93 results on '"Mohammad, SS"'
Search Results
2. 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
3. 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.
- Published
- 2019
4. Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children
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Tantsis, Em, Prelog, K, Alper, G, Benson, L, Gorman, M, Lim, M, Mohammad, Ss, Ramanathan, S, Brilot, F, Dale, Rc, Paediatric Myelitis Mri Study Group, Antony, Joby, Ardern-Holmes, S, Banwell, B, Camposano, S, Gill, D, Hopkins, S, Menezes, M, Nosadini, M, Ouvrier, R, Procopis, P, Riney, K, and Webster, R.
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Male ,030506 rehabilitation ,Pathology ,medicine.medical_specialty ,Cord ,Multiple Sclerosis ,Adolescent ,Myelitis ,Grey matter ,Transverse myelitis ,03 medical and health sciences ,Myelin ,0302 clinical medicine ,Developmental Neuroscience ,children ,myelin oligodendrocyte glycoprotein antibody ,Medicine ,Humans ,Child ,Autoantibodies ,Retrospective Studies ,First episode ,Aquaporin 4 ,aquaporin-4 antibody ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Brain ,Infant ,Magnetic resonance imaging ,enterovirus-71 ,medicine.disease ,Magnetic Resonance Imaging ,Enterovirus A, Human ,medicine.anatomical_structure ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Myelin-Oligodendrocyte Glycoprotein ,Neurology (clinical) ,0305 other medical science ,business ,Magnetic resonance imaging, enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, multiple sclerosis, myelitis, children ,030217 neurology & neurosurgery - Abstract
We used magnetic resonance imaging (MRI) to compare the neuroimaging of children with their first episode of clinical enterovirus 71-associated transverse myelitis (EV71-TM), myelin oligodendrocyte glycoprotein antibody positive transverse myelitis (MOG-TM), aquaporin-4 antibody positive transverse myelitis (AQP4-TM), transverse myelitis in multiple sclerosis (MS-TM), and unclassified transverse myelitis (UNC-TM).We performed a retrospective blinded radiological assessment and compared the neuroimaging of 52 children (32 females, 20 males; mean age 9y 8mo, SD 5y 5mo, range 5mo-17y) presenting with their first episode of myelitis caused by EV71-TM (n=11), MOG-TM (n=10), AQP4-TM (n=9), MS-TM (n=13), and UNC-TM (n=9).In the EV71-TM group, lesions were distributed throughout the cord and enhancement of nerve roots (ventral and dorsal) was common. The MOG-TM group had lesions distributed throughout the cord and most commonly longitudinally extensive transverse myelitis and lesions involving the grey matter alone on axial scans. The AQP4-TM group had lesions distributed in the cervicothoracic spine, cavitation, and contrast enhancing lesions. All patients with AQP4-TM had an abnormal brain MRI scan. The MS-TM group characteristically had multiple short segment lesions of the cord involving the cervicothoracic spine. The UNC-TM group did not have distinctive spinal MRI findings but had a relative paucity of lesions on their brain MRI scans.There are neuroimaging findings that are helpful in differentiating between myelitis associated with EV71, MOG, AQP4, and multiple sclerosis in children. These features may be useful early in the presentation of transverse myelitis while awaiting infectious/immunological testing, and/or further demyelinating events.Magnetic resonance imaging can help identify aetiologies for children presenting with a first episode of myelitis. Entervirus-71-associated myelitis lesions are distributed throughout the cord and enhancement of nerve roots is common. Lesions distributed throughout the cord are commonly seen in myelin oligodendrocyte-associated myelitis. Aquaporin-4-associated myelitis lesions are distributed in the cervicothoracic spine, cavitation and contrast enhancing lesions are common. Short segment lesions in the cervicothoracic spine are commonly seen in multiple sclerosis-associated myelitis.IMÁGENES DE RESONANCIA MAGNÉTICA EN ENTEROVIRUS-71, ANTICUERPOS DE GLICOPROTEÍNA DE LA MIELINA DEL OLIGODENDROCITO, ANTICUERPOS AQUAPORIN-4, Y ESCLEROSIS MÚLTIPLE-ASOCIADA A MIELITIS EN NIÑOS: OBJETIVO: Utilizamos imágenes de resonancia magnética (IRM) para comparar la neuroimagen de los niños con su primer episodio clínico de enterovirus 71-asociado a mielitis transversa (EV71-TM), mielitis transversa con anticuerpos de glicoproteína de la mielina del oligodendrocito positivos (MOG-TM), mielitis transversa con anticuerpos aquaporin-4 positivos (AQP4-TM), mielitis transversa en esclerosis múltiple (MS-TM) y mielitis transversa no clasificada (UNC-TM). MÉTODO: Se realizó un análisis radiológico, ciego, retrospectivo y se comparó la neuroimagen de 52 niños (32 mujeres, 20 varones; con edad promedio 9 años 8 meses, La DS 5 años 5 meses, el rango de 5 meses -17 años) que presentaron su primer episodio de mielitis causada por EV71-TM (n= 11), MOG-TM (n= 10), AQP4-TM (n= 9), MS-TM (n= 13) y UNC-TM (n= 9). RESULTADOS: En el grupo de EV71-TM, fue común observar lesiones distribuidas a través de la medula con realce de las raíces de nervio (ventrales y dorsales). El grupo de MOG-TM tenía lesiones distribuidas a través de la médula, más comúnmente mielitis transversa longitudinalmente extensa y lesiones que implican solamente la sustancia gris en exploraciones axiales. El grupo AQP4-TM tenía lesiones distribuidas en la medula cervicodorsal, cavitación y lesiones con realce en el contraste. Todos Pacientes con AQP4-TM tenían una IRM cerebral anormal. El grupo de MS-TM característicamente tenía lesiones múltiples de segmentos pequeños de la medula que involucran las regiones cervical y dorsal. El grupo UNC-TM no tenía hallazgos de IRM distintivos en la medula espinal, pero tenía una relativa escasez de lesiones cerebrales IRM. INTERPRETACIÓN: Hay hallazgos de neuroimagen en niños que son útiles en diferenciar entre mielitis asociada a EV71, a MOG, a AQP4, y esclerosis múltiple. Estas características pueden ser útiles al inicio de la presentación de la mielitis transversa mientras se espera la prueba infecciosa/inmunológica y/u otros acontecimientos desmielinizantes.IMAGEM POR RESSONÂNCIA MAGNÉTICA EM ENTEROVÍRUS-71, ANTICORPO DA GLICOPROTEÍNA DE OLIGODENDRÓCITO DA MIELINA, ANTICORPO AQUAPORINA-4, E MIELITE ASSOCIADA A ESCLEROSE MÚLTIPLA EM CRIANÇAS: OBJETIVO: Usamos imagens de ressonância funcional (IRM) para comparar as neuroimagens de crianças com o primeiro episósio de mielite transversa clínica associada a enterovírus-71 (MT-EV71), mielite transversa positiva para anticorpo da glicoproteína de oligodendrócit oda mielina (MT-GOM), mielite transversa positiva para anticorpo aquaporina-4 (MT-AQP4), mielite transversa em esclerose múltipla (MT-EM), e mielite transversa não classificada (MT-NC). MÉTODO: Realizamos uma avaliação radiológica retrospectiva cega, e comparamos a neuroimagem de 52 crianças (32 do sexo feminino, 20 do sexo masculino; média de idade 9a 8m, DP 5a 5m, variação 5m-17a) apresentando seu primeiro episódio de mielite causada por MT-EV71 (n=11), MT-GOM (n=10), MT-AQP4 (n=9), MT-EM (n=13), e MT-NC (n=9). RESULTADOS: No grupo MT-EV71, as lesões se distribuíram por toda a medula, e realces das raízes nervosas (ventrais e dorsais) eram comuns. O grupo MT-GOM teve lesões distribuídas por toda a medula, e mais comumente mielite transversa extensiva longitudinalmente e lesões envolvendo apenas a substância cinzenta nas imagens axiais. O grupo MT-AQP4 teve lesões distribuídas na coluna cérvico-torácica, cavitação, e lesões realçadas pelo contraste. Todos os pacientes com MT-AQP4 -tiveram uma IRM cerebral anormal. O grupo MT-EM caracteristicamente teve múltiplas lesões de segmentos curtos da medula envolvendo a região cérvico-torácica. O grupo MT-NC não teve achados distintivos de IRM espinhal, mas tiveram relativamente menos lesões nas imagens cerebrais. INTERPRETAÇÃO: Há achados de neuroimagem úteis para diferenciar a mielite associada com EV71, GOM, AQP4 e esclerose múltipla em crianças. Estes aspectos podem ser úteis na apresentação precoce da mielite transversa, enquanto se aguarda testes infecciosos/imunológicos, e e/ou outros eventos desmielinizantes.
