43 results on '"Kothur, K"'
Search Results
2. Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants
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Pham, DH, Pitman, MR, Kumar, R, Jolly, LA, Schulz, R, Gardner, AE, de Nys, R, Heron, SE, Corbett, MA, Kothur, K, Gill, D, Rajagopalan, S, Kolc, KL, Halliday, BJ, Robertson, SP, Regan, BM, Kirsch, HE, Berkovic, SF, Scheffer, IE, Pitson, SM, Petrovski, S, Gecz, J, Pham, DH, Pitman, MR, Kumar, R, Jolly, LA, Schulz, R, Gardner, AE, de Nys, R, Heron, SE, Corbett, MA, Kothur, K, Gill, D, Rajagopalan, S, Kolc, KL, Halliday, BJ, Robertson, SP, Regan, BM, Kirsch, HE, Berkovic, SF, Scheffer, IE, Pitson, SM, Petrovski, S, and Gecz, J
- Abstract
PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification.
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- 2021
3. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination
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Ramanathan, S, Mohammad, S, Tantsis, E, Nguyen, Tk, Merheb, V, Fung, Vsc, White, Ob, Broadley, S, Lechner-Scott, J, Vucic, S, Henderson, Apd, Barnett, Mh, Reddel, Sw, Brilot, F, Dale, Rc, Australasian and New Zealand MOG Study Group Andrews, P, Barton, J, Burrow, J, Butzkueven, H, Cairns, A, Calvert, S, Caruana, P, Chelakkadan, S, Clark, D, Fraser, C, Freeman, J, Gill, D, Grattan-Smith, P, Gupta, S, Hardy, T, Kothur, K, Ling, S, Lopez, J, Malone, S, Marriott, M, Nosadini, M, O'Grady, G, Orr, C, Ouvrier, R, Parratt, J, Patrick, E, Pilli, D, Riminton, D, Riney, K, Rodriguez-Casero, V, Ryan, M, Scheffer, I, Shah, U, Shuey, N, Spooner, C, Subramanian, G, Tea, F, Thomas, T, Thompson, J, Troedson, C, Ware, T, Webster, R, Yiannikas, C, Yiu, E, and Zou, A.
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Male ,0301 basic medicine ,Journal Club ,medicine.medical_treatment ,Demyelinating Autoimmune Diseases, CNS ,Cohort Studies ,0302 clinical medicine ,Prednisone ,Child ,10. No inequality ,MOG antibody, demyelination, treatment ,treatment ,biology ,Encephalomyelitis, Acute Disseminated ,Neuromyelitis Optica ,Brain ,Immunoglobulins, Intravenous ,Middle Aged ,Magnetic Resonance Imaging ,3. Good health ,Psychiatry and Mental health ,Child, Preschool ,Acute disseminated encephalomyelitis ,Cohort ,Female ,demyelination ,Immunotherapy ,Antibody ,Rituximab ,Immunosuppressive Agents ,medicine.drug ,MOG antibody ,Adult ,medicine.medical_specialty ,Optic Neuritis ,Adolescent ,Myelitis, Transverse ,Myelin oligodendrocyte glycoprotein ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Immunologic Factors ,Optic neuritis ,Aged ,Autoantibodies ,Expanded Disability Status Scale ,business.industry ,Infant ,Mycophenolic Acid ,medicine.disease ,030104 developmental biology ,Immunology ,biology.protein ,Myelin-Oligodendrocyte Glycoprotein ,Surgery ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveWe characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination.MethodsWe evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients.ResultsThe most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses ConclusionRelapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.
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- 2017
4. Hashimoto’s encephalopathy in an adolescent boy
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Ray, Munni, Kothur, K., Padhy, S. K., and Saran, P.
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- 2007
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5. Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring
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Jones, Hf, Acc, Ho, Sharma, S, Mohammad, Ss, Kothur, K, Patel, S, Brilot, F, Guastella, Aj, Dale, Rc, Immune-Neurodevelopment (Imm-Nd) Study Group, Nosadini, M, Shah, U, Down, J, Gold, W, and Hofer, Mj.
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Male ,030506 rehabilitation ,Psychosis ,Pediatrics ,medicine.medical_specialty ,Tics ,Adolescent ,Offspring ,Autism Spectrum Disorder ,Thyroid Gland ,Hashimoto Disease ,medicine.disease_cause ,Tourette syndrome ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,Pregnancy ,mental disorders ,medicine ,Humans ,Maternal thyroid autoimmunity, neuropsychiatric disorders, regression ,Maternal thyroid autoimmunity ,Child ,business.industry ,medicine.disease ,Anxiety Disorders ,neuropsychiatric disorders ,Autism spectrum disorder ,In utero ,Neurodevelopmental Disorders ,Child, Preschool ,Prenatal Exposure Delayed Effects ,Tic Disorders ,Pediatrics, Perinatology and Child Health ,regression ,Female ,Neurology (clinical) ,0305 other medical science ,business ,030217 neurology & neurosurgery - Abstract
Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.AUTOINMUNIDAD MATERNA TIROIDEA ASOCIADA CON TRASTORNOS NEUROPSIQUIÁTRICOS DE INICIO AGUDO Y REGRESIÓN GLOBAL EN LA DESCENDENCIA: Los estudios epidemiológicos, los modelos animales y los estudios de casos y controles indican que la activación inmune materna puede ser un factor importante involucrado en la expresión de la enfermedad del trastorno del espectro autista (TEA), el síndrome de Tourette y el trastorno obsesivo compulsivo (TOC). Informamos ocho niños (edad media 6 años de edad y 6 meses [rango 4-15 años]; 6 varones y 2 mujeres) remitidos durante un período de 2 años con al menos uno de estos trastornos del desarrollo neurológico más un historial materno de autoinmunidad tiroidea. Siete de ocho niños presentaron un inicio brusco de síntomas neuropsiquiátricos (TOC [n = 6], tics [n = 5] y / o psicosis [n = 1]), asociados con una regresión autista o global. Cuatro niños tenían un diagnóstico preexistente de TEA. Seis presentaciones fueron precedidas por infección, y los síntomas siguieron un curso de recaídas y remisiones en siete niños. Todos los niños respondieron al tratamiento inmunomodulador según lo indicado por una reducción en los síntomas psiquiátricos, y siete niños también fueron tratados con tratamiento convencional con una mejora adicional. Proponemos que la autoinmunidad materna puede activar la microglía fetal o alterar la transcripción de la vulnerabilidad del desarrollo neurológico y / o los genes inmunes en el útero, y es un factor ambiental que aumenta la expresión y la gravedad de los problemas del desarrollo neurológico, y la susceptibilidad a deterioros después de estímulos infecciosos o estresantes.AUTOIMUNIDADE TIREÓIDE MATERNA ASSOCIADA COM DESORDENS NEUROPSIQUIÁTRICAS DE INÍCIO AGUDO E REGRESSÃO GLOBAL NA PROLE: Estudos epidemiológicos, modelos animais, e estudos de caso-controle indicam que a ativação imune materna pode ser um importante fator envolvido na expressão de doenças do transtorno do espectro autista (TEA), síndrome de Tourette, e transtorno obsessivo compulsivo (TOC). Reportamos oito crianças (média de idade 6a 6m [variação 4-15a]; 6 do sexo masculino e 2 do sexo feminino) encaminhadas em um período de 2 anos com pelo menos uma desordem neurodesenvolvimental e história de auto-imunidade tireóide materna. Sete das oito crianças apresentaram início agudo de sintomas neuropsiquiátricos (TOC [n=6], tiques [n=5], e/ou psicose [n=1]), associados com regressão autística ou global. Quatro crianças tinham diagnóstico pré-existente de TEA. Seis apresentações foram precedidas por infecção, e os sintomas seguiram um curso recorrência-remisão em sete crianças. Todas as crianças responderam ao tratamento imunomodulatório, indicado pela redução nos sintomas psiquiátricos, e sete crianças também foram abordadas com tratamento convencional, com melhora adicional. Nós propomos que a autoimunidade maternal pode ativar a microglia fetal ou alterar a transcrição de genes de vulnerabilidade neurodesenvolvimental e/ou imunes, e um fator ambiental pode aumentar a expressão e severidade de problemas neurodesenvolvimentais e suscetibilidade a deterioração após estímulo infeccioso ou estresse.
