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OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732.
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Neuromielitis Óptica , Humanos , Acuaporina 4 , Glicoproteína Mielina-Oligodendrócito , Autoanticuerpos , Inmunoglobulina G , RecurrenciaRESUMEN
Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.
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Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.
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Anoctamina-1 , Enfermedad de Moyamoya , Niño , Humanos , Adulto Joven , Anoctamina-1/genética , Canales de Cloruro/genética , Enfermedad de Moyamoya/genética , Proteínas de Neoplasias/genéticaRESUMEN
BACKGROUND: Susac syndrome (SuS) is a rare autoimmune disease that leads to hearing impairment, visual field deficits, and encephalopathy due to an occlusion of precapillary arterioles in the brain, retina, and inner ear. Given the potentially disastrous outcome and difficulties in distinguishing SuS from its differential diagnoses, such as multiple sclerosis (MS), our exploratory study aimed at identifying potential new SuS-specific neuroimaging markers. METHODS: Seven patients with a definite diagnosis of SuS underwent magnetic resonance imaging (MRI) at 7 Tesla (7T), including T2* weighted and quantitative susceptibility mapping (QSM) sequences. T2 weighted hyperintense lesions were analyzed with regard to number, volume, localization, central vein sign, T1 hypointensity, and focal iron deposits in the center of SuS lesions ("iron dots"). Seven T MRI datasets from the same institute, comprising 75 patients with, among others, MS, served as controls. RESULTS: The "iron dot" sign was present in 71.4% (5/7) of the SuS patients, compared to 0% in our control cohort. Thus, sensitivity was 71.4% and specificity 100%. A central vein sign was only incidentally detected. CONCLUSION: We are the first to demonstrate this type of "iron dot" lesions on highly resolving 7T T2*w and QSM images in vivo as a promising neuroimaging marker of SuS, corroborating previous histopathological ex vivo findings.
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Esclerosis Múltiple , Síndrome de Susac , Humanos , Síndrome de Susac/diagnóstico por imagen , Síndrome de Susac/patología , Hierro , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagenRESUMEN
BACKGROUND: Fabry disease is an inherited metabolic disorder with various symptoms. Neurological manifestations are small fiber neuropathy, cerebral white matter lesions (WML), megadolicho basilar artery, and stroke. The relevance of the D313Y variant in the galactosidase alpha gene is controversially discussed. OBJECTIVES: We aimed at elucidating the implications of this differential diagnosis of multiple sclerosis (MS), focussing on the analysis of WML over time and correlations with other markers. METHODS: We reviewed retrospectively the clinical, laboratory, and magnetic resonance imaging data of 21 carriers of the D313Y variant at a single German outpatient clinic for MS between 2004 and 2021. RESULTS: In our cohort (15 females, 6 males), mean age at diagnosis was 44.1 ± 16.3 years, and mean follow-up duration was 3.1 ± 3.9 years. WML were rated on both, the Fazekas scale and the age-related white matter changes rating scale, and were of variable interindividual extent. Follow-up imaging showed virtually no progress. WML did not correlate with the severity of clinical findings or lysoGb3 levels. Symptomatic carriers of the variant are characterized by an almost complete lack of internal organ manifestations and laboratory findings, usually associated with Fabry disease. CONCLUSION: WML in carriers of the D313Y variant do not seem to be suitable for assessing or predicting the (para-) clinical status. Concerning MS patients, the variant and its clinical signs can be a differential diagnosis, but also a co-factor. Imaging and cerebrospinal fluid findings facilitate the distinction between both entities.