- Published
- 2018
5. The movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study
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Varley, J, Webb, A, Balint, B, Fung, V, Sethi, K, Tijssen, MAJ, Lynch, T, Mohammad, SS, Britton, F, Evans, M, Hacohen, Y, Lin, JP, Nardocci, N, Granata, T, Dale, RC, Lim, RM, Bhatia, K, Lang, A, Irani, SR, and Movement Disorder (MD)
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CHILDREN - Published
- 2018
6. Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder
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Nosadini, M, Alper, G, Riney, CJ, Benson, LA, Mohammad, SS, Ramanathan, S, Nolan, M, Appleton, R, Leventer, RJ, Deiva, K, Brilot, F, Gorman, MP, Waldman, AT, Banwell, B, Dale, RC, Nosadini, M, Alper, G, Riney, CJ, Benson, LA, Mohammad, SS, Ramanathan, S, Nolan, M, Appleton, R, Leventer, RJ, Deiva, K, Brilot, F, Gorman, MP, Waldman, AT, Banwell, B, and Dale, RC
- Abstract
OBJECTIVE: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. METHODS: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as "repopulation," "depletion," or "depletion failure" relapses (repopulation threshold CD19 ≥10 × 10(6) cells/L). RESULTS: The 16 patients (14 girls; mean age 9.6 years, range 1.8-15.3) had a mean of 6.1 events (range 1-11) during a mean follow-up of 6.1 years (range 1.6-13.6) and received a total of 76 rituximab courses (mean 4.7, range 2-9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 "repopulation," 3 "depletion," and 4 "depletion failure" relapses. Of the 13 "repopulation" relapses, 4 had CD19 10-50 × 10(6) cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. CONCLUSION: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses.
- Published
- 2016
7. Content and readability of patient educational materials about neuromodulation for childhood movement disorders.
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Barnacoat JM, Lewis J, Stewart K, Mohammad SS, and Paget S
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Purpose: To assess content and readability of online patient educational materials (PEMs) for paediatric deep brain stimulation (DBS) and intrathecal baclofen (ITB)., Methods: A content analysis of PEMs identified from top children's hospitals, institutions affiliated with published neuromodulation research, and DBS and ITB device manufacturers was conducted. PEM content was analysed using a predetermined framework. Readability was assessed using the Simple Measure of Gobbledygook (SMOG)., Results: Of 109 PEMs (72 DBS; 37 ITB) identified, most (77 (71%)) originated in the United States. More ITB PEMs (27 (73%)) contained specific paediatric information than DBS PEMs (16 (22%)). PEMS more frequently described benefits (DBS: 92%; ITB: 89%) than risks (DBS: 49%; ITB: 78%). Frequent content included pre- and post-operative care, procedural details, and device information. Less common content included long-term lifestyle considerations, alternatives, patient experiences, and financial details. Median readability of PEMs was 13.2 (interquartile range [IQR]: 11.4-14.45) for DBS and 11.8 (IQR: 11-12.9) for ITB., Conclusions: Available ITB and DBS PEMs often miss important broader details of the treatments, and have additional shortcomings such as poor readability scores. Our findings highlight need for more holistic content within neuromodulation PEMs, improved accessibility, and more balanced representation of risks and benefits.
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- 2024
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8. International consensus definitions for infection-triggered encephalopathy syndromes.
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Sakuma H, Thomas T, Debinski C, Eyre M, Han VX, Jones HF, Kawano G, Lee VW, Malone S, Matsuishi T, Mohammad SS, Mori T, Nishida H, Nosadini M, Takanashi JI, Mizuguchi M, Lim M, and Dale RC
- Abstract
Aim: To develop standardized diagnostic criteria for 'infection-triggered encephalopathy syndrome (ITES)' and five specific clinical syndromes of ITES., Method: The draft definitions were based on existing criteria, standardized, and discussed by a panel of international experts using nominal group technique over 18 months to achieve consensus. All criteria use the same format: (1) presence of infection/fever; (2) clinical features including encephalopathy; (3) neuroradiological features on magnetic resonance imaging; (4) exclusion of other causes., Results: We first highlighted differences between ITES and infectious and autoimmune encephalitis, which is the most important differential diagnosis. Consensus was achieved to define five specific ITESs: acute encephalopathy with biphasic seizures and late reduced diffusion; acute necrotizing encephalopathy; mild encephalopathy with a reversible splenial lesion; acute fulminant cerebral oedema; and acute shock with encephalopathy and multiorgan failure. Two further conditions that are currently classified as epilepsy syndromes but have similar features to ITES, namely febrile infection-related epilepsy syndrome and hemiconvulsion-hemiplegia-epilepsy syndrome, are also discussed., Interpretation: The consensus definition is expected to improve awareness of this disease concept, provide diagnostic framework, and facilitate future international research and clinical trials., (© 2024 The Author(s). 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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9. Editorial: Movement disorders in neurometabolic conditions.
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Garg D, Sharma S, Mohammad SS, and Prasad AN
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Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2024
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10. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.
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Kooshavar D, Amor DJ, Boggs K, Baker N, Barnett C, de Silva MG, Edwards S, Fahey MC, Marum JE, Snell P, Bozaoglu K, Pope K, Mohammad SS, Riney K, Sachdev R, Scheffer IE, Schenscher S, Silberstein J, Smith N, Tom M, Ware TL, Lockhart PJ, and Leventer RJ
- Abstract
This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A . This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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11. Movement disorders associated with pediatric encephalitis.
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Dale RC and Mohammad SS
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- Adolescent, Child, Child, Preschool, Humans, Autoantibodies metabolism, Anti-N-Methyl-D-Aspartate Receptor Encephalitis complications, Anti-N-Methyl-D-Aspartate Receptor Encephalitis diagnosis, Catatonia, Chorea, Movement Disorders etiology, Subacute Sclerosing Panencephalitis complications
- Abstract
New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis is one of the more important causes of new onset movement disorders, and movement disorders are a common feature (~25%) of all encephalitis. However, all encephalitides are not the same, and movement disorders are a key diagnostic feature that can help the clinician identify the etiology of the encephalitis, and therefore appropriate treatment is required. Movement disorders are a characteristic feature of autoimmune encephalitis such as anti-NMDAR encephalitis, herpes simplex virus encephalitis-induced autoimmune encephalitis, and basal ganglia encephalitis. Other rarer autoantibody-associated encephalitis syndromes with movement disorder associations include encephalitis associated with glycine receptor, DPPX, and neurexin-3 alpha autoantibodies. In addition, movement disorders can accompany acute disseminated encephalomyelitis with and without myelin oligodendrocyte glycoprotein antibodies. Extremely important infectious encephalitides that have characteristic movement disorder associations include Japanese encephalitis, dengue fever, West Nile virus, subacute sclerosing panencephalitis (SSPE), and SARS-CoV-2 (COVID-19). This chapter discusses how specific movement disorder phenomenology can aid clinician diagnostic suspicion, such as stereotypy, perseveration, and catatonia in anti-NMDAR encephalitis, dystonia-Parkinsonism in basal ganglia encephalitis, and myoclonus in SSPE. In addition, the chapter discusses how the age of the patients can influence the movement disorder phenomenology, such as in anti-NMDAR encephalitis where chorea is typical in young children, even though catatonia and akinesia is more common in adolescents and adults., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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12. DHDDS and NUS1: A Converging Pathway and Common Phenotype.
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Williams LJ, Waller S, Qiu J, Innes E, Elserafy N, Procopis P, Sampaio H, Mahant N, Tchan MC, Mohammad SS, Morales-Briceño H, and Fung VSC
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- Infant, Newborn, Humans, Diphosphates, Phenotype, Ataxia, Dolichols metabolism, Receptors, Cell Surface, Myoclonus, Movement Disorders
- Abstract
Background: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis., Cases: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles., Literature Review: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific., Conclusions: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels., (© 2023 Commonwealth of Australia. Movement Disorders Clinical © 2023 International Parkinson and Movement Disorder Society.)