- Published
- 2018
6. Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination
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Tea, F, Lopez, JA, Ramanathan, S, Merheb, V, Lee, FXZ, Zou, A, Pilli, D, Patrick, E, van der Walt, A, Monif, M, Tantsis, EM, Yiu, EM, Vucic, S, Henderson, APD, Fok, A, Fraser, CL, Lechner-Scott, J, Reddel, SW, Broadley, S, Barnett, MH, Brown, DA, Lunemann, JD, Dale, RC, Brilot, F, Sinclair, A, Kermode, AG, Kornberg, A, Bye, A, McGettigan, B, Trewin, B, Brew, B, Taylor, B, Bundell, C, Miteff, C, Troedson, C, Pridmore, C, Spooner, C, Yiannikas, C, O'Gorman, C, Clark, D, Suan, D, Jones, D, Kilfoyle, D, Gill, D, Wakefield, D, Hofmann, D, Mathey, E, O'Grady, G, Jones, HF, Beadnall, H, Butzkueven, H, Joshi, H, Andrews, I, Sutton, I, MacIntyre, J, Sandbach, JM, Freeman, J, King, J, O'Neill, JH, Parratt, J, Barton, J, Garber, J, Ahmad, K, Riney, K, Buzzard, K, Kothur, K, Cantrill, LC, Menezes, MP, Paine, MA, Marriot, M, Ghadiri, M, Boggild, M, Lawlor, M, Badve, M, Ryan, M, Aaqib, M, Shuey, N, Jordan, N, Urriola, N, Lawn, N, White, O, McCombe, P, Patel, R, Leventer, R, Webster, R, Smith, R, Gupta, S, Mohammad, SS, Pillai, S, Hawke, S, Simon, S, Calvert, S, Blum, S, Malone, S, Hodgkinson, S, Nguyen, TK, Hardy, TA, Kalincik, T, Ware, T, Fung, VSC, Huynh, W, Tea, F, Lopez, JA, Ramanathan, S, Merheb, V, Lee, FXZ, Zou, A, Pilli, D, Patrick, E, van der Walt, A, Monif, M, Tantsis, EM, Yiu, EM, Vucic, S, Henderson, APD, Fok, A, Fraser, CL, Lechner-Scott, J, Reddel, SW, Broadley, S, Barnett, MH, Brown, DA, Lunemann, JD, Dale, RC, Brilot, F, Sinclair, A, Kermode, AG, Kornberg, A, Bye, A, McGettigan, B, Trewin, B, Brew, B, Taylor, B, Bundell, C, Miteff, C, Troedson, C, Pridmore, C, Spooner, C, Yiannikas, C, O'Gorman, C, Clark, D, Suan, D, Jones, D, Kilfoyle, D, Gill, D, Wakefield, D, Hofmann, D, Mathey, E, O'Grady, G, Jones, HF, Beadnall, H, Butzkueven, H, Joshi, H, Andrews, I, Sutton, I, MacIntyre, J, Sandbach, JM, Freeman, J, King, J, O'Neill, JH, Parratt, J, Barton, J, Garber, J, Ahmad, K, Riney, K, Buzzard, K, Kothur, K, Cantrill, LC, Menezes, MP, Paine, MA, Marriot, M, Ghadiri, M, Boggild, M, Lawlor, M, Badve, M, Ryan, M, Aaqib, M, Shuey, N, Jordan, N, Urriola, N, Lawn, N, White, O, McCombe, P, Patel, R, Leventer, R, Webster, R, Smith, R, Gupta, S, Mohammad, SS, Pillai, S, Hawke, S, Simon, S, Calvert, S, Blum, S, Malone, S, Hodgkinson, S, Nguyen, TK, Hardy, TA, Kalincik, T, Ware, T, Fung, VSC, and Huynh, W
- Abstract
Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.
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- 2019
7. Perinatal Tuberculosis a Case Series
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Singh, M., primary, Kothur, K., additional, Dayal, D., additional, and Kusuma, S., additional
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- 2006
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8. Correlation of autism with temporal tubers in tuberous sclerosis complex.
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Kothur K, Ray M, Malhi P, Kothur, Kavitha, Ray, Munni, and Malhi, Prahbhjot
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Tuberous sclerosis complex (TSC) is an inherited genetic disorder commonly associated with neuropsychiatric complications like epilepsy, mental retardation, autism and other behavioral problems and constitutes about 1-4% of the autistic population. Mental retardation and seizures, particularly infantile spasms are significant risk factors for the development of autism. Patients of TSC with autism are more likely to have temporal tubers than those cases without autism. We describe clinical and neuroimaging features of two such cases of tuberous sclerosis with autism. [ABSTRACT FROM AUTHOR]
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- 2008
9. Bilateral idiopathic vocal cord palsy.
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Kothur K, Singh M, Dayal D, and Gupta AK
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- 2007
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10. Clinical features associated with epilepsy occurrence, resolution, and drug resistance in children with cerebral palsy: A population-based study.
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Feroze N, Karim T, Ostojic K, Mcintyre S, Barnes EH, Lee BC, Dale RC, Gill D, and Kothur K
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- Humans, Male, Female, Child, Preschool, Child, Intellectual Disability, Anticonvulsants therapeutic use, Registries, New South Wales epidemiology, Infant, Severity of Illness Index, Drug Resistance, Vision Disorders etiology, Cerebral Palsy complications, Epilepsy drug therapy, Drug Resistant Epilepsy drug therapy, Drug Resistant Epilepsy genetics
- Abstract
Aim: To investigate clinicoradiological features associated with epilepsy, its resolution, and drug resistance in children with cerebral palsy (CP)., Method: Data were gathered from the New South Wales/Australian Capital Territory CP Register, encompassing children with CP born between 2003 and 2015 (n = 1916). Clinical features and the severity of impairments were compared among three groups: children with current epilepsy (n = 604), those with resolved epilepsy by age 5 years (n = 109), and those without epilepsy (n = 1203). Additionally, a subset of the registry cohort attending Children's Hospital Westmead (n = 256) was analysed to compare epilepsy and treatment characteristics between drug-responsive (n = 83) and drug-resistant groups (n = 147) using logistic regression and hierarchical cluster analysis., Results: Manual Ability Classification System levels IV and V, intellectual impairment, and vision impairment were found to be associated with epilepsy in children with CP on multivariable analysis (p < 0.01). Moderate to severe intellectual impairment and bilateral spastic CP were independent positive and negative predictors of epilepsy persistence at the age of 5 years respectively (p < 0.05). Microcephaly and multiple seizure types were predictors of drug-resistant epilepsy (area under the receiver operating characteristic curve of 0.83; 95% confidence interval 0.77-0.9). Children with a known genetic cause (14%) and CP epilepsy surgery group (4.3%) formed specific clinical subgroups in CP epilepsy., Interpretation: Our study highlights important clinical associations of epilepsy, its resolution, and treatment response in children with CP, providing valuable knowledge to aid in counselling families and identifying distinct prognostic groups for effective medical surveillance and optimal treatment., What This Paper Adds: Severe motor and non-motor impairments in cerebral palsy (CP) increase epilepsy risk. Epilepsy more likely resolves in bilateral spastic and milder CP impairments. Epilepsy in CP often manifests at an early age with multiple seizure types and high drug resistance. Children with a known genetic cause and CP epilepsy surgery group represent distinct clinical subgroups., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)
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- 2024
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11. Epilepsy with eyelid myoclonia with atonic seizures and generalized paroxysmal fast activity: A novel electroclinical phenotype associated with SETD1B pathogenic variant.
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Ng VHL, Hart F, Kothur K, Buckley M, Harb C, and Gill D
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- Humans, Electroencephalography, Eyelids pathology, Phenotype, Seizures genetics, Histone-Lysine N-Methyltransferase genetics, Epilepsy genetics, Epilepsy, Absence, Epilepsy, Generalized genetics, Myoclonus genetics
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- 2024
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12. Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders.
