RESUMEN
Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01â¼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05â¼DQB1*05:01, HLA-DQA1*01:01â¼DQB1*05:01 and HLA-DQA1*01:04â¼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11â years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05â¼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.
Asunto(s)
Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Cadenas HLA-DRB1/genética , Masculino , Cadenas beta de HLA-DQ/genética , Femenino , Persona de Mediana Edad , Adulto , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/inmunología , Anciano , Autoanticuerpos/inmunología , Predisposición Genética a la Enfermedad , Adulto Joven , Adolescente , GenotipoRESUMEN
Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (â¼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that â¼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.
Asunto(s)
Pruebas Genéticas , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Pruebas Genéticas/métodos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Glucosilceramidasa/genética , alfa-Sinucleína/genética , Predisposición Genética a la Enfermedad , Ubiquitina-Proteína Ligasas/genética , Estudios de Cohortes , Proteínas Quinasas/genética , Mutación , AdultoRESUMEN
A 78-year-old woman presented with involuntary movements of her abdomen, which started after a right hemispheric stroke. She had irregular, variable, hyperkinetic predominantly right-sided abdominal wall movements. MR scan of brain confirmed a recent infarct in the right occipitotemporal lobe and the right cerebellum. Diaphragmatic fluoroscopy confirmed high-frequency flutter as the cause of her abdominal movements and confirmed the diagnosis of van Leeuwenhoek's disease. Anthonie van Leeuwenhoek first described this condition in 1723 and had the condition himself. He was a Dutch businessman who is often acknowledged as the first microscopist and microbiologist. He disagreed with his physician who attributed his ailment as being of cardiac origin. Diaphragmatic flutter is a rare disorder that requires a high index of suspicion with symptoms including abnormal abdominal wall movements, dyspnoea and respiratory distress. Despite medical treatment, the patient was still highly symptomatic, so she is currently being considered for a phrenic nerve crush.
Asunto(s)
Diafragma/fisiopatología , Mioclonía/complicaciones , Insuficiencia Respiratoria/complicaciones , Anciano , Cerebelo/diagnóstico por imagen , Femenino , Fluoroscopía , Historia del Siglo XVII , Historia del Siglo XVIII , Humanos , Mioclonía/etiología , Mioclonía/historia , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/historia , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patologíaRESUMEN
A 21-year-old woman of south Asian origin presented with cervical dystonia which had progressed over the previous three years. Her symptoms started as writer's cramp since the age of seven years. She did not respond to medications and needed botulinum toxin injection for generalised dystonia. Subsequent whole genome sequencing revealed a likely pathogenic c.98G>A p.(Cys33Tyr) heterozygous variant in the THAP1 gene. She underwent bilateral posteroventral globus pallidus interna (GPi) deep brain stimulation (Medtronic Activa PC) implantation at the age of thirty-one years. She responded well to the deep brain stimulation even after more than 8 years post-surgery though she needs botulinum toxin injection for her cervical dystonia.
Asunto(s)
Toxinas Botulínicas , Estimulación Encefálica Profunda , Trastornos Distónicos , Tortícolis , Femenino , Humanos , Niño , Adulto , Adulto Joven , Globo Pálido , Trastornos Distónicos/genética , Trastornos Distónicos/terapia , Proteínas de Unión al ADN , Proteínas Reguladoras de la ApoptosisAsunto(s)
Cocaína/efectos adversos , Infarto/inducido químicamente , Infarto/diagnóstico por imagen , Médula Espinal/irrigación sanguínea , Médula Espinal/diagnóstico por imagen , Cocaína/administración & dosificación , Humanos , Masculino , Médula Espinal/efectos de los fármacos , Vasoconstrictores/administración & dosificación , Vasoconstrictores/efectos adversos , Adulto JovenRESUMEN
A 21-year-old patient presented with sudden-onset headache, visual disturbance and left hand incoordination. She was diagnosed with a left vertebral artery dissection of the V3 segment resulting in multiple cerebellar and cerebral infarcts. There were no risk factors for dissection other than recent COVID-19 infection. She was treated initially with antiplatelets, followed by anticoagulation, but experienced recurrent ischaemia. Although guidance suggests endovascular repair may be beneficial for patients with cerebral artery dissection (CAD) who experience recurrent strokes on medical therapy, evidence is limited. After multidisciplinary team consideration of the individual patient anatomy and risks and benefits of different endovascular techniques, the patient was treated with endovascular coiling. At 10 months follow-up, she had no further strokes and improving neurological symptoms. The case highlighted COVID-19 as a potential trigger for CAD and the use of endovascular coiling in preventing catastrophic cerebral ischaemia in CAD refractive to medical therapy.