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- 2024
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13. Oculomotor Apraxia as an Early Presenting Sign of Juvenile-Onset Huntington's Disease.
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Innes EA, Qiu J, Morales-Briceño H, Farrar MA, and Mohammad SS
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- 2023
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14. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.
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Palmer EE, Pusch M, Picollo A, Forwood C, Nguyen MH, Suckow V, Gibbons J, Hoff A, Sigfrid L, Megarbane A, Nizon M, Cogné B, Beneteau C, Alkuraya FS, Chedrawi A, Hashem MO, Stamberger H, Weckhuysen S, Vanlander A, Ceulemans B, Rajagopalan S, Nunn K, Arpin S, Raynaud M, Motter CS, Ward-Melver C, Janssens K, Meuwissen M, Beysen D, Dikow N, Grimmel M, Haack TB, Clement E, McTague A, Hunt D, Townshend S, Ward M, Richards LJ, Simons C, Costain G, Dupuis L, Mendoza-Londono R, Dudding-Byth T, Boyle J, Saunders C, Fleming E, El Chehadeh S, Spitz MA, Piton A, Gerard B, Abi Warde MT, Rea G, McKenna C, Douzgou S, Banka S, Akman C, Bain JM, Sands TT, Wilson GN, Silvertooth EJ, Miller L, Lederer D, Sachdev R, Macintosh R, Monestier O, Karadurmus D, Collins F, Carter M, Rohena L, Willemsen MH, Ockeloen CW, Pfundt R, Kroft SD, Field M, Laranjeira FER, Fortuna AM, Soares AR, Michaud V, Naudion S, Golla S, Weaver DD, Bird LM, Friedman J, Clowes V, Joss S, Pölsler L, Campeau PM, Blazo M, Bijlsma EK, Rosenfeld JA, Beetz C, Powis Z, McWalter K, Brandt T, Torti E, Mathot M, Mohammad SS, Armstrong R, and Kalscheuer VM
- Subjects
- Male, Female, Humans, Mutation, Missense, Genes, X-Linked, Phenotype, Chloride Channels genetics, Neurodevelopmental Disorders genetics
- Abstract
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis., (© 2022. The Author(s).)
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- 2023
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15. The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.
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Pérez-Dueñas B, Gorman K, Marcé-Grau A, Ortigoza-Escobar JD, Macaya A, Danti FR, Barwick K, Papandreou A, Ng J, Meyer E, Mohammad SS, Smith M, Muntoni F, Munot P, Uusimaa J, Vieira P, Sheridan E, Guerrini R, Cobben J, Yilmaz S, De Grandis E, Dale RC, Pons R, Peall KJ, Leuzzi V, and Kurian MA
- Subjects
- Child, Humans, Hyperkinesis, Nerve Tissue Proteins, Forkhead Transcription Factors, Phosphoric Diester Hydrolases, Sodium-Potassium-Exchanging ATPase, GTP-Binding Protein alpha Subunits, Gi-Go genetics, Movement Disorders genetics, Movement Disorders diagnosis, Dystonic Disorders genetics, Chorea diagnosis, Chorea genetics, Dystonia
- Abstract
Background and Objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders., Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria., Results: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia., Conclusions: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
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- 2022
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16. Levodopa Responsive Dystonia Parkinsonism, Intellectual Disability, and Optic Atrophy Due to a Heterozygous Missense Variant in AFG3L2 .
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Wong WK, Troedson C, Dale RC, Roscioli T, Field M, Palmer E, Martin EM, Kumar KR, and Mohammad SS
- Abstract
Competing Interests: No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work.
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- 2022
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17. Acute encephalopathy with biphasic seizures and restricted diffusion.
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Nguyen KL, McGurty D, Innes EA, Goetti R, Thomas T, Dal S, Bandodkar S, Yan J, Wong M, Dale RC, and Mohammad SS
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- Acute Disease, Humans, Infant, Seizures etiology, Brain Diseases
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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
- Abstract
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. SPG11 presenting with dystonic tremor in childhood.
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Innes EA, Goetti R, Mahant N, Ho G, Williams L, Gill D, Dale RC, and Mohammad SS
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- Humans, Mutation genetics, Phenotype, Proteins genetics, Tremor etiology, Tremor genetics, Spastic Paraplegia, Hereditary diagnosis, Spastic Paraplegia, Hereditary genetics
- Abstract
This is a unique case of SPG11 mutation presenting as childhood onset dystonic tremor without weakness or spastic paraplegia. Hereditary spastic paraplegia is the most common phenotype of SPG11 mutation though there are reports of an extended phenotype of SPG11 including dopa-responsive dystonia and tremor., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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20. Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study.
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Méneret A, Mohammad SS, Cif L, Doummar D, DeGusmao C, Anheim M, Barth M, Damier P, Demonceau N, Friedman J, Gallea C, Gras D, Gurgel-Giannetti J, Innes EA, Necpál J, Riant F, Sagnes S, Sarret C, Seliverstov Y, Paramanandam V, Shetty K, Tranchant C, Doulazmi M, Vidailhet M, Pringsheim T, and Roze E
- Subjects
- Adenylyl Cyclases genetics, Caffeine therapeutic use, Child, Humans, Retrospective Studies, Dyskinesias etiology, Dyskinesias genetics, Movement Disorders genetics
- Abstract
Background: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine., Objective: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia., Methods: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire., Results: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening., Conclusion: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)
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- 2022
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21. Postinfectious Acute Cerebellar Syndromes in Children: A Nationally Ascertained Case Series From Australia 2013-2018.
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Gunaratna GPS, Mohammad SS, Blyth CC, Clark J, Crawford N, Marshall H, Dale RC, Jones CA, and Britton PN
- Abstract
Introduction: Postinfectious acute cerebellar syndromes show a wide spectrum of acute severity and can occur with acute febrile illness or vaccine receipt. Varicella has historically been the most common cause, associated with up to 25% of cases in large cohorts. This study aimed to describe the spectrum of syndromes in a setting with high varicella vaccine coverage., Method: Data were collected on children initially identified as "suspected encephalitis" subsequently designated "not-encephalitis" at participating children's hospitals in the Paediatric Active Enhanced Disease Surveillance (PAEDS) network, Australia, as part of the Acute Childhood Encephalitis study. A comprehensive descriptive analysis was undertaken on prospectively identified, national series of children with postinfectious acute cerebellar syndromes from 2013 to 2018. Cases were classified using a previously validated severity score, and the outcome was assessed at 12 months using the Liverpool Outcome Scale score., Results: A total of 20 cases (65% were vaccinated for varicella) were included, of which 70% were subcategorized as acute cerebellar ataxia (ACA), 20% acute cerebellitis (AC), and 10% acute fulminant cerebellitis (AFC). An acute febrile illness was noted in 55% and none were related to varicella or were temporally related to varicella vaccination or other childhood vaccines. A subset (total of 7 children) followed up at 12 months all showed reduced Liverpool Outcome Scale scores., Discussion: The study provides an overall description of this uncommon spectrum of neurologic syndromes and shows the infrequency of varicella zoster virus as a cause in a vaccinated population.
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- 2022
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22. Improving epilepsy control among children with cerebral palsy in rural Bangladesh: a prospective cohort-based study.