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Houdayer C, Phillips AM, Chabbert M, Bourreau J, Maroofian R, Houlden H, Richards K, Saadi NW, Dad'ová E, Van Bogaert P, Rupin M, Keren B, Charles P, Smol T, Riquet A, Pais L, O'Donnell-Luria A, VanNoy GE, Bayat A, Møller RS, Olofsson K, Abou Jamra R, Syrbe S, Dasouki M, Seaver LH, Sullivan JA, Shashi V, Alkuraya FS, Poss AF, Spence JE, Schnur RE, Forster IC, Mckenzie CE, Simons C, Wang M, Snell P, Kothur K, Buckley M, Roscioli T, Elserafy N, Dauriat B, Procaccio V, Henrion D, Lenaers G, Colin E, Verbeek NE, Van Gassen KL, Legendre C, Bonneau D, Reid CA, Howell KB, Ziegler A, and Legros C
- Abstract
Hyperpolarization activated Cyclic Nucleotide (HCN) gated channels are crucial for various neurophysiological functions, including learning and sensory functions, and their dysfunction are responsible for brain disorders, such as epilepsy. To date, HCN2 variants have only been associated with mild epilepsy and recently, one monoallelic missense variant has been linked to developmental and epileptic encephalopathy. Here, we expand the phenotypic spectrum of HCN2- related disorders by describing twenty-one additional individuals from fifteen unrelated families carrying HCN2 variants. Seventeen individuals had developmental delay/intellectual disability (DD/ID), two had borderline DD/ID, and one had borderline DD. Ten individuals had epilepsy with DD/ID, with median age of onset of 10 months, and one had epilepsy with normal development. Molecular diagnosis identified thirteen different pathogenic HCN2 variants, including eleven missense variants affecting highly conserved amino acids, one frameshift variant, and one in-frame deletion. Seven variants were monoallelic of which five occurred de novo, one was not maternally inherited, one was inherited from a father with mild learning disabilities, and one was of unknown inheritance. The remaining six variants were biallelic, with four homozygous and two compound heterozygous variants. Functional studies using two-electrode voltage-clamp recordings in Xenopus laevis oocytes were performed on three monoallelic variants, p.(Arg324His), p.(Ala363Val), and p.(Met374Leu), and three biallelic variants, p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp). The p.(Arg324His) variant induced a strong increase of HCN2 conductance, while p.(Ala363Val) and p.(Met374Leu) displayed dominant negative effects, leading to a partial loss of HCN2 channel function. By confocal imaging, we found that the p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp) pathogenic variants impaired membrane trafficking, resulting in a complete loss of HCN2 elicited currents in Xenopus oocytes. Structural 3D-analysis in depolarized and hyperpolarized states of HCN2 channels, revealed that the pathogenic variants p.(His205Gln), p.(Ser409Leu), p.(Arg324Cys), p.(Asn369Ser) and p.(Gly460Asp) modify molecular interactions altering HCN2 function. Taken together, our data broadens the clinical spectrum associated with HCN2 variants, and disclose that HCN2 is involved in developmental encephalopathy with or without epilepsy.
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- 2024
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13. GABRA1-Related Disorders: From Genetic to Functional Pathways.
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Musto E, Liao VWY, Johannesen KM, Fenger CD, Lederer D, Kothur K, Fisk K, Bennetts B, Vrielynck P, Delaby D, Ceulemans B, Weckhuysen S, Sparber P, Bouman A, Ardern-Holmes S, Troedson C, Battaglia DI, Goel H, Feyma T, Bakhtiari S, Tjoa L, Boxill M, Demina N, Shchagina O, Dadali E, Kruer M, Cantalupo G, Contaldo I, Polster T, Isidor B, Bova SM, Fazeli W, Wouters L, Miranda MJ, Darra F, Pede E, Le Duc D, Jamra RA, Küry S, Proietti J, McSweeney N, Brokamp E, Andrews PI, Gouray Garcia M, Chebib M, Møller RS, Ahring PK, and Gardella E
- Abstract
Objective: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations., Methods: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants., Results: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy., Interpretation: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023., (© 2023 American Neurological Association.)
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- 2023
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14. CSF neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in FIRES and other infection-triggered encephalopathy syndromes.
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Dale RC, Thomas T, Patel S, Han VX, Kothur K, Troedson C, Gupta S, Gill D, Malone S, Waak M, Calvert S, Subramanian G, Andrews PI, Kandula T, Menezes MP, Ardern-Holmes S, Mohammad S, Bandodkar S, and Yan J
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- Humans, Neopterin, Quinolinic Acid metabolism, Kynurenine, Syndrome, Neuroinflammatory Diseases, Chromatography, Liquid, Tandem Mass Spectrometry, Seizures, Biomarkers, Brain Diseases etiology, Brain Diseases diagnosis, Status Epilepticus, Encephalitis
- Abstract
Objective: Infection-triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes., Methods: We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20)., Results: The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection-related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p < 0.0002). The ROC (area under curve) for CSF neopterin (99.3%, CI 98.1-100) was significantly better than CSF pleocytosis (87.3% CI 76.4-98.2) (p = 0.028). Elevated CSF neopterin could discriminate ITES from other causes of seizures, status epilepticus and febrile status epilepticus (all p < 0.0002). The elevated CSF metabolites normalised during longitudinal testing in two patients with FIRES., Interpretation: CSF neopterin and quinolinic acid are neuroinflammatory and excitotoxic metabolites. This CSF metabolomic inflammatory panel can discriminate ITES from other causes of new onset seizures or status epilepticus, and rapid results (4 h) may facilitate early immune modulatory therapy., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2023
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15. CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.
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Yan J, Kothur K, Mohammad S, Chung J, Patel S, Jones HF, Keating BA, Han VX, Webster R, Ardern-Holmes S, Antony J, Menezes MP, Tantsis E, Gill D, Gupta S, Kandula T, Sampaio H, Farrar MA, Troedson C, Andrews PI, Pillai SC, Heng B, Guillemin GJ, Guller A, Bandodkar S, and Dale RC
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- Male, Humans, Child, Infant, Child, Preschool, Adolescent, Kynurenine, Neopterin metabolism, Quinolinic Acid cerebrospinal fluid, Neuroinflammatory Diseases, Leukocytosis, Inflammation diagnosis, Inflammation metabolism, Biomarkers metabolism, Tryptophan metabolism, Nervous System Diseases
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Background: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy., Methods: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32)., Findings: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups., Interpretation: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases., Funding: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University., Competing Interests: Declaration of interests M Farrar reports grants from NHMRC and Cerebral Palsy Alliance Research Foundation, honoraria for educational presentations from Roche, Biogen and Novartis, participation on advisory board for Novartis Gene therapies and Roche, being medical director for Muscular dystrophy NSW and member of scientific and medical committee of Childhood dementia and Friedreich's ataxia. R Dale reports honorarium from Beijing pediatric neurology conference. The other authors have declared that no conflict of interest exists., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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16. Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids.
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Yan J, Kothur K, Innes EA, Han VX, Jones HF, Patel S, Tsang E, Webster R, Gupta S, Troedson C, Menezes MP, Antony J, Ardern-Holmes S, Tantsis E, Mohammad S, Wienholt L, Pires AS, Heng B, Guillemin GJ, Guller A, Gill D, Bandodkar S, and Dale RC
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- 3-Hydroxyanthranilic Acid, Adrenal Cortex Hormones, Animals, Biomarkers, Chromatography, Liquid, Kynurenine cerebrospinal fluid, Male, Quinolinic Acid cerebrospinal fluid, Spasm, Tandem Mass Spectrometry, Tryptophan metabolism, Epilepsy drug therapy, Kynurenic Acid cerebrospinal fluid
- Abstract
Background: Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations., Methods: A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3-3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3-3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1-2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8-2.5 yrs)., Findings: There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively)., Interpretation: This study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored., Funding: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University., Competing Interests: Declaration of interests DG has received honoraria for speaking from UCB, BioMarin and Eisai. The other authors have declared that no conflict of interest exists., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2022
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17. Predictors of longitudinal seizure outcomes after epilepsy surgery in childhood.
