls, ages 5-10 years, completed MR spectroscopy at 7T. Single voxel STEAM acquisitions from the anterior cingulate cortex, premotor cortex, dorsolateral prefrontal cortex, and striatum were obtained, and metabolites were quantified with respect to Cr by using LCModel. The 7T...
Auto antibodies found in the mothers of children with autistic disorder (MCAD) when passively tra... more Auto antibodies found in the mothers of children with autistic disorder (MCAD) when passively transferred to pregnant mice cause behavioral alterations in juvenile and adult offspring. The goal of this study was to identify whether intraperitoneal injection of MCAD-IgG during gestation affected postnatal cell proliferation and survival in P7 offspring. Pooled MCAD-IgG or IgG from mothers of unaffected children (MUC) or phosphate-buffered saline was injected daily into C57BL/J6 pregnant dams (gestational days E13-E18). MCAD-IgG exposure significantly increased cell proliferation in the subventricular and subgranular zones. In contrast, BrdU-labeled cells on P1 and surviving until P7 (P1-generated cells) showed reduced cell densities in layers 2-4 of frontal and parietal cortices of MCAD mice compared to those in MUC and PBS-injected mice. In conclusion, significant increases in cell proliferation at P7 and reduced densities of P1-generated cells distinguish in utero exposure to MCAD ...
From the Departmentaof Ophthalmology (MI. Lasker), Neurology (DIE. Zee. Hain, and Singer), and Ps... more From the Departmentaof Ophthalmology (MI. Lasker), Neurology (DIE. Zee. Hain, and Singer), and Psychiatry (Dr. Folstein),
Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thi... more Over a period of five years, antemortem diagnosis of leptomeningeal spread was made in six of thirteen children with high grade astrocytomas. These included four of seven children with hemispheral tumors and two of six children with malignant brainstem gliomas. Leptomeningeal spread was diagnosed by the clinical picture and CSF profile. Meningeal spread occurred an average of 5 months (range 0-16) after initial diagnosis of tumor was made. Several patients responded well to local radiation and/or chemotherapy. Mean survival after evidence of meningeal spread was 7 months (range 2 16) with one patient still alive. Meningeal spread of malignant childhood astrocytomas appears to be common and should be sought for in these patients as local radiation is beneficial. Serious consideration should be given to a controlled trial of prophylactic craniospinal radiation in thee tumors. The role of chemotherapy also requires further study.
Although typically described in autistic, mentally retarded, and sensory-deprived individuals, mo... more Although typically described in autistic, mentally retarded, and sensory-deprived individuals, motor stereotypies also occur in normal children. In this preliminary report, the behavior modification techniques of habit reversal and differential reinforcement of other behavior were evaluated as a therapeutic modality for the suppression of stereotypic movements in nonautistic subjects. Twelve children, ages 6 to 14 years, with physiologic stereotypies were treated using a standardized treatment protocol. Clinical outcomes were based on differences between assessments obtained at baseline and on telephone follow-up. Evaluation scales included measures of the frequency, intensity, interference, and number of stereotypies (Stereotypy Severity Scale motor portion and Stereotypy Linear Analog Scale) and assessment of global function (Child Global Assessment Scale and Stereotypy Severity Scale global portion). The results were correlated with the child's level of motivation and the num...
Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbal... more Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR.We identified distinct multiexonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism.The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.
In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12... more In patients with Tourette's disorder, is risperidone as effective and safe as pimozide? Design 12 week randomised (allocation concealed*), blinded (unclear)*, controlled trial. 12 neurological and psychiatric outpatient clinics in Belgium, the Netherlands, and South Africa.
We will present a comparison of serum antineuronal antibody profiles in children with OCD-only (n... more We will present a comparison of serum antineuronal antibody profiles in children with OCD-only (n=13), PANDAS + OCD (n=20), CTD + OCD (n=23), and age-matched controls (n=29). Detection methods used to evaluate anti-brain antibodies included immunohistochemistry (striatum), ELISA (BA 9/10, BA 11, caudate, and cingulate gyrus), and Western immunoblotting (BA 9/10, BA 11, caudate, and cingulate gyrus). Immunublotting was further used to assess the presence and concentration of putative antigens identified in post-streptococcal patients, i.e., *-and *-enolase, aldolase C, pyruvate kinase M1 and tubulin. Anti-lysoganglioside GM1 activity was measured by competitive inhibition.
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Papers by Harvey Singer