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Karim T, Das MC, Muhit M, Badawi N, Khandaker G, and Mohammad SS
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- Anticonvulsants therapeutic use, Bangladesh epidemiology, Child, Humans, Prospective Studies, Cerebral Palsy complications, Cerebral Palsy epidemiology, Epilepsy drug therapy, Epilepsy epidemiology
- Abstract
Objective: To define the prevalence and seizure subtypes among children with cerebral palsy (CP) in rural Bangladesh and explore barriers to optimum epilepsy control., Design: Prospective cohort study., Setting: The study was conducted in Shahjadpur, a rural subdistrict of Bangladesh., Participants: Children (<18 years) with CP and epilepsy identified using the Bangladesh CP Register (BCPR) in the study site., Methods: Assessments were conducted in three focused epilepsy clinics overseen by a paediatric neurologist between December 2016 and January 2018, with intervening phone and video-conference follow-ups. Details of event type, frequency and medication compliance were collected. Antiepileptic drugs (AEDs) were prescribed based on seizure type, family income, comorbidity and medication availability., Results: 23.4% (170/726) of the BCPR cohort had a clinical diagnosis of epilepsy of whom 166 were assessed. Following the focused epilepsy clinics, 62.0% (103/166) children were clinically determined to have ongoing epileptic seizures. 62.1% (64/103) had generalised onset tonic clonic seizures, 27.2% (28/103) had focal onset seizures with impaired awareness and 10.7% (11/103) had other seizure types. None of the children with prolonged seizures (31/103) had an emergency seizure management plan. Non-epileptic events were being pharmacologically treated as seizures in 18.1% (30/166) children. Financial constraints were the main reason for non-compliance on follow-up., Conclusions: Gaps in optimum epilepsy management in rural Bangladesh are amenable to improvement anchored with local healthcare workers. Training and clinical care focused on recognition of common seizure types, seizure mimics and rationalising use of available AEDs can be facilitated by better referral pathways and telehealth support., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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23. BCAS3-Related Neurodevelopmental Disorder Shows Magnetic Resonance Imaging Features Resembling Brain Iron Accumulation.
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Wong WK, Troedson C, Damme M, Goetti R, Temple SEL, Schöls L, Balousha G, Prelog K, Buckley M, Roscioli T, Hengel H, and Mohammad SS
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- Brain diagnostic imaging, Brain metabolism, Humans, Iron, Neoplasm Proteins metabolism, Magnetic Resonance Imaging, Neurodevelopmental Disorders
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- 2022
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24. Improvised bubble continuous positive airway pressure ventilation use in neonates in resource-limited settings: a systematic review and meta-analysis.
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Usman F, Farouk ZL, Tsiga-Ahmed FI, Abdussalam M, Jalo RI, Mohammad SS, and Aliyu MH
- Abstract
Objectives: In the face of limited fiscal and technical resources, improvised methods have been used to provide effective and sustainable ventilatory support in low-resource settings to reduce neonatal mortality associated with respiratory complications. This study assessed the use of improvised bubble continuous positive airway pressure (ibCPAP) ventilation among neonates with respiratory complications and determined its effect on neonatal outcomes in low- and middle-income countries (LMICs)., Content: Hospital-based studies conducted between 2010 and 2020 in LMICs were reviewed. Rayyan
® software for systematic review was used for screening and article selection. We used Stata® Statacorp Texas USA software to estimate pooled prevalence, proportion estimates, weighted mean differences and 95% Confidence Interval (CI), using the random effects model., Summary: A total of 193 articles were generated and 125 were reviewed. Thirteen articles with 806 neonates on ibCPAP ventilation were included. The pooled prevalence of ibCPAP use was 7.0% (95% CI: 3.0%-13.0%). There was a significant difference in mean oxygen saturation before and after ibCPAP use (-1.34% [95% CI: -1.65% to -1.02%, p<0.01). The duration of oxygen requirement among neonates on ibCPAP was 6.5 hours less than controls (0.27 days [95%CI: -0.49 to -0.05, p<0.01)., Outlook: IbCPAP had no effect on the respiratory rate, duration of admission, mortality and survival. IbCPAP use in LMIC hospitals is low and its use improved oxygen saturation and duration on oxygen among the neonates, but had no impact on length of stay, respiratory rate, mortality or survival., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)- Published
- 2022
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25. Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy.
- Author
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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
- Subjects
- 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
- Abstract
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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26. 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
- Subjects
- Child, Preschool, Female, Humans, Microcephaly diagnosis, Microcephaly genetics, Amino Acyl-tRNA Synthetases genetics, Epilepsy diagnosis, Epilepsy genetics
- Abstract
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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27. Cerebrospinal fluid neopterin as a biomarker of treatment response to Janus kinase inhibition in Aicardi-Goutières syndrome.
- Author
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Han VX, Mohammad SS, Jones HF, Bandodkar S, Crow YJ, and Dale RC
- Subjects
- Adolescent, Biomarkers cerebrospinal fluid, Child, Child, Preschool, Female, Humans, Janus Kinase 1 antagonists & inhibitors, Male, Retrospective Studies, Autoimmune Diseases of the Nervous System cerebrospinal fluid, Autoimmune Diseases of the Nervous System drug therapy, Janus Kinase Inhibitors pharmacology, Neopterin cerebrospinal fluid, Nervous System Malformations cerebrospinal fluid, Nervous System Malformations drug therapy
- Abstract
Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutières syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range -36% to -88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range -63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response., (© 2021 Mac Keith Press.)
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- 2022
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28. Emerging evidence of Toll-like receptors as a putative pathway linking maternal inflammation and neurodevelopmental disorders in human offspring: A systematic review.
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Han VX, Jones HF, Patel S, Mohammad SS, Hofer MJ, Alshammery S, Maple-Brown E, Gold W, Brilot F, and Dale RC
- Subjects
- Animals, Female, Humans, Inflammation metabolism, Obesity metabolism, Pregnancy, Toll-Like Receptors metabolism, Neurodevelopmental Disorders metabolism, Placenta metabolism
- Abstract
Inflammation is increasingly recognised to play a major role in gene-environment interactions in neurodevelopmental disorders (NDDs). The effects of aberrant immune responses to environmental stimuli in the mother and in the child can affect neuroimmune signalling that is central to brain development. Toll-like receptors (TLR) are the best known innate immune pattern and danger recognition sensors to various environmental threats. In animal models, maternal immune activation (MIA), secondary to inflammatory factors including maternal gestational infection, obesity, diabetes, and stress activate the TLR pathway in maternal blood, placenta, and fetal brain, which correlate with offspring neurobehavioral abnormalities. Given the central role of TLR activation in animal MIA models, we systematically reviewed the human evidence for TLR activation and response to stimulation across the maternal-fetal interface. Firstly, we included 59 TLR studies performed in peripheral blood of adults in general population (outside of pregnancy) with six chronic inflammatory factors which have epidemiological evidence for increased risk of offspring NDDs, namely, obesity, diabetes mellitus, depression, low socio-economic status, autoimmune diseases, and asthma. Secondly, eight TLR studies done in human pregnancies with chronic inflammatory factors, involving maternal blood, placenta, and cord blood, were reviewed. Lastly, ten TLR studies performed in peripheral blood of individuals with NDDs were included. Despite these studies, there were no studies which examined TLR function in both the pregnant mother and their offspring. Increased TLR2 and TLR4 mRNA and/or protein levels in peripheral blood were common in obesity, diabetes mellitus, depression, autoimmune thyroid disease, and rheumatoid arthritis. To a lesser degree, TLR 3, 7, 8, and 9 activation were found in peripheral blood of humans with autoimmune diseases and depression. In pregnancy, increased TLR4 mRNA levels were found in the peripheral blood of women with diabetes mellitus and systemic lupus erythematosus. Placental TLR activation was found in mothers with obesity or diabetes. Postnatally, dysregulated TLR response to stimulation was found in peripheral blood of individuals with NDDs. This systematic review found emerging evidence that TLR activation may represent a mechanistic link between maternal inflammation and offspring NDD, however the literature is incomplete and longitudinal outcome studies are lacking. Identification of pathogenic mechanisms in MIA could create preventive and therapeutic opportunities to mitigate NDD prevalence and severity., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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29. Possible EIF2AK2 -Associated Stress-Related Neurological Decompensation with Combined Dystonia and Striatal Lesions.