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Ka A, Taher A, D'Souza S, Barnes EH, Gupta S, Troedson C, Wade F, Teo O, Dale RC, Wong C, Bleasel AF, Dexter M, Kothur K, and Gill D
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There is a paucity of data on longitudinal seizure outcome of children undergoing epilepsy surgery. All children (n = 132) who underwent resective epilepsy surgery from January 1998 to December 2015 were identified. Relevant clinical, neurophysiological, imaging, surgical and seizure outcome data were extracted. Multivariable logistic regression analysis and Kaplan-Meier survival with Cox proportional hazard modelling were performed. The mean age at surgery was 7.8 years (range 0.2-17.9). 71% were seizure-free at a mean follow up of 5.3 ± 2.7 years. Of those who were seizure-free, 65 patients were able to completely wean off anti- seizure medications successfully. Using survival analysis, the probability of Engel Class I outcome at one year after surgery was 81% (95% confidence interval [CI] 87%-75%). This dropped to 73% at two years (95% CI 81%-65%), 58% at five years (95% CI 67.8%-48%), and 47% at ten years. Proportional hazard modelling showed that the presence of moderate to severe developmental disability (HR 6.5; p = 0.02) and lack of complete resection (HR 0.4; p = 0.02) maintain association as negative predictors of seizure-free outcome. Our study demonstrates favorable long-term seizure control following pediatric epilepsy surgery and highlights important predictors of seizure outcome guiding case selection and counseling of expectations prior to surgery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)
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- 2022
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18. Rapid onset functional tic-like behaviours in children and adolescents during COVID-19: Clinical features, assessment and biopsychosocial treatment approach.
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Han VX, Kozlowska K, Kothur K, Lorentzos M, Wong WK, Mohammad SS, Savage B, Chudleigh C, and Dale RC
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- Adolescent, Child, Female, Humans, Male, Pandemics, Retrospective Studies, COVID-19 epidemiology, COVID-19 therapy, Tic Disorders diagnosis, Tic Disorders epidemiology, Tic Disorders therapy, Tics, Tourette Syndrome
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Aim: To report the prevalence and clinical characteristics of children with rapid onset functional tic-like behaviours during the COVID-19 pandemic., Methods: Single centre, retrospective cohort study of children (<18 years) referred to the tic clinic from January 2018 to July 2021. We calculate the prevalence of newly diagnosed functional tics, and compare the clinical features to chronic tic disorder/Tourette syndrome (CTD/TS)., Results: A total of 185 new patients were referred to the tic clinic between 2018 and 2021. There was a significant increase in the percentage of functional tics in 2020 and 2021 (2% in 2018, 5.6% in 2019, 10.6% in 2020 and 36% in 2021). Differences between functional tics (n = 22) and CTD/TS (n = 163) include female predominance (100 vs. 28%, P < 0.0001), later age of onset (mean age 13.8 vs. 6.8 years, P < 0.0001) and higher rates of anxiety/depression (95 vs. 41%, P < 0.0001). The functional tic group were more likely to present with coprolalia-like behaviours (77 vs. 10%, P < 0.0001), complex phrases (45 vs. 0.6%, P < 0.0001), copropraxia (45 vs. 2%, P < 0.0001), self-injury (50 vs. 4%, P < 0.0001), hospitalisation/emergency visits (36 vs. 2%, P < 0.0001) and school absenteeism (56 vs. 7%, P < 0.0001). A total of 18.2% of patients with functional tics reported preceding exposure to social media content involving tics., Conclusions: There is an increase in adolescent females presenting with rapid onset functional tic-like behaviours during the COVID-19 pandemic. We highlight differences in clinical features between the functional tic group and CTD/TS to aid diagnosis and management in the community. Based on our findings, we propose a mixed model of neuropsychiatric vulnerability and social media contagion in this group of adolescents with functional tics., (© 2022 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)
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- 2022
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19. Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy.
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Jones HF, Stoll M, Ho G, O'Neill D, Han VX, Paget S, Stewart K, Lewis J, Kothur K, Troedson C, Crow YJ, Dale RC, and Mohammad SS
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- Autoimmune Diseases of the Nervous System drug therapy, Cerebral Palsy diagnosis, Child, Preschool, Diagnosis, Differential, Humans, Infant, Nervous System Malformations drug therapy, Spastic Paraplegia, Hereditary diagnosis, Adenosine Deaminase genetics, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System genetics, Nervous System Malformations diagnosis, Nervous System Malformations genetics, RNA-Binding Proteins genetics
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Background: The type 1 interferonopathy, Aicardi-Goutières syndrome 6 (AGS6), is classically caused by biallelic ADAR mutations whereas dominant ADAR mutations are associated with dyschromatosis symmetrica hereditaria (DSH). The unique dominant ADAR c.3019G>A variant is associated with neurological manifestations which mimic spastic paraplegia and cerebral palsy (CP)., Case Summaries: We report three cases of spastic paraplegia or CP diagnosed with AGS6 caused by the ADAR c.3019G>A variant. Two children inherited the variant from an asymptomatic parent, and each child had a different clinical course. The youngest case demonstrated relentless progressive symptoms but responded to immunomodulation using steroids and ruxolitinib., Conclusion: The ADAR c.3019G>A variant has incomplete penetrance and is a likely underrecognized imitator of spastic paraplegia and dystonic CP. A high level of clinical suspicion is required to diagnose this form of AGS, and disease progression may be ameliorated by immunomodulatory treatment with selective Janus kinase inhibitors., (Copyright © 2021 The Japanese Society of Child Neurology. All rights reserved.)
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- 2022
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20. A case of QARS1 associated epileptic encephalopathy and review of epilepsy in aminoacyl-tRNA synthetase disorders.
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Chan DL, Rudinger-Thirion J, Frugier M, Riley LG, Ho G, Kothur K, and Mohammad SS
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- Child, Preschool, Female, Humans, Microcephaly diagnosis, Microcephaly genetics, Amino Acyl-tRNA Synthetases genetics, Epilepsy diagnosis, Epilepsy genetics
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Introduction: Mutations in QARS1, which encodes human glutaminyl-tRNA synthetase, have been associated with epilepsy, developmental regression, progressive microcephaly and cerebral atrophy. Epilepsy caused by variants in QARS1 is usually drug-resistant and intractable. Childhood onset epilepsy is also reported in various aminoacyl-tRNA synthetase disorders. We describe a case with a milder neurological phenotype than previously reported with QARS1 variants and review the seizure associations with aminoacyl-tRNA synthetase disorders., Case Report: The patient is a 4-year-old girl presenting at 6 weeks of age with orofacial dyskinesia and hand stereotypies. She developed focal seizures at 7 months of age. Serial electroencephalograms showed shifting focality. Her seizures were controlled after introduction of carbamazepine. Progress MRI showed very mild cortical volume loss without myelination abnormalities or cerebellar atrophy. She was found to have novel compound heterozygous variants in QARS1 (NM_005051.2): c.[1132C > T];[1574G > A], p.[(Arg378Cys)];[(Arg525Gln)] originally classified as "variants of uncertain significance" and later upgraded to "likely pathogenic" based on functional testing and updated variant database review. Functional testing showed reduced solubility of the corresponding QARS1 mutants in vitro, but only mild two-fold loss in catalytic efficiency with the c.1132C > T variant and no noted change in tRNA
Gln aminoacylation with the c.1574G > A variant., Conclusion: We describe two QARS1 variants associated with overall conserved tRNA aminoacylation activity but characterized by significantly reduced QARS protein solubility, resulting in a milder clinical phenotype. 86% of previous patients reported with QARS1 had epilepsy and 79% were pharmaco-resistant. We also summarise literature regarding epilepsy in aminoacyl-tRNA synthetase disorders, which is also often early onset, severe and drug-refractory., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Japanese Society of Child Neurology. All rights reserved.)- Published
- 2022
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21. Cerebrospinal fluid free light chain quantitation is a specific biomarker for inflammatory neurological disorders in a paediatric patient cohort.
