RESUMO
BACKGROUND: Anti-N-methyl-d-aspartate "anti-NMDA" receptor encephalitis is one of the most common autoimmune encephalitis for which first- and second-line therapies have been recommended following international consensus. However, some refractory cases do not respond to the first- and second-line therapy and require further immune-modulatory therapies such as intra-thecal methotrexate. In this study, we reviewed six confirmed cases of refractory anti-NMDA receptor encephalitis from two tertiary centers in Saudi Arabia that required escalation of treatment and received a six-month course of intra-thecal methotrexate. The aim of this study was to evaluate the effectiveness of intra-thecal methotrexate as immunomodulatory therapy for refractory anti-NMDA receptor encephalitis. METHODS: We retrospectively evaluated six confirmed cases of refractory anti-NMDA receptor encephalitis who did not improve after first- and second-line therapy and received monthly intra-thecal methotrexate treatment course for six consecutive months. We reviewed patient demography, underlying etiologies, and compared their modified Rankin score prior to receiving intra-thecal methotrexate and six months after completing the treatment. RESULTS: Three of the six patients showed a marked response to intra-thecal methotrexate with a modified Rankin scale of 0-1 at 6-month follow-up. None of the patients experienced any side effects during or after intra-thecal methotrexate treatment, and no flareups were observed. CONCLUSION: Intra-thecal methotrexate may be a potentially effective and relatively safe escalation option for immunomodulatory therapy of refractory anti-NMDA receptor encephalitis. Future studies on intra-thecal methotrexate -specific treatment regimens may further support its utility, efficacy, and safety in treating refractory anti-NMDA receptor encephalitis.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Doença de Hashimoto , Humanos , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Metotrexato/uso terapêutico , Estudos Retrospectivos , Anticorpos , Receptores de N-Metil-D-AspartatoRESUMO
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited neurometabolic disorder that can lead to severe physical and developmental impairment. This report includes 16 patients from the Middle East and is the largest series of patients with confirmed AADC deficiency from this region reported to date. The patients displayed a range of signs and symptoms at presentation and almost all failed to reach major motor milestones. Missed and delayed diagnoses were common leading to the late introduction of targeted treatments. Eight unique variants were identified in the DDC gene, including six missense and two intronic variants. A previously undescribed variant was identified: an intronic variant between exons 13 and 14 (c.1243-10A>G). The patients were mostly treated with currently recommended medications, including dopamine agonists, vitamin B6, and monoamine oxidase inhibitors. One patient responded well, but treatment outcomes were otherwise mostly limited to mild symptomatic improvements. Five patients had died by the time of data collection, confirming that the condition is associated with premature mortality. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. Conclusions: Delays in the diagnosis of AADC deficiency are common. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. What is Known: ⢠Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disorder that can lead to severe physical and developmental impairment. ⢠Currently recommended medications provide mostly mild symptomatic improvements. What is New: ⢠The clinical presentation of sixteen patients with confirmed AADC deficiency varied considerably and almost all failed to reach major motor milestones. ⢠There is an urgent need for earlier diagnosis, given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Descarboxilases de Aminoácido-L-Aromático , Humanos , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Descarboxilases de Aminoácido-L-Aromático/genética , Descarboxilases de Aminoácido-L-Aromático/uso terapêutico , Agonistas de Dopamina/uso terapêutico , MutaçãoRESUMO
Inherited metabolic diseases usually present a complex clinical picture in which seizures are one of various neurological manifestations, which include developmental delays/regression, acute encephalopathy, neuropsychiatric manifestations, and movement disorders. However, a seizure can be the prominent feature in inherited metabolic disease. The specific diagnosis of an underlying inherited metabolic disorder in epileptic patients may help design specific treatments that can improve the seizures and stop neurodegeneration. In several inherited metabolic diseases such as vitamin-responsive epilepsies and other metabolic epilepsies, seizures are refractory to antiseizure medications but respond to specific treatments based on vitamin and cofactor supplementation or diet. This review discusses our current understanding of these inherited metabolic disorders associated with epilepsy, where early diagnosis and treatment initiation will significantly improve the outcome.
Assuntos
Epilepsia , Doenças Metabólicas , Epilepsia/diagnóstico , Epilepsia/terapia , Humanos , Doenças Metabólicas/complicações , Doenças Metabólicas/diagnóstico , ConvulsõesRESUMO
Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder caused by variants in ATM gene and characterized by progressive neurologic impairment, cerebellar ataxia, and oculo-cutaneous telangiectasia. Immunodeficiency with a recurrent sinopulmonary infections are observed in patients with A-T. Here, we report a novel stop codon variant, c.5944 C>T (p.Gln1982*), revealed by whole-exome sequencing in a 9-year old boy. He presented with recurrent upper respiratory tract infections, failure to thrive, developmental delay, ataxic gait, and bulbar telangiectasia.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Códon sem Sentido , Adulto , Ataxia Telangiectasia/patologia , Humanos , Masculino , Sequenciamento do ExomaRESUMO
We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty-seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients, 26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%), SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, which translates to a minimum disease burden of 14 patients per 1,000,000. Our study provides comprehensive epidemiologic information and prevalence figures for each of these CDG in a large cohort of congenital disorder of glycosylation patients.