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Waller SE, Morales-Briceño H, Williams L, Mohammad SS, Fellner A, Kumar KR, Tchan M, and Fung VSC
- Abstract
Background: Variants in EIF2AK2 have been recently associated with a spectrum of neurological disease encompassing isolated dystonia to fever-related neurological decompensation, movement disorders and leukodystrophy., Case: A 32-year old patient presented with childhood-onset episodes of neurological decompensation after febrile illness, progressive anarthria, dystonia and spasticity. The T2/FLAIR MRI showed bilateral posterolateral putamen hyperintensities and white matter changes suggestive of leukodystrophy. Initial extensive metabolic workup and whole genome sequencing (WGS) was unremarkable. Re-analysis of the WGS data revealed a variant in exon 3 of the EIF2AK2 gene [ (NM_001135651.3): c.92C > G (p.Pro31Arg)]. EIF2AK2 -associated disorders should be incorporated into the differential diagnosis of the syndrome of fever-related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging., Literature Review: Disease-causing variants in EIF2AK2 have been reported in 24 individuals from 16 families in the literature to date. Two broad phenotypes have been described, including: (1) childhood-onset generalized dystonia and a normal brain MRI; and (2) early childhood-onset developmental delay combined with movement disorders, spasticity, and seizures in some. Notably, 92% of these patients have neurological deterioration after febrile illness or other physiological stress. Hypomyelination or delayed myelination and thin corpus callosum are seen in most patients and lower medullary lessions are common. Basal ganglia lesions have been reported previously in one case., Conclusions: EIF2AK2 -associated disorders should be incorporated into the differential diagnosis of the syndrome of fever-related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging., Competing Interests: The authors report no specific grants for this research financial disclosure. No conflicts of interest are reported by the authors., (© 2021 International Parkinson and Movement Disorder Society.)
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- 2021
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30. TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.
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Goodman LD, Cope H, Nil Z, Ravenscroft TA, Charng WL, Lu S, Tien AC, Pfundt R, Koolen DA, Haaxma CA, Veenstra-Knol HE, Wassink-Ruiter JSK, Wevers MR, Jones M, Walsh LE, Klee VH, Theunis M, Legius E, Steel D, Barwick KES, Kurian MA, Mohammad SS, Dale RC, Terhal PA, van Binsbergen E, Kirmse B, Robinette B, Cogné B, Isidor B, Grebe TA, Kulch P, Hainline BE, Sapp K, Morava E, Klee EW, Macke EL, Trapane P, Spencer C, Si Y, Begtrup A, Moulton MJ, Dutta D, Kanca O, Wangler MF, Yamamoto S, Bellen HJ, and Tan QK
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- Alleles, Amino Acid Sequence, Animals, Developmental Disabilities metabolism, Developmental Disabilities pathology, Drosophila Proteins antagonists & inhibitors, Drosophila Proteins metabolism, Drosophila melanogaster genetics, Drosophila melanogaster growth & development, Drosophila melanogaster metabolism, Eye Diseases, Hereditary metabolism, Eye Diseases, Hereditary pathology, Female, Gene Dosage, Gene Expression Regulation, Developmental, Genome, Human, Humans, Infant, Infant, Newborn, Intellectual Disability metabolism, Intellectual Disability pathology, Karyopherins antagonists & inhibitors, Karyopherins metabolism, Male, Musculoskeletal Abnormalities metabolism, Musculoskeletal Abnormalities pathology, Mutation, Neurons metabolism, Neurons pathology, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Sequence Alignment, Sequence Homology, Amino Acid, Whole Genome Sequencing, beta Karyopherins metabolism, ran GTP-Binding Protein metabolism, Developmental Disabilities genetics, Drosophila Proteins genetics, Eye Diseases, Hereditary genetics, Intellectual Disability genetics, Karyopherins genetics, Musculoskeletal Abnormalities genetics, beta Karyopherins genetics, ran GTP-Binding Protein genetics
- Abstract
Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. Y.S. and A.B. are employees of GeneDx, Inc., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2021
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31. Neuroinflammation triggered by SARS-CoV-2 infection: syndromes and therapies.
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Dale RC, Mohammad SS, and Britton PN
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- Humans, Syndrome, COVID-19, SARS-CoV-2
- Abstract
Competing Interests: We declare no competing interests.
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- 2021
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32. A description of novel variants and review of phenotypic spectrum in UBA5 -related early epileptic encephalopathy.
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Briere LC, Walker MA, High FA, Cooper C, Rogers CA, Callahan CJ, Ishimura R, Ichimura Y, Caruso PA, Sharma N, Brokamp E, Koziura ME, Mohammad SS, Dale RC, Riley LG, Phillips JA, Komatsu M, and Sweetser DA
- Subjects
- Adolescent, Brain diagnostic imaging, Brain physiology, Child, Cohort Studies, Epilepsy genetics, Female, Genetic Association Studies, HEK293 Cells, Humans, Male, Muscle Hypotonia, Mutation, Missense, Proteins genetics, Proteins metabolism, Spasms, Infantile diagnostic imaging, Spasms, Infantile pathology, Young Adult, Phenotype, Spasms, Infantile genetics, Spasms, Infantile metabolism, Ubiquitin-Activating Enzymes genetics, Ubiquitin-Activating Enzymes metabolism
- Abstract
Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in UBA5 , a gene involved in a ubiquitin-like post-translational modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in UBA5 All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in UBA5 All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in trans with a second UBA5 variant. One patient has the previously described c.562C > T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T > C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T > C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic UBA5 variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype-phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy., (© 2021 Briere et al.; Published by Cold Spring Harbor Laboratory Press.)
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- 2021
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33. 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
- Abstract
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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34. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.
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Stamberger H, Hammer TB, Gardella E, Vlaskamp DRM, Bertelsen B, Mandelstam S, de Lange I, Zhang J, Myers CT, Fenger C, Afawi Z, Almanza Fuerte EP, Andrade DM, Balcik Y, Ben Zeev B, Bennett MF, Berkovic SF, Isidor B, Bouman A, Brilstra E, Busk ØL, Cairns A, Caumes R, Chatron N, Dale RC, de Geus C, Edery P, Gill D, Granild-Jensen JB, Gunderson L, Gunning B, Heimer G, Helle JR, Hildebrand MS, Hollingsworth G, Kharytonov V, Klee EW, Koeleman BPC, Koolen DA, Korff C, Küry S, Lesca G, Lev D, Leventer RJ, Mackay MT, Macke EL, McEntagart M, Mohammad SS, Monin P, Montomoli M, Morava E, Moutton S, Muir AM, Parrini E, Procopis P, Ranza E, Reed L, Reif PS, Rosenow F, Rossi M, Sadleir LG, Sadoway T, Schelhaas HJ, Schneider AL, Shah K, Shalev R, Sisodiya SM, Smol T, Stumpel CTRM, Stuurman K, Symonds JD, Mau-Them FT, Verbeek N, Verhoeven JS, Wallace G, Yosovich K, Zarate YA, Zerem A, Zuberi SM, Guerrini R, Mefford HC, Patel C, Zhang YH, Møller RS, and Scheffer IE
- Subjects
- Female, Genes, X-Linked genetics, Humans, Male, Nerve Tissue Proteins, Seizures genetics, Autism Spectrum Disorder genetics, Brain Diseases genetics, Epilepsy genetics
- Abstract
Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy., Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy., Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism., Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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- 2021
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35. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review.
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Han VX, Patel S, Jones HF, Nielsen TC, Mohammad SS, Hofer MJ, Gold W, Brilot F, Lain SJ, Nassar N, and Dale RC
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- Female, Humans, Inflammation, Pregnancy, Risk Factors, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Neurodevelopmental Disorders, Prenatal Exposure Delayed Effects
- Abstract
Inflammation is increasingly recognized as a cause or consequence of common problems of humanity including obesity, stress, depression, pollution and disease states such as autoimmunity, asthma, and infection. Maternal immune activation (MIA), triggered by both acute and systemic chronic inflammation, is hypothesized to be one of the mechanisms implicated in the pathogenesis of neurodevelopmental disorders (NDD). Although there is substantial preclinical evidence to support the MIA hypothesis, the human evidence is disparate. We performed a systematic review on human studies examining associations between maternal inflammatory states and offspring NDDs (autism spectrum disorder- ASD, attention deficit hyperactivity disorder-ADHD, Tourette syndrome-TS). 32 meta-analyses and 26 additional individual studies were identified. Maternal states associated with ASD include obesity, gestational diabetes mellitus, pre-eclampsia, pollution, stress, depression, autoimmune diseases, and infection. Maternal states associated with ADHD include obesity, pre-eclampsia, smoking, low socioeconomic status (SES), stress, autoimmune disease, and asthma. Maternal states associated with TS include low SES, depression, and autoimmune diseases. Diverse maternal inflammatory states in pregnancy are associated with common offspring NDDs. Given the increased prevalence of NDDs, there is urgent need to explore relative and cumulative maternal risk factors and disease mechanisms. Defining preventable risk factors in high-risk pregnancies could mitigate the expression and severity of NDDs.