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Wienholt L, Kane A, Adelstein S, Richardson A, Kothur K, Brilot F, and Dale RC
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- Biomarkers analysis, Child, Cohort Studies, Diagnostic Tests, Routine methods, Humans, Inflammation diagnosis, Nervous System Diseases diagnosis, Immunoglobulin Light Chains cerebrospinal fluid, Immunoglobulin kappa-Chains cerebrospinal fluid, Inflammation pathology, Nervous System Diseases pathology
- Abstract
The analysis of cerebrospinal fluid (CSF) is routinely used in the diagnostic work-up of a range of inflammatory, infective, and congenital neurological conditions. Many diagnostic tests used in this analysis have poor sensitivity; as such, we investigated the utility of CSF free light chain (FLC) analysis as an adjunct to currently used assays in a paediatric population with neurological disorders. Kappa (κ) and lambda (λ) FLC levels were quantitated in blinded CSF samples by two nephelometric platforms. Results were correlated to clinical diagnoses and classified according to inflammatory/infective or non-inflammatory pathogenesis. FLC results were also compared to currently used CSF diagnostic tests including oligoclonal bands (OCB), CSF IgG and albumin levels, and differential cell count. Of 70 samples analysed, 29 (41%) had an inflammatory or infective diagnosis and 41 (59%) presented with a range of non-inflammatory aetiologies. Thirteen patients had elevated κFLC or λFLC as detected on the IMMAGE 800, defined as greater than the detection limit of the assay (0.600 mg/L for CSF κFLC, and 0.490 mg/L for CSF λFLC), and of these 12 (92%) had an inflammatory disease (sensitivity 41.4%, specificity 97.6%). On the BN II using optimal cut-offs of 0.27 mg/L and 0.12 mg/L for CSF κFLC and λFLC respectively, 24 (34%) patients had elevated results, of which 21 (88%) had an inflammatory disease (sensitivity 72.4%, specificity 92.7%). Analysis of FLC correlated better with diagnostic classification of the diseases than OCB, cell counts and CSF IgG levels. The results of this study support the use of CSF FLC analysis in the diagnosis of paediatric neuroinflammatory conditions., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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22. Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants.
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Pham DH, Pitman MR, Kumar R, Jolly LA, Schulz R, Gardner AE, de Nys R, Heron SE, Corbett MA, Kothur K, Gill D, Rajagopalan S, Kolc KL, Halliday BJ, Robertson SP, Regan BM, Kirsch HE, Berkovic SF, Scheffer IE, Pitson SM, Petrovski S, and Gecz J
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- Humans, Mutation, Missense, Protocadherins, Sequence Analysis, DNA, Cadherins genetics, Epilepsy
- Abstract
PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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23. Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.
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Jones HF, Han VX, Patel S, Gloss BS, Soler N, Ho A, Sharma S, Kothur K, Nosadini M, Wienholt L, Hardwick C, Barnes EH, Lim JR, Alshammery S, Nielsen TC, Wong M, Hofer MJ, Nassar N, Gold W, Brilot F, Mohammad SS, and Dale RC
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- Autoimmunity genetics, Child, Female, Humans, Immunity, Innate genetics, Infant, Newborn, Inflammation genetics, Pregnancy, Transcriptome, Obsessive-Compulsive Disorder genetics, Tic Disorders, Tics
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Although genetic variation is a major risk factor of neurodevelopmental disorders, environmental factors during pregnancy and early life are also important in disease expression. Animal models demonstrate that maternal inflammation causes fetal neuroinflammation and neurodevelopmental deficits, and brain transcriptomics of neurodevelopmental disorders in humans show upregulated differentially expressed genes are enriched in immune pathways. We prospectively recruited 200 sequentially referred children with tic disorders/obsessive-compulsive disorder (OCD), 100 autoimmune neurological controls, and 100 age-matched healthy controls. A structured interview captured the maternal and family history of autoimmune disease and other pro-inflammatory states. Maternal blood and published Tourette brain transcriptomes were analysed for overlapping enriched pathways. Mothers of children with tics/OCD had a higher rate of autoimmune disease compared with mothers of children with autoimmune neurological conditions (p = 0.054), and mothers of healthy controls (p = 0.0004). Autoimmunity was similarly elevated in first- and second-degree maternal relatives of children with tics/OCD (p < 0.0001 and p = 0.014 respectively). Other pro-inflammatory states were also more common in mothers of children with tics/OCD than controls (p < 0.0001). Upregulated differentially expressed genes in maternal autoimmune disease and Tourette brain transcriptomes were commonly enriched in innate immune processes. Pro-inflammatory states, including autoimmune disease, are more common in the mothers and families of children with tics/OCD. Exploratory transcriptome analysis indicates innate immune signalling may link maternal inflammation and childhood tics/OCD. Targeting inflammation may represent preventative strategies in pregnancy and treatment opportunities for children with neurodevelopmental disorders., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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24. Deficits in all aspects of social competence identified in children who have undergone epilepsy surgery.
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Azevedo S, Kothur K, Gupta S, Webster R, Dale RC, Wade F, Gill D, and Lah S
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- Child, Cross-Sectional Studies, Humans, Social Skills, Surveys and Questionnaires, Treatment Outcome, Drug Resistant Epilepsy surgery, Epilepsy surgery
- Abstract
Research on social competence of children who undergo epilepsy surgery is limited. This cross-sectional study aimed to determine the frequency and pattern of impairments in social competence (domains: social skills, social adjustment, and social performance) in a cohort of children who underwent surgery for intractable epilepsy at a single epilepsy surgical center. In addition, we explored the relationships between social competence with epilepsy variables, surgical variables, and seizure outcomes. Fifteen children (5 to 16 years) who underwent focal cortical resection for intractable epilepsy more than 2 years ago (2.58-7.42 years) participated. Parents completed standardized, age-normed questionnaires, assessing three domains of social competence. Demographic and clinical information were obtained from parents and medical records and verified by Pediatric Neurologists and Clinical Nurse Consultant. Individual and group analyses were conducted. Seventy-three percent (n = 11/15) of children were seizure-free. Individual analyses revealed high rates of impairments (scores >1 standard deviation of the mean); 11 out of 15 children (73.3%) obtained a score that fell in the impaired range on at least one domain of social competence, with 5 of these 15 children (30.0%) obtaining impaired scores across domains. Conversely, group analyses of questionnaires completed by parents revealed that compared with norms, children had significant difficulties in all domains of social competence: social skills, social adjustment, and social performance. No significant relationships were found between domains of social competence and epilepsy and surgical variables. In conclusion, children who underwent epilepsy surgery have significantly reduced social competence relative to the norms. Longitudinal studies examining social competence pre- and postsurgery are needed to determine whether surgery improves social competence and whether this is dependent on epilepsy outcomes., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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25. Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.
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Absalom NL, Liao VWY, Kothur K, Indurthi DC, Bennetts B, Troedson C, Mohammad SS, Gupta S, McGregor IS, Bowen MT, Lederer D, Mary S, De Waele L, Jansen K, Gill D, Kurian MA, McTague A, Møller RS, Ahring PK, Dale RC, and Chebib M
- Abstract
Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2020
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26. Acute Hemorrhagic Leukoencephalopathy: Pathological Features and Cerebrospinal Fluid Cytokine Profiles.
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Waak M, Malone S, Sinclair K, Phillips G, Bandodkar S, Wienholt L, Robertson T, Whitehead B, Trnka P, Kothur K, and Dale RC
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- Adolescent, Humans, Magnetic Resonance Imaging, Male, Cytokines cerebrospinal fluid, Leukoencephalitis, Acute Hemorrhagic cerebrospinal fluid, Leukoencephalitis, Acute Hemorrhagic immunology, Leukoencephalitis, Acute Hemorrhagic pathology, Leukoencephalitis, Acute Hemorrhagic physiopathology
- Abstract
Background: Acute hemorrhagic leukoencephalopathy is a rare encephalopathy of unknown etiology, causing fulminant, hemorrhagic central nervous system demyelination with high mortality. It is unclear whether acute hemorrhagic leukoencephalopathy is an entirely distinct entity from acute disseminated encephalomyelitis., Patients and Methods: We report two patients with rapidly progressive neurological illness resulting in raised intracranial pressure and coma, with biopsy-proven acute hemorrhagic leukoencephalopathy (perivascular hemorrhages and demyelination, predominantly neutrophil infiltrates)., Results: Acute cerebrospinal fluid showed pronounced T cell-associated cytokine elevation (interleukins 6, 8, and 17A) and CCL2 or CCL3, higher than in patients with acute disseminated encephalomyelitis, but no B cell-associated cytokine elevation., Conclusion: Improved understanding of the immune process may provide rationale for use of anticytokine biologic agents., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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27. Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring.