Asunto(s)
COVID-19 , Procedimientos Endovasculares , Disección de la Arteria Vertebral , Adulto , Procedimientos Endovasculares/métodos , Femenino , Humanos , Radiología Intervencionista , SARS-CoV-2 , Arteria Vertebral , Disección de la Arteria Vertebral/diagnóstico por imagen , Disección de la Arteria Vertebral/terapia , Adulto JovenRESUMEN
BACKGROUND: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. OBJECTIVE: To survey the accessible MD clinical training in these regions. METHODS: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. RESULTS: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. CONCLUSION: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.
Asunto(s)
Acreditación/estadística & datos numéricos , Curriculum/estadística & datos numéricos , Educación de Postgrado en Medicina/estadística & datos numéricos , Trastornos del Movimiento , Neurología/educación , Neurología/estadística & datos numéricos , Egipto , Europa (Continente) , Encuestas de Atención de la Salud/estadística & datos numéricos , Humanos , TúnezRESUMEN
Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive condition that is caused by a mutation in the alpha tocopherol transfer protein gene. It is almost indistinguishable clinically from Friedreich's ataxia but with appropriate treatment its devastating neurological features can be prevented. Patients can present with a progressive cerebellar ataxia, pyramidal spasticity, and evidence of a neuropathy with absent deep tendon reflexes. It is important to screen for this condition on initial evaluation of a young patient presenting with progressive ataxia and it should be considered in patients with a long standing ataxia without any diagnosis in view of the potential therapeutics and genetic counselling. In this case report we present a patient who was initially diagnosed with Friedreich's ataxia but was later found to have AVED.
RESUMEN
PURPOSE: To report a rare case of bilateral optic disc edema as presentation of an obstructing spinal plasmacytoma. METHODS: Case report. RESULTS: A 41-year-old healthy man presented with distortion of his peripheral vision for 9 months. He denied headaches or neurologic symptoms. Examination showed bilateral optic disc swelling, radial disc hemorrhages, and absent spontaneous venous pulsations. Brain magnetic resonance imaging (MRI) and magnetic resonance venography were unrevealing. Lumbar puncture showed a normal opening pressure of 19 cm cerebrospinal fluid (CSF). CSF protein was significantly elevated at 3.22 g/L (0.10-0.45 g/L). Spinal MRI with contrast revealed a tumor in the T9 vertebral body extending through the disc spaces into T8 and T10, compressing the spinal cord. Computed tomography-guided biopsy confirmed a spinal plasmacytoma. He received radiotherapy to the spine T7-T11 to reduce spinal cord compression followed by a 6-month course of chemotherapy with dexamethasone, cyclophosphamide, and thalidomide. Disc swelling improved on starting radiotherapy with complete resolution 8 months posttreatment. MRI spine showed reduction of tumor. CONCLUSIONS: This case highlights the importance of spinal imaging in patients with normal cranial scans and raised CSF protein levels who lack the typical idiopathic intracranial hypertension phenotype.
Asunto(s)
Líquido Cefalorraquídeo , Papiledema/diagnóstico , Plasmacitoma/diagnóstico , Seudotumor Cerebral/diagnóstico , Compresión de la Médula Espinal/diagnóstico , Neoplasias de la Columna Vertebral/diagnóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Proteínas del Líquido Cefalorraquídeo/metabolismo , Terapia Combinada , Humanos , Presión Intracraneal , Imagen por Resonancia Magnética , Masculino , Papiledema/etiología , Papiledema/terapia , Plasmacitoma/complicaciones , Plasmacitoma/terapia , Seudotumor Cerebral/terapia , Radioterapia Adyuvante , Compresión de la Médula Espinal/terapia , Neoplasias de la Columna Vertebral/complicaciones , Neoplasias de la Columna Vertebral/terapia , Vértebras Torácicas , Tomografía de Coherencia Óptica , Tomografía Computarizada por Rayos XRESUMEN
We describe a patient who developed significant cognitive decline with profound amnesia following non-dominant temporal lobectomy for refractory seizures, in whom the original suspicion of structural pathology was revised following the discovery of clinical and neuropathological markers of inflammation, neuropsychological evidence of bilateral involvement, and high titres of antibodies directed against glutamic acid decarboxylase (GAD). This case adds to the evidence that the diagnosis of non-paraneoplastic anti-GAD limbic encephalitis merits consideration in any patient with a refractory seizure disorder and cognitive decline.