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- 2021
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36. Dominant SCN2A mutation with variable phenotype in two generations.
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Passi GR and Mohammad SS
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- Ataxia genetics, Family Characteristics, Female, Genes, Dominant genetics, Hemiplegia genetics, Humans, Infant, Male, Neurodevelopmental Disorders genetics, Phenotype, NAV1.2 Voltage-Gated Sodium Channel genetics, NAV1.2 Voltage-Gated Sodium Channel metabolism
- Abstract
Background: SCN2A mutations are some of the commonest causes of neurodevelopmental disorders including epilepsy, movement disorders, autism spectrum disorder, intellectual disability and rarely episodic ataxia., Case Report: We present a patient with a dominantly inherited SCN2A mutation presenting as episodic ataxia in a boy and episodic hemiplegia in his father. We have briefly reviewed the literature of SCN2A mutations presenting with episodic ataxia., Conclusion: Our report has expanded the phenotype for SCN2A mutations., 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 © 2020 The Japanese Society of Child Neurology. All rights reserved.)
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- 2021
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37. Psychiatric comorbidity is common in dystonia and other movement disorders.
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Lorentzos MS, Heyman I, Baig BJ, Coughtrey AE, McWilliams A, Dossetor DR, Waugh MC, Evans RA, Hollywood J, Burns J, Menezes MP, Mohammad SS, Grattan-Smith P, Gorman KM, Crowe BHA, Goodman R, Kurian MA, and Dale RC
- Subjects
- Australia, Case-Control Studies, Child, Cohort Studies, Comorbidity, Depressive Disorder psychology, Diagnostic and Statistical Manual of Mental Disorders, Emergency Service, Hospital, England, Female, Humans, Male, Psychometrics, Depressive Disorder diagnosis, Dystonia psychology, Movement Disorders psychology
- Abstract
Objective: To determine rates of psychiatric comorbidity in a clinical sample of childhood movement disorders (MDs)., Design: Cohort study., Setting: Tertiary children's hospital MD clinics in Sydney, Australia and London, UK., Patients: Cases were children with tic MDs (n=158) and non-tic MDs (n=102), including 66 children with dystonia. Comparison was made with emergency department controls (n=100), neurology controls with peripheral neuropathy or epilepsy (n=37), and community controls (n=10 438)., Interventions: On-line development and well-being assessment which was additionally clinically rated by experienced child psychiatrists., Main Outcome Measures: Diagnostic schedule and manual of mental disorders-5 criteria for psychiatric diagnoses., Results: Psychiatric comorbidity in the non-tic MD cohort (39.2%) was comparable to the tic cohort (41.8%) (not significant). Psychiatric comorbidity in the non-tic MD cohort was greater than the emergency control group (18%, p<0.0001) and the community cohort (9.5%, p<0.00001), but not the neurology controls (29.7%, p=0.31). Almost half of the patients within the tic cohort with psychiatric comorbidity were receiving medical psychiatric treatment (45.5%) or psychology interventions (43.9%), compared with only 22.5% and 15.0%, respectively, of the non-tic MD cohort with psychiatric comorbidity., Conclusions: Psychiatric comorbidity is common in non-tic MDs such as dystonia. These psychiatric comorbidities appear to be under-recognised and undertreated., Competing Interests: Competing interests: RG and his family are the owners of Youthinmind Limited, which provides no-cost and low-cost measures of child mental health, including the Strengths and Difficulties Questionnaire (SDQ) and development and well-being assessment (DAWBA)., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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38. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.
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Cif L, Demailly D, Lin JP, Barwick KE, Sa M, Abela L, Malhotra S, Chong WK, Steel D, Sanchis-Juan A, Ngoh A, Trump N, Meyer E, Vasques X, Rankin J, Allain MW, Applegate CD, Attaripour Isfahani S, Baleine J, Balint B, Bassetti JA, Baple EL, Bhatia KP, Blanchet C, Burglen L, Cambonie G, Seng EC, Bastaraud SC, Cyprien F, Coubes C, d'Hardemare V, Doja A, Dorison N, Doummar D, Dy-Hollins ME, Farrelly E, Fitzpatrick DR, Fearon C, Fieg EL, Fogel BL, Forman EB, Fox RG, Gahl WA, Galosi S, Gonzalez V, Graves TD, Gregory A, Hallett M, Hasegawa H, Hayflick SJ, Hamosh A, Hully M, Jansen S, Jeong SY, Krier JB, Krystal S, Kumar KR, Laurencin C, Lee H, Lesca G, François LL, Lynch T, Mahant N, Martinez-Agosto JA, Milesi C, Mills KA, Mondain M, Morales-Briceno H, Ostergaard JR, Pal S, Pallais JC, Pavillard F, Perrigault PF, Petersen AK, Polo G, Poulen G, Rinne T, Roujeau T, Rogers C, Roubertie A, Sahagian M, Schaefer E, Selim L, Selway R, Sharma N, Signer R, Soldatos AG, Stevenson DA, Stewart F, Tchan M, Verma IC, de Vries BBA, Wilson JL, Wong DA, Zaitoun R, Zhen D, Znaczko A, Dale RC, de Gusmão CM, Friedman J, Fung VSC, King MD, Mohammad SS, Rohena L, Waugh JL, Toro C, Raymond FL, Topf M, Coubes P, Gorman KM, and Kurian MA
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Cohort Studies, Computer Simulation, Deep Brain Stimulation, Disease Progression, Dystonic Disorders therapy, Endocrine System Diseases complications, Endocrine System Diseases genetics, Female, Fetal Growth Retardation genetics, Gait Disorders, Neurologic etiology, Gait Disorders, Neurologic therapy, Humans, Laryngeal Diseases etiology, Laryngeal Diseases therapy, Male, Mutation, Mutation, Missense, Phenotype, Quality of Life, Treatment Outcome, Young Adult, Dystonic Disorders genetics, Histone-Lysine N-Methyltransferase genetics
- Abstract
Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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39. Magnetic resonance imaging pattern recognition in childhood bilateral basal ganglia disorders.
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Mohammad SS, Angiti RR, Biggin A, Morales-Briceño H, Goetti R, Perez-Dueñas B, Gregory A, Hogarth P, Ng J, Papandreou A, Bhattacharya K, Rahman S, Prelog K, Webster RI, Wassmer E, Hayflick S, Livingston J, Kurian M, Chong WK, and Dale RC
- Abstract
Bilateral basal ganglia abnormalities on MRI are observed in a wide variety of childhood disorders. MRI pattern recognition can enable rationalization of investigations and also complement clinical and molecular findings, particularly confirming genomic findings and also enabling new gene discovery. A pattern recognition approach in children with bilateral basal ganglia abnormalities on brain MRI was undertaken in this international multicentre cohort study. Three hundred and five MRI scans belonging to 201 children with 34 different disorders were rated using a standard radiological scoring proforma. In addition, literature review on MRI patterns was undertaken in these 34 disorders and 59 additional disorders reported with bilateral basal ganglia MRI abnormalities. Cluster analysis on first MRI findings from the study cohort grouped them into four clusters: Cluster 1-T
2 -weighted hyperintensities in the putamen; Cluster 2-T2 -weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3-T2 -weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4-T1 -weighted hyperintensities in the basal ganglia. The 34 diagnostic categories included in this study showed dominant clustering in one of the above four clusters. Inflammatory disorders grouped together in Cluster 1. Mitochondrial and other neurometabolic disorders were distributed across clusters 1, 2 and 3, according to lesions dominantly affecting the striatum (Cluster 1: glutaric aciduria type 1, propionic acidaemia, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome and thiamine responsive basal ganglia disease associated with SLC19A3 ), pallidum (Cluster 2: methylmalonic acidaemia, Kearns Sayre syndrome, pyruvate dehydrogenase complex deficiency and succinic semialdehyde dehydrogenase deficiency) or pallidum, brainstem and cerebellum (Cluster 3: vigabatrin toxicity, Krabbe disease). The Cluster 4 pattern was exemplified by distinct T1 -weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to SLC39A14 and SLC30A10 . Within the clusters, distinctive basal ganglia MRI patterns were noted in acquired disorders such as cerebral palsy due to hypoxic ischaemic encephalopathy in full-term babies, kernicterus and vigabatrin toxicity and in rare genetic disorders such as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome, thiamine responsive basal ganglia disease, pantothenate kinase-associated neurodegeneration, TUBB4A and hypermanganesemia. Integrated findings from the study cohort and literature review were used to propose a diagnostic algorithm to approach bilateral basal ganglia abnormalities on MRI. After integrating clinical summaries and MRI findings from the literature review, we developed a prototypic decision-making electronic tool to be tested using further cohorts and clinical practice., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)- Published
- 2020
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40. 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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41. Autoimmune Encephalitis in Children: An Update.