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Jones HF, Ho ACC, Sharma S, Mohammad SS, Kothur K, Patel S, Brilot F, Guastella AJ, and Dale RC
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- Adolescent, Anxiety Disorders psychology, Autism Spectrum Disorder psychology, Child, Child, Preschool, Female, Hashimoto Disease psychology, Humans, Male, Neurodevelopmental Disorders psychology, Pregnancy, Prenatal Exposure Delayed Effects psychology, Tic Disorders psychology, Anxiety Disorders immunology, Autism Spectrum Disorder immunology, Hashimoto Disease immunology, Neurodevelopmental Disorders immunology, Prenatal Exposure Delayed Effects immunology, Thyroid Gland immunology, Tic Disorders immunology
- Abstract
Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero., (© 2019 Mac Keith Press.)
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- 2019
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28. Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection-related epilepsy syndrome and febrile status epilepticus.
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Kothur K, Bandodkar S, Wienholt L, Chu S, Pope A, Gill D, and Dale RC
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- Biomarkers cerebrospinal fluid, Child, Child, Preschool, Epilepsy etiology, Female, Fever cerebrospinal fluid, Humans, Infant, Inflammation cerebrospinal fluid, Inflammation complications, Male, Seizures cerebrospinal fluid, Seizures etiology, Status Epilepticus etiology, Chemokines cerebrospinal fluid, Cytokines cerebrospinal fluid, Epilepsy cerebrospinal fluid, Fever complications, Status Epilepticus cerebrospinal fluid
- Abstract
Objective: To investigate intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in a subgroup of pediatric epilepsy patients with frequent daily seizures., Methods: We measured 32 cytokines/chemokines using multiplex immunoassay in CSF collected from pediatric patients with febrile infection-related epilepsy syndrome (FIRES)/FIRES-related disorders (FRD; n = 6), febrile status epilepticus (FSE; n = 8), afebrile status epilepticus (ASE; n = 8), and chronic epilepsy with frequent daily seizures (n = 21) and compared the results with noninflammatory neurological disorders (NIND; n = 20) and encephalitis (n = 43). We also performed longitudinal CSF cytokine/chemokine studies in three cases with FIRES/FRD., Results: The median age of onset of seizures was 2.4 years (range = 0.08-12.5). Median CSF timing from the onset of seizures was longer in chronic epilepsy (540 days), whereas FIRES, FSE, and ASE had CSF tested within 1-2 days of onset of seizures (P < .001). The elevation of cytokines/chemokines was higher in FIRES followed by FSE, when compared to chronic epilepsy and NIND controls. Th1-associated cytokines/chemokines (TNF-α, CXCL9, CXCL10, CXCL11), IL-6, CCL2, CCL19, and CXCL1 (P < .05) were elevated in FIRES, in contrast to the elevation of a broader network of cytokines/chemokines in encephalitis. The cytokines/chemokines (CXCL9, CXCL10, CXCL11, and CCL19) were elevated in FSE when compared to ASE despite the similar median seizure duration and timing of CSF testing in relation to seizures. Chronic epilepsy generally lacked significant elevation of cytokines/chemokines despite frequent daily seizures. The median concentrations of the cytokines/chemokines rapidly declined on serial testing during the course of illness in all three FIRES/FRD cases., Significance: We identify significant differences in CSF cytokine/chemokine profile between FIRES/FRD and encephalitis. The prominent elevation of CSF cytokines and chemokines in FIRES/FRD and to a lesser extent FSE highlights that the cytokine/chemokine elevation is significantly associated with the etiology of the underlying process rather than purely reactive. However, it is unclear whether the immune activation contributes to the disease process., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)
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- 2019
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29. Elevation of cerebrospinal fluid cytokine/chemokines involved in innate, T cell, and granulocyte inflammation in pediatric focal cerebral arteriopathy.
- Author
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Kothur K, Troedson C, Webster R, Bandodkar S, Chu S, Wienholt L, Pope A, Mackay MT, and Dale RC
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Immunity, Innate, Inflammation, Male, Up-Regulation, Biomarkers cerebrospinal fluid, CADASIL diagnosis, Chemokines cerebrospinal fluid, Cytokines cerebrospinal fluid, Granulocytes immunology, T-Lymphocytes immunology
- Abstract
Aim: To determine the role of inflammation in pediatric transient focal cerebral arteriopathy using cerebrospinal fluid cytokine/chemokines as biomarkers., Methods: We measured 32 cytokine/chemokines in acute cerebrospinal fluid collected from children with stroke due to focal cerebral arteriopathy (n = 5) using multiplex immunoassay and compared with two patients with arterial ischemic stroke due to other causes (non-focal cerebral arteriopathy group, vertebral dissection, n = 1; cryptogenic, n = 1), pediatric encephalitis (n = 43), and non-inflammatory neurological disease controls (n = 20)., Results: Median age in the focal cerebral arteriopathy group was 9.3 years (range, 2.8-13 years). In the focal cerebral arteriopathy group (n = 5), four patients had middle cerebral ± distal carotid arteriopathy; one patient had posterior circulation arteriopathy. The median time from symptom onset to cerebrospinal fluid sampling was four days (range, 0.6-7 days). Only IL-6, IL-8, CXCL1, and CXCL10 levels were significantly higher in the acute cerebrospinal fluid of focal cerebral arteriopathy patients compared to non-inflammatory neurological disease controls and non-focal cerebral arteriopathy stroke. In contrast to focal cerebral arteriopathy, a broad array of Th1, Th2, Treg, Th17, B-cell related, and other broad spectrum cytokine/chemokines were elevated in encephalitis., Conclusion: The elevated cerebrospinal fluid cytokine/chemokines support innate, T cell, and granulocyte inflammatory mechanisms in children with focal cerebral arteriopathy. This warrants larger cohort studies to discriminate primary inflammatory signals of the arteriopathy from secondary inflammation due to the stroke itself.
- Published
- 2019
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30. Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy.
- Author
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Kothur K, Holman K, Farnsworth E, Ho G, Lorentzos M, Troedson C, Gupta S, Webster R, Procopis PG, Menezes MP, Antony J, Ardern-Holmes S, Dale RC, Christodoulou J, Gill D, and Bennetts B
- Subjects
- Adolescent, Child, Child, Preschool, Cost-Benefit Analysis, Epilepsy economics, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Infant, Male, Phenotype, Retrospective Studies, Epilepsy diagnosis, Epilepsy genetics, Genetic Testing economics, Genetic Testing methods, High-Throughput Nucleotide Sequencing economics
- Abstract
Purpose: To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy., Method: We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants., Results: The yield of pathogenic variants was 28.5% (n = 30/105), highest in early onset EE <3 months including Ohtahara syndrome (52%, n = 10/19) and lowest in generalized epilepsy (0/17). Patients identified with pathogenic variants had earlier onset of seizures (median 3.6 m vs 1.1y, p < 0.001, OR 0.6/year, P < 0.02) compared to those without pathogenic variants. Pathogenic/likely pathogenic variants were found in ALDH7A1 (2), CACNA1A (1), CDKL5 (3), FOXG1 (2), GABRB3 (1), GRIN2A (1), KCNQ2 (4), KCNQ3 (1), PRRT2 (1), SCN1A (6), SCN2A (2), SCN8A (2), SYNGAP1 (1), UBE3A (2) and WWOX (1) genes. This study expands the inheritance pattern caused by KCNQ3 mutations to include an autosomal recessive severe phenotype with neonatal seizures and severe developmental delay. The average cost of etiological evaluation was less with early use of EE panel compared to the traditional investigation approach ($5990 Australian dollars (AUD) vs $13069 AUD ; p = 0.02) among the patients with identified pathogenic variants., Conclusion: Targeted MPS testing is a comprehensive and economical investigation that enables early genetic diagnosis in children with EE. Careful clinical triage and selection of patients with young onset EE may maximize the yield of EE panel testing., (Copyright © 2018 British Epilepsy Association. All rights reserved.)