Assuntos
Biomarcadores Tumorais/genética , Defeitos Congênitos da Glicosilação/genética , Mutação , Proteínas Adaptadoras de Transporte Vesicular/genética , Adolescente , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/epidemiologia , Feminino , Glicosilação , Homozigoto , Humanos , Lactente , Masculino , Manosiltransferases/genética , Proteínas de Membrana/genética , Oxigenases de Função Mista/genética , Proteínas de Transporte de Monossacarídeos/genética , N-Acetilglucosaminiltransferases/genética , Fenótipo , Estudos Retrospectivos , Arábia Saudita/epidemiologiaRESUMO
Iron_sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they contribute to various core cellular functions. Until recently, only a few human diseases related to mitochondrial ISC biogenesis defects have been described. Such diseases include Friedreich ataxia, combined oxidative phosphorylation deficiency 19, infantile complex II/III deficiency defect, hereditary myopathy with lactic acidosis and mitochondrial muscle myopathy, lipoic acid biosynthesis defects, multiple mitochondrial dysfunctions syndromes and non ketotic hyperglycinemia due to glutaredoxin 5 gene defect. Disorders of mitochondrial import, export and translation, including sideroblastic anemia with ataxia, EVEN-PLUS syndrome and mitochondrial complex I deficiency due to nucleotide-binding protein-like protein gene defect, have also been implicated in ISC biogenesis defects. With advances in next generation sequencing technologies, more disorders related to ISC biogenesis defects are expected to be elucidated. In this article, we aim to shed the light on mitochondrial ISC biogenesis, related proteins and their function, pathophysiology, clinical phenotypes of related disorders, diagnostic approach, and future implications.
Assuntos
Proteínas Ferro-Enxofre/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , HumanosRESUMO
Background and Objectives: Noncentrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CLASP family of molecules. To date, no human monogenic disorder has been associated with the CLASP1 gene. In this study, we aimed to delineate the clinical and neuroradiologic phenotype associated with biallelic CLASP1 variants. Methods: We analyzed clinical characteristics, MRI data, and genotypes of a cohort of 3 patients with homozygous variants in CLASP1. Results: Homozygous CLASP1 variant is associated with primary microcephaly, severe neurodevelopmental delay, and early-onset refractory epilepsy. The neuroradiologic phenotype comprises a highly recognizable combination of classic lissencephaly, with the posterior gradient more severe than the anterior gradient, a thin/hypoplastic splenium of the corpus callosum, mild enlargement of the lateral ventricles primarily posteriorly with a squared pattern, and pontine hypoplasia. Discussion: This study underscores the role of CLASP1 in brain development and suggests that the identified variant disrupts CLASP1 interaction with the microtubule cytoskeleton, contributing to lissencephaly pathogenesis.
RESUMO
Despite the availability of international recommendations for the management of Infantile Epileptic Spasms Syndrome (IESS), there is a lack of recommendations adapted to the local context of clinical practice of pediatric neurology in the Gulf Cooperation Council (GCC) countries. By an initiative from the Saudi Pediatric Neurology Society (SPNS), a literature review was performed and an expert panel comprised of 13 pediatric neurologists from all GCC countries (Saudi Arabia, Kuwait, Bahrain, Oman, Qatar, and the United Arab Emirates) was subsequently convened to discuss all issues related to the management and diagnosis practices of IESS in the GCC. The overall aim of this consensus document was to develop practical recommendations to support the care of patients with IESS in the GCC and to reflect on how clinical management approaches compare with those adopted internationally.
Assuntos
Consenso , Espasmos Infantis , Humanos , Lactente , Anticonvulsivantes/uso terapêutico , Gerenciamento Clínico , Oriente Médio , Espasmos Infantis/diagnóstico , Espasmos Infantis/terapia , Emirados Árabes UnidosRESUMO
The neurological complications of coronavirus disease 2019 (COVID-19) can range from simple tremors and dystonia to features of encephalopathy. Toll-like receptor 7 (TLR7) belongs to a family of innate immune receptors responsible for viral RNA detection (such as SARS-CoV-2) and immune response initiation. TLR7 loss of function variants have been previously reported as genetic risk factors for severe COVID-19 infection in young patients with no comorbidities. In this case, we report a pediatric patient who developed severe long-term neurological deterioration following his COVID-19 infection. Presenting first to the clinic with episodic dystonia and finger spasticity, the patient's condition rapidly deteriorated with a significant drop in the Glasgow Coma Scale (GCS). Despite improvement following initial treatment with rituximab and intravenous immunoglobulin, the patient's symptoms relapsed, and GCS further dropped to 3/15. Serial brain magnetic resonance imaging scans revealed diffuse parenchymal atrophy, ventricular enlargement, and spinal cord thickening. Autoimmune investigations were negative but clinical whole genome sequencing prioritized four gene variants, the most significant of which was a novel frameshift null variant of the X chromosomal TLR7 gene (c.1386_1389dup, p.[His464Ilefs*7]). This case illustrates a role for TLR7 in long-term COVID-19 complications and highlights that TLR7 deficiency in the future may be addressed as a therapeutic measure.