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Garg D, Mohammad SS, and Sharma S
- Subjects
- Autoantibodies, Child, Epilepsy, Humans, Movement Disorders, Seizures, Anti-N-Methyl-D-Aspartate Receptor Encephalitis, Encephalitis, Hashimoto Disease
- Abstract
Context: Autoimmune encephalitis has acquired immense significance as a treatable cause of encephalopathy, epilepsy and movement disorders in children. In this review, we discuss the various clinical syndromes, diagnosis, treatment and prognosis in children., Evidence Acquisition: A MEDLINE search strategy using the following terms (1998-2019) was adopted for this review. Limits of 'Human' and 'English' were applied. Search terms included: "autoimmune encephalitis", "autoimmune encephalitis AND epidemiology", "pathophysiology", "diagnosis" and "treatment" for studies in children. Review articles, practice parameters, guidelines, systematic reviews, meta-analyses, randomized controlled trials, cohort studies, case series and case reports were included., Conclusions: Autoimmune encephalitis is being increasingly recognized in children. Anti-NMDAR encephalitis is the most common form. Children present with a polysymptomatic presentation including behavioral changes, psychosis, sleep disturbances, mutism, seizures, movement disorders, memory impairment as well as other neurocognitive deficits. Diagnosis is based on suggestive history and ancillary investigations including magnetic resonance imaging, cerebrospinal fluid analysis, and serology for autoantibodies. Treatment is based on immunomodulation of the acute episode followed by maintenance therapy, with earlier initiation being associated with better outcomes. Prognosis depends on the type of clinical syndrome.
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- 2020
42. Clinical and neuroimaging phenotypes of genetic parkinsonism from infancy to adolescence.
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Morales-Briceño H, Mohammad SS, Post B, Fois AF, Dale RC, Tchan M, and Fung VSC
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- Age Factors, Humans, Movement Disorders complications, Mutation genetics, Parkinsonian Disorders complications, Movement Disorders diagnosis, Movement Disorders diagnostic imaging, Movement Disorders genetics, Parkinsonian Disorders diagnosis, Parkinsonian Disorders diagnostic imaging, Parkinsonian Disorders genetics
- Abstract
Genetic early-onset parkinsonism presenting from infancy to adolescence (≤21 years old) is a clinically diverse syndrome often combined with other hyperkinetic movement disorders, neurological and imaging abnormalities. The syndrome is genetically heterogeneous, with many causative genes already known. With the increased use of next-generation sequencing in clinical practice, there have been novel and unexpected insights into phenotype-genotype correlations and the discovery of new disease-causing genes. It is now recognized that mutations in a single gene can give rise to a broad phenotypic spectrum and that, conversely different genetic disorders can manifest with a similar phenotype. Accurate phenotypic characterization remains an essential step in interpreting genetic findings in undiagnosed patients. However, in the past decade, there has been a marked expansion in knowledge about the number of both disease-causing genes and phenotypic spectrum of early-onset cases. Detailed knowledge of genetic disorders and their clinical expression is required for rational planning of genetic and molecular testing, as well as correct interpretation of next-generation sequencing results. In this review we examine the relevant literature of genetic parkinsonism with ≤21 years onset, extracting data on associated movement disorders as well as other neurological and imaging features, to delineate syndromic patterns associated with early-onset parkinsonism. Excluding PRKN (parkin) mutations, >90% of the presenting phenotypes have a complex or atypical presentation, with dystonia, abnormal cognition, pyramidal signs, neuropsychiatric disorders, abnormal imaging and abnormal eye movements being the most common features. Furthermore, several imaging features and extraneurological manifestations are relatively specific for certain disorders and are important diagnostic clues. From the currently available literature, the most commonly implicated causes of early-onset parkinsonism have been elucidated but diagnosis is still challenging in many cases. Mutations in ∼70 different genes have been associated with early-onset parkinsonism or may feature parkinsonism as part of their phenotypic spectrum. Most of the cases are caused by recessively inherited mutations, followed by dominant and X-linked mutations, and rarely by mitochondrially inherited mutations. In infantile-onset parkinsonism, the phenotype of hypokinetic-rigid syndrome is most commonly caused by disorders of monoamine synthesis. In childhood and juvenile-onset cases, common genotypes include PRKN, HTT, ATP13A2, ATP1A3, FBX07, PINK1 and PLA2G6 mutations. Moreover, Wilson's disease and mutations in the manganese transporter are potentially treatable conditions and should always be considered in the differential diagnosis in any patient with early-onset parkinsonism., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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43. Sensory dysregulation in tic disorders is associated with executive dysfunction and comorbidities.
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Soler N, Hardwick C, Perkes IE, Mohammad SS, Dossetor D, Nunn K, Bray P, and Dale RC
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- Adolescent, Case-Control Studies, Child, Child, Preschool, Comorbidity, Cross-Sectional Studies, Developmental Disabilities complications, Female, Humans, Male, Mental Disorders complications, Prevalence, Psychiatric Status Rating Scales, Quality of Life, Sensation Disorders complications, Sensation Disorders epidemiology, Surveys and Questionnaires, Tic Disorders complications, Tic Disorders epidemiology, Executive Function, Sensation Disorders physiopathology, Tic Disorders physiopathology
- Abstract
Background: Tics are conceptualized as a sensorimotor phenomenon with a premonitory urge typically described by patients. As observed in other neurodevelopmental disorders, we have observed sensory dysregulation symptoms, such as tactile hypersensitivity to clothing, in children with tic disorders; however, formal clinical research in this area is limited., Objective: To define the presence of sensory dysregulation symptoms in tic disorders, and their clinical associations., Methods: Prevalence of sensory dysregulation in 102 children with tic disorders was compared to 61 age- and sex-matched healthy controls. Sensory dysregulation, executive function, and quality of life data were obtained through the Short Sensory Profile-2, Sensory Profile-2, Sensory Processing Measure, Behaviour Rating Inventory of Executive Function-2, and Strength and Difficulties Questionnaire and Pediatric Quality of Life Inventory. Tics were assessed with the Yale Global Tic Severity Scale., Results: Children with tics, in the presence of comorbidity, had elevated sensory dysregulation compared to healthy controls (P < 0.001). There was a positive correlation between sensory dysregulation and global executive difficulties in children with tics and comorbidity (n = 87; rho = 0.716; P < 0.001) and a negative correlation of sensory dysregulation with quality of life (n = 87; rho = -0.595; P < 0.001). In children with tics, there was an association between sensory dysregulation and number of comorbidities (P < 0.001)., Conclusion: In the presence of comorbidity, children with tic disorders have broad sensory dysregulation symptoms beyond the premonitory urge. There was a statistically significant association between sensory dysregulation and executive function difficulties and the presence of neurodevelopmental and psychiatric comorbidity. Sensory dysregulation can be considered neurodevelopmental symptoms, providing insight into the neurobiology of tics and opportunities for therapeutic intervention. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)
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- 2019
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44. Neuropsychological outcomes of childhood acute necrotizing encephalopathy.