- Published
- 2018
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31. An open-label trial of JAK 1/2 blockade in progressive IFIH1 -associated neuroinflammation.
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Kothur K, Bandodkar S, Chu S, Wienholt L, Johnson A, Barclay P, Brogan PA, Rice GI, Crow YJ, and Dale RC
- Subjects
- Child, Preschool, Cytokines cerebrospinal fluid, Disease Progression, Humans, Inflammation cerebrospinal fluid, Inflammation genetics, Longitudinal Studies, Male, Mutation genetics, Nitriles, Pyrimidines, Signal Transduction drug effects, Enzyme Inhibitors therapeutic use, Inflammation drug therapy, Interferon-Induced Helicase, IFIH1 genetics, Janus Kinases metabolism, Pyrazoles therapeutic use
- Published
- 2018
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32. Cerebrospinal fluid cyto-/chemokine profile during acute herpes simplex virus induced anti-N-methyl-d-aspartate receptor encephalitis and in chronic neurological sequelae.
- Author
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Kothur K, Gill D, Wong M, Mohammad SS, Bandodkar S, Arbunckle S, Wienholt L, and Dale RC
- Subjects
- Child, Preschool, Encephalitis, Herpes Simplex complications, Female, Humans, Infant, Male, Nervous System Diseases etiology, S100 Calcium Binding Protein beta Subunit cerebrospinal fluid, Anti-N-Methyl-D-Aspartate Receptor Encephalitis cerebrospinal fluid, Chemokines cerebrospinal fluid, Encephalitis, Herpes Simplex cerebrospinal fluid, Nervous System Diseases cerebrospinal fluid, Simplexvirus pathogenicity
- Abstract
Aim: To examine the cytokine/chemokine profile of cerebrospinal fluid (CSF) during acute herpes simplex virus-induced N-methyl-d-aspartate receptor (NMDAR) autoimmunity and in chronic/relapsing post-herpes simplex virus encephalitis (HSE) neurological syndromes., Method: We measured longitudinal serial CSF cyto-/chemokines (n=34) and a glial marker (calcium-binding astroglial protein, S100B) in one patient during acute HSE and subsequent anti-NMDAR encephalitis, and compared the results with those from two patients with anti-NMDAR encephalitis without preceding HSE. We also compared cyto-/chemokines in cross-sectional CSF samples from three children with previous HSE who had ongoing chronic or relapsing neurological symptoms (2yr 9 mo-16y after HSE) with those in a group of children having non-inflammatory neurological conditions (n=20)., Results: Acute HSE showed elevation of a broad range of all T-helper-subset-related cyto-/chemokines and S100B whereas the post-HSE anti-NMDAR encephalitis phase showed persistent elevation of two of five T-helper-1 (chemokine [C-X-C motif] ligand 9 [CXCL9], CXCL10), three of five predominantly B-cell (CXCL13, CCL19, a proliferation-inducing ligand [APRIL])-mediated cyto-/chemokines, and interferon-α. The post-HSE anti-NMDAR encephalitis inflammatory response was more pronounced than anti-NMDAR encephalitis. All three chronic post-HSE cases showed persistent elevation of CXCL9, CXCL10, and interferon-α, and there was histopathological evidence of chronic lymphocytic inflammation in one biopsied case 7 years after HSE. Two of three chronic cases showed a modest response to immune therapy., Interpretation: HSE-induced anti-NMDAR encephalitis is a complex and pronounced inflammatory syndrome. There is persistent CSF upregulation of cyto-/chemokines in chronic or relapsing post-HSE neurological symptoms, which may be modifiable with immune therapy. The elevated cyto-/chemokines may be targets of monoclonal therapies., (© 2017 Mac Keith Press.)
- Published
- 2017
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33. Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases.
- Author
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Nosadini M, Mohammad SS, Corazza F, Ruga EM, Kothur K, Perilongo G, Frigo AC, Toldo I, Dale RC, and Sartori S
- Subjects
- Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis complications, Anti-N-Methyl-D-Aspartate Receptor Encephalitis etiology, Anti-N-Methyl-D-Aspartate Receptor Encephalitis microbiology, Child, Encephalitis, Herpes Simplex complications, Female, Humans, Mental Disorders etiology, Movement Disorders etiology, Anti-N-Methyl-D-Aspartate Receptor Encephalitis physiopathology, Encephalitis, Herpes Simplex physiopathology, Mental Disorders physiopathology, Movement Disorders physiopathology, Simplexvirus pathogenicity
- Abstract
Aim: To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis., Method: We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%)., Results: Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively; p<0.001), and significantly lower rate of seizures (70% vs 30% respectively; p=0.001). Compared with adults, during anti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo)., Interpretation: Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence., (© 2017 Mac Keith Press.)
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- 2017
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34. Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis.
- Author
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Kothur K, Wienholt L, Mohammad SS, Tantsis EM, Pillai S, Britton PN, Jones CA, Angiti RR, Barnes EH, Schlub T, Bandodkar S, Brilot F, and Dale RC
- Subjects
- Adolescent, Anti-N-Methyl-D-Aspartate Receptor Encephalitis diagnosis, Biomarkers cerebrospinal fluid, Child, Child, Preschool, DNA-Binding Proteins cerebrospinal fluid, DNA-Binding Proteins metabolism, Diagnosis, Differential, Encephalitis, Viral diagnosis, Encephalomyelitis, Acute Disseminated diagnosis, Enterovirus Infections diagnosis, Female, Humans, Infant, Logistic Models, Male, Proto-Oncogene Proteins B-raf cerebrospinal fluid, Proto-Oncogene Proteins B-raf metabolism, ROC Curve, Transcription Factors cerebrospinal fluid, Transcription Factors metabolism, Anti-N-Methyl-D-Aspartate Receptor Encephalitis immunology, Chemokines cerebrospinal fluid, Cytokines cerebrospinal fluid, Encephalitis, Viral immunology, Encephalomyelitis, Acute Disseminated immunology, Enterovirus Infections immunology
- Abstract
Background: Despite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications., Aim: To study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis., Methods: We measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups., Results: In descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97-1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E). Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis. There was no correlation between CSF neopterin and IFN-γ or IFN-α., Conclusion: A combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain. Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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35. B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination.
- Author
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Kothur K, Wienholt L, Tantsis EM, Earl J, Bandodkar S, Prelog K, Tea F, Ramanathan S, Brilot F, and Dale RC
- Subjects
- Adolescent, Autoantibodies blood, Brain immunology, Brain metabolism, Brain pathology, Chemokines cerebrospinal fluid, Child, Child, Preschool, Cytokines cerebrospinal fluid, Demyelinating Diseases immunology, Demyelinating Diseases pathology, Encephalomyelitis, Acute Disseminated immunology, Encephalomyelitis, Acute Disseminated metabolism, Encephalomyelitis, Acute Disseminated pathology, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Myelitis, Transverse immunology, Myelitis, Transverse metabolism, Myelitis, Transverse pathology, B-Lymphocytes metabolism, Chemokines metabolism, Cytokines metabolism, Demyelinating Diseases metabolism, Myelin-Oligodendrocyte Glycoprotein immunology, Neutrophils metabolism, Th17 Cells metabolism
- Abstract
Background: Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination., Aim: To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and -negative (NEG) groups., Methods: We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8), transverse myelitis (TM = 2) n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls., Results: The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies., Conclusion: Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.
- Published
- 2016
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36. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review.