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Williams TA, Brunsdon RK, Burton KLO, Drevensek S, Brady C, Dale RC, and Mohammad SS
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- Brain pathology, Brain Diseases pathology, Child, Child, Preschool, Humans, Infant, Longitudinal Studies, Magnetic Resonance Imaging, Neuroimaging, Neuropsychological Tests, Thalamus pathology, Leukoencephalitis, Acute Hemorrhagic diagnosis, Leukoencephalitis, Acute Hemorrhagic physiopathology
- Abstract
Acute necrotizing encephalopathy (ANE) is a rare form of acute encephalopathy, predominantly occurring in childhood, which has a typical radiological phenotype including bilateral, symmetrical, diffusion-restricted lesions of the thalami; posterior putamen; cerebellum; and brainstem. To date, no study has systematically examined the long-term cognitive and psychological impact of ANE. The current study describes the neuropsychological outcomes of three paediatric cases of ANE, ranging from 18 months to 10 years post ANE. All three cases displayed inattention, fine motor difficulties and anxiety. Social difficulties were also reported in all cases. The severity of long-term impairment was associated with acute presentation, as well as convalescent neuroimaging. These findings highlight the need for detailed neuropsychological assessment and long-term rehabilitation., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
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- 2019
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45. Yield of comparative genomic hybridization microarray in pediatric neurology practice.
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Misra S, Peters G, Barnes E, Ardern-Holmes S, Webster R, Troedson C, Mohammad SS, Gill D, Menezes M, Gupta S, Procopis P, Antony J, Kurian MA, and Dale RC
- Abstract
Objective: The present study investigated the diagnostic yield of array comparative genomic hybridization (aCGH) in a large cohort of children with diverse neurologic disorders as seen in child neurology practice to test whether pathogenic copy number variants (CNVs) were more likely to be detected in specific neurologic phenotypes., Methods: A retrospective cross-sectional analysis was performed on 555 children in whom a genetic etiology was suspected and who underwent whole-genome aCGH testing between 2006 and 2012. Neurologic phenotyping was performed using hospital medical records. An assessment of pathogenicity was made for each CNV, based on recent developments in the literature., Results: Forty-seven patients were found to carry a pathogenic CNV, giving an overall diagnostic yield of 8.59%. Certain phenotypes predicted for the presence of a pathogenic CNV, including developmental delay (odds ratio [OR] 3.69 [1.30-10.51]), cortical visual impairment (OR 2.73 [1.18-6.28]), dysmorphism (OR 2.75 [1.38-5.50]), and microcephaly (OR 2.16 [1.01-4.61]). The combination of developmental delay/intellectual disability with dysmorphism and abnormal head circumference was also predictive for a pathogenic CNV (OR 2.86 [1.02-8.00]). For every additional clinical feature, there was an increased likelihood of detecting a pathogenic CNV (OR 1.18 [1.01-1.38])., Conclusions: The use of aCGH led to a pathogenic finding in 8.59% of patients. The results support the use of aCGH as a first tier investigation in children with diverse neurologic disorders, although whole-genome sequencing may replace aCGH as the detection method in the future. In particular, the yield was increased in children with developmental delay, dysmorphism, cortical visual impairment, and microcephaly., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2019
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46. Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
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Tantsis EM, Prelog K, Alper G, Benson L, Gorman M, Lim M, Mohammad SS, Ramanathan S, Brilot F, and Dale RC
- Subjects
- Adolescent, Autoantibodies, Child, Child, Preschool, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Multiple Sclerosis immunology, Myelitis immunology, Retrospective Studies, Aquaporin 4 immunology, Brain diagnostic imaging, Enterovirus A, Human immunology, Multiple Sclerosis diagnostic imaging, Myelin-Oligodendrocyte Glycoprotein immunology, Myelitis diagnostic imaging
- Abstract
Aim: We used magnetic resonance imaging (MRI) to compare the neuroimaging of children with their first episode of clinical enterovirus 71-associated transverse myelitis (EV71-TM), myelin oligodendrocyte glycoprotein antibody positive transverse myelitis (MOG-TM), aquaporin-4 antibody positive transverse myelitis (AQP4-TM), transverse myelitis in multiple sclerosis (MS-TM), and unclassified transverse myelitis (UNC-TM)., Method: We performed a retrospective blinded radiological assessment and compared the neuroimaging of 52 children (32 females, 20 males; mean age 9y 8mo, SD 5y 5mo, range 5mo-17y) presenting with their first episode of myelitis caused by EV71-TM (n=11), MOG-TM (n=10), AQP4-TM (n=9), MS-TM (n=13), and UNC-TM (n=9)., Results: In the EV71-TM group, lesions were distributed throughout the cord and enhancement of nerve roots (ventral and dorsal) was common. The MOG-TM group had lesions distributed throughout the cord and most commonly longitudinally extensive transverse myelitis and lesions involving the grey matter alone on axial scans. The AQP4-TM group had lesions distributed in the cervicothoracic spine, cavitation, and contrast enhancing lesions. All patients with AQP4-TM had an abnormal brain MRI scan. The MS-TM group characteristically had multiple short segment lesions of the cord involving the cervicothoracic spine. The UNC-TM group did not have distinctive spinal MRI findings but had a relative paucity of lesions on their brain MRI scans., Interpretation: There are neuroimaging findings that are helpful in differentiating between myelitis associated with EV71, MOG, AQP4, and multiple sclerosis in children. These features may be useful early in the presentation of transverse myelitis while awaiting infectious/immunological testing, and/or further demyelinating events., What This Paper Adds: Magnetic resonance imaging can help identify aetiologies for children presenting with a first episode of myelitis. Entervirus-71-associated myelitis lesions are distributed throughout the cord and enhancement of nerve roots is common. Lesions distributed throughout the cord are commonly seen in myelin oligodendrocyte-associated myelitis. Aquaporin-4-associated myelitis lesions are distributed in the cervicothoracic spine, cavitation and contrast enhancing lesions are common. Short segment lesions in the cervicothoracic spine are commonly seen in multiple sclerosis-associated myelitis., (© 2018 Mac Keith Press.)
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- 2019
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47. 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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48. Myoclonus-dystonia caused by GNB1 mutation responsive to deep brain stimulation.
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Jones HF, Morales-Briceño H, Barwick K, Lewis J, Sanchis-Juan A, Raymond FL, Stewart K, Waugh MC, Mahant N, Kurian MA, Dale RC, and Mohammad SS
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- Adolescent, Dystonic Disorders diagnosis, Female, Globus Pallidus surgery, Humans, Myoclonus genetics, Myoclonus therapy, Deep Brain Stimulation, Dystonic Disorders genetics, Dystonic Disorders therapy, GTP-Binding Protein beta Subunits genetics, Mutation genetics
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- 2019
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49. The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study.
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Varley JA, Webb AJS, Balint B, Fung VSC, Sethi KD, Tijssen MAJ, Lynch T, Mohammad SS, Britton F, Evans M, Hacohen Y, Lin JP, Nardocci N, Granata T, Dale RC, Lim MJ, Bhatia KP, Lang AE, and Irani SR
- Subjects
- Adolescent, Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis diagnosis, Anti-N-Methyl-D-Aspartate Receptor Encephalitis physiopathology, Child, Child, Preschool, Female, Humans, Infant, Male, Young Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis complications, Movement Disorders diagnosis, Movement Disorders etiology
- Abstract
Competing Interests: Competing interests: SRI is a co-applicant and receives royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies.
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- 2019
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50. Current therapies and therapeutic decision making for childhood-onset movement disorders.
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Mohammad SS, Paget SP, and Dale RC
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- Adrenergic alpha-Agonists therapeutic use, Anticonvulsants therapeutic use, Autoimmune Diseases of the Nervous System complications, Botulinum Toxins, Type A therapeutic use, Cannabinoids therapeutic use, Cell- and Tissue-Based Therapy, Chelating Agents therapeutic use, Chenodeoxycholic Acid therapeutic use, Child, Dietary Supplements, Dopamine Agents therapeutic use, Enzyme Replacement Therapy, GABA Agents therapeutic use, Gastrointestinal Agents therapeutic use, Glucocorticoids therapeutic use, Humans, Immunoglobulins, Intravenous therapeutic use, Metabolism, Inborn Errors complications, Monoamine Oxidase Inhibitors therapeutic use, Movement Disorders etiology, Neuromuscular Agents therapeutic use, Organophosphorus Compounds therapeutic use, Pterins therapeutic use, Autoimmune Diseases of the Nervous System therapy, Clinical Decision-Making, Deep Brain Stimulation, Diet Therapy, Genetic Therapy, Immunologic Factors therapeutic use, Metabolism, Inborn Errors therapy, Movement Disorders therapy
- Abstract
Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early-onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease-modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease-modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha-adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of "disease-specific" therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood-onset movement disorders. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)
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- 2019
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