- Author
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Kothur K, Wienholt L, Brilot F, and Dale RC
- Subjects
- Autoimmune Diseases diagnosis, B-Cell Activating Factor cerebrospinal fluid, Chemokine CXCL13 cerebrospinal fluid, Humans, Inflammation Mediators cerebrospinal fluid, Interferon-gamma cerebrospinal fluid, Nervous System Diseases diagnosis, Sensitivity and Specificity, Autoimmune Diseases cerebrospinal fluid, Biomarkers cerebrospinal fluid, Cytokines cerebrospinal fluid, Nervous System Diseases cerebrospinal fluid
- Abstract
Despite improved understanding of the pathogenesis of neuroinflammatory disorders of the brain and development of new diagnostic markers, our biomarker repertoire to demonstrate and monitor inflammation remains limited. Using PubMed database, we reviewed 83 studies on CSF cytokines and chemokines and describe the pattern of elevation and possible role of cytokines/chemokines as biomarkers in viral and autoimmune inflammatory neurological disorders of the CNS. Despite inconsistencies and overlap of cytokines and chemokines in different neuroinflammation syndromes, there are some trends regarding the pattern of cytokines/chemokine elevation. Namely B cell markers, such as CXCL13 and BAFF are predominantly investigated and found to be elevated in autoantibody-associated disorders, whereas interferon gamma (IFN-γ) is elevated mainly in viral encephalitis. Th2 and Th17 cytokines are frequently elevated in acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), whereas Th1 and Th17 cytokines are more commonly elevated in multiple sclerosis (MS). Cytokine/chemokine profiling might provide new insights into disease pathogenesis, and improve our ability to monitor inflammation and response to treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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37. Managing non-epileptic seizures and psychogenic dystonia in an adolescent girl with preterm brain injury.
- Author
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Chudleigh C, Kozlowska K, Kothur K, Davies F, Baxter H, Landini A, Hazell P, and Baslet G
- Subjects
- Adolescent, Adrenergic alpha-2 Receptor Agonists therapeutic use, Antipsychotic Agents therapeutic use, Clonidine therapeutic use, Combined Modality Therapy, Dibenzothiazepines therapeutic use, Dystonic Disorders complications, Dystonic Disorders drug therapy, Female, Fetal Diseases physiopathology, Humans, Intracranial Hemorrhages embryology, Physical Therapy Modalities, Psychotherapy, Quetiapine Fumarate, Seizures complications, Seizures drug therapy, Dystonic Disorders therapy, Seizures therapy
- Published
- 2013
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38. Use of thrombolytic therapy in cerebral venous sinus thrombosis with ulcerative colitis.
- Author
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Kothur K, Kaul S, Rammurthi S, Bandaru VC, Suryaprabha SA, and Mrudula KR
- Abstract
Cerebral venous thrombosis developing concurrently with active ulcerative colitis poses a therapeutic dilemma. We report the case of a 31-year-old woman who developed dural venous sinus thrombosis during the course of active ulcerative colitis in whom we accomplished clot lysis using intrasinus urokinase. The success of the procedure was assessed by improvement in the patient's neurological condition and resolution of imaging features without any bleeding complications. We also reviewed literature on various modalities of treatment of sinus venous thrombosis in patients with ulcerative colitis and outcome.
- Published
- 2012
- Full Text
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39. Prospective follow-up cardiac evaluation of children with Kawasaki disease in Northern India using the Japanese echocardiography criteria.
- Author
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Kothur K, Singh S, Sharma Y, and Mittal BR
- Subjects
- Child, Child, Preschool, Developing Countries, Echocardiography, Female, Follow-Up Studies, Humans, Immunoglobulins, Intravenous therapeutic use, India, Infant, Male, Mucocutaneous Lymph Node Syndrome diagnostic imaging, Mucocutaneous Lymph Node Syndrome drug therapy, Prospective Studies, Mucocutaneous Lymph Node Syndrome physiopathology
- Abstract
Objectives: There is no information available on the follow-up of children with Kawasaki disease (KD) in developing countries. This prospective study was undertaken to evaluate the cardiac abnormalities in a cohort of children with KD from a tertiary care centre in Northern India., Methods: Twenty children with diagnoses of KD and followed-up for at least 3 months in the Pediatric Rheumatology and Immunology Clinic of the Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh were evaluated between July 2002 to January 2006. Age of onset of disease ranged from 12 months to 10 years. The male: female ratio was 4:1. All patients had received intravenous immunoglobulin (IVIG) administration in the acute stage. Chest radiography showed no abnormalities in the 15 patients in whom it was done. Electrocardiographic abnormalities were seen in 3 patients in the form of T wave inversion in 3, ST segment changes in 2, and prolonged PR interval in 1 patient which normalized on follow-up. The mean time interval between the diagnosis of KD and first follow-up echocardiography was 7.9 +/- 3.5 months (range 4.4-11.4 months), which was repeated at 1 year and 2 years follow-up in patients who had abnormal findings. When we analyzed coronary artery diameters using Japanese Ministry of Health criteria, none of our patients could qualify for a diagnosis of coronary aneurysm. However, 3 had coronary artery diameters more than + 2 SD when the body surface area adjusted coronary dimensions were used., Results: One of our patients also had increased left ventricular dimensions but also had normal ejection fraction and shortening fraction, and there were no regional wall motion abnormalities. Mitral valve was thickened in 2 patients and trivial mitral regurgitation was noticed in 1 patient. Repeat echocardiography done 1 year and 2 years later on follow-up, showed persistence of thickening of the mitral valve leaflet in one of these but there was no regurgitation. None of our patients had evidence of cardiac failure, arrhythmia or myocardial infarction. There was no mortality in this series. Thallium scans were carried out during follow-up on 14 patients in this cohort and 2 patients showed perfusion defects in anterior wall, septum and posterior wall of lateral ventricle., Conclusions: We conclude that significant myocardial dysfunction and coronary artery changes due to KD were uncommon in our cohort. We speculate that this can be attributed to the IVIG given to the patients during the acute phase of the illness. To the best of our knowledge, this is the first study on detailed cardiac follow-up of children with KD from a developing country.
- Published
- 2007
40. Pulmonary sarcoidosis masquerading as tuberculosis.
- Author
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Singh M and Kothur K
- Subjects
- Child, Diagnosis, Differential, Female, Humans, Sarcoidosis, Pulmonary diagnosis, Tuberculosis, Pulmonary diagnosis
- Abstract
Pulmonary manifestations of sarcoidosis are common and may be initially confused with other common diseases like tuberculosis. We report an 11 yr old girl who presented with chronic cough, low grade fever, recent exposure to tuberculosis and hilar lymphadenopathy. She was provisionally diagnosed as pulmonary tuberculosis and treated accordingly. As she had poor response to anti tubercular therapy, diagnosis was subsequently revised to sarcoidosis by lung biopsy. Treatment with steroids resulted in significant clinical improvement.
- Published
- 2007
41. Perinatal tuberculosis a case series.
- Author
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Singh M, Kothur K, Dayal D, and Kusuma S
- Subjects
- Female, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases etiology, Infant, Newborn, Diseases physiopathology, Infectious Disease Transmission, Vertical, Intensive Care Units, Neonatal, Male, Tomography, X-Ray Computed, Tuberculosis, Pulmonary congenital, Tuberculosis, Pulmonary transmission, Infant, Newborn, Diseases diagnosis, Tuberculosis, Pulmonary diagnosis
- Abstract
Perinatal tuberculosis is insufficiently understood and has been rarely reported even in areas endemic for the disease, and unless a high index of suspicion is maintained the diagnosis can be missed. Differentiation of congenital from early postnatally acquired tuberculosis is only of epidemiological importance. We hereby report one case of congenital tuberculosis and three cases of perinatal tuberculosis, and problems faced during investigation and management and emphasize need for improved screening of women at risk and sensitization of the medical community about this entity.
- Published
- 2007
- Full Text
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42. Antenatal MRI in the diagnosis of tuberous sclerosis.
- Author
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Kothur K and Ray M
- Subjects
- Adult, Female, Humans, Pregnancy, Fetal Diseases diagnosis, Magnetic Resonance Imaging, Prenatal Diagnosis, Tuberous Sclerosis diagnosis
- Published
- 2006
43. Ciprofloxacin-induced anaphylactoid reaction.
- Author
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Kothur K, Singh M, and Dayal D
- Subjects
- Administration, Oral, Adolescent, Anaphylaxis therapy, Anti-Infective Agents administration & dosage, Anti-Inflammatory Agents therapeutic use, Ciprofloxacin administration & dosage, Diphenhydramine therapeutic use, Epinephrine therapeutic use, Female, Fluid Therapy, Histamine H1 Antagonists therapeutic use, Humans, Hydrocortisone therapeutic use, Sympathomimetics therapeutic use, Anaphylaxis chemically induced, Anti-Infective Agents adverse effects, Ciprofloxacin adverse effects
- Published
- 2006
- Full Text
- View/download PDF
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