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Enfermedad de Fabry , Esclerosis Múltiple , Sustancia Blanca , Masculino , Femenino , Humanos , alfa-Galactosidasa/genética , Enfermedad de Fabry/diagnóstico por imagen , Enfermedad de Fabry/genética , Enfermedad de Fabry/complicaciones , Sustancia Blanca/patología , Estudios Retrospectivos , Estudios de Seguimiento , Esclerosis Múltiple/complicaciones , Imagen por Resonancia Magnética , Encéfalo/patologíaRESUMEN
Here we present for the first time a potential wound dressing material implementing aptamers as binding entities to remove pathogenic cells from newly contaminated surfaces of wound matrix-mimicking collagen gels. The model pathogen in this study was the Gram-negative opportunistic bacterium Pseudomonas aeruginosa, which represents a considerable health threat in hospital environments as a cause of severe infections of burn or post-surgery wounds. A two-layered hydrogel composite material was constructed based on an established eight-membered focused anti-P. aeruginosa polyclonal aptamer library, which was chemically crosslinked to the material surface to form a trapping zone for efficient binding of the pathogen. A drug-loaded zone of the composite released the C14R antimicrobial peptide to deliver it directly to the bound pathogenic cells. We demonstrate that this material combining aptamer-mediated affinity and peptide-dependent pathogen eradication can quantitatively remove bacterial cells from the "wound" surface, and we show that the surface-trapped bacteria are completely killed. The drug delivery function of the composite thus represents an extra safeguarding property and thus probably one of the most important additional advances of a next-generation or smart wound dressing ensuring the complete removal and/or eradication of the pathogen of a freshly infected wound.
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Hidrogeles , Infección de Heridas , Humanos , Pseudomonas aeruginosa , Péptidos Antimicrobianos , Infección de Heridas/microbiología , Vendajes , AntibacterianosRESUMEN
This case report describes a 59-year-old man with myelin oligodendrocyte glycoprotein (MOG)-positive longitudinal extensive transverse myelitis (LETM) after being vaccinated with the COVID-19 vaccine ChAdOx1 nCoV-19. He presented with urinary retention, gait disturbance, hypoesthesia and brisk reflexes in his lower extremities without paresis. Due to the ineffectiveness of high-dose intravenous methylprednisolone, therapeutic plasma exchange was performed, gradually improving the patient's condition. Vaccination as a trigger for an excessive immunological response seems plausible, though unspecific for the ChAdOx1 nCoV-19 vaccine.
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COVID-19 , ChAdOx1 nCoV-19 , Mielitis Transversa , Autoanticuerpos , COVID-19/prevención & control , ChAdOx1 nCoV-19/efectos adversos , Humanos , Masculino , Glicoproteína Mielina-Oligodendrócito/inmunología , Mielitis Transversa/inducido químicamente , Vacunación/efectos adversosRESUMEN
Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in the age group over 50 years. It requires prompt diagnostics and treatment to avoid severe complications, such as visual loss or stroke. The tendency to relapse makes a glucocorticoid (GC) treatment necessary for several years and sometimes lifelong, which increases the risk of GC-induced long-term side effects. Therefore, additive GC-sparing treatment is recommended in the majority of patients. For this purpose, the anti-IL6 receptor antibody tocilizumab is available as an approved substance for subcutaneous application; alternatively, methotrexate (MTX) can be used (off-label).
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Arteritis de Células Gigantes , Quimioterapia Combinada , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Humanos , Metotrexato/uso terapéutico , Persona de Mediana Edad , RecurrenciaRESUMEN
BACKGROUND AND PURPOSE: Moyamoya angiopathy (MA) is a progressive cerebrovascular disease with a poorly understood pathophysiology. It is mainly characterized by progressive bilateral stenosis of the terminal intracranial part of the supraclinoid internal carotid arteries and the proximal parts of the middle and anterior cerebral arteries. This results in early-onset ischemic or hemorrhagic strokes. The disease may be idiopathic (known as Moyamoya disease) or associated with other heritable or acquired conditions, including type 1 neurofibromatosis or other RASopathies, sickle cell disease, Down syndrome, or autoimmune disorders (known as Moyamoya syndrome). Apart from the brain, other organ manifestations including cutaneous ones have also been described in MA patients. MATERIALS AND METHODS: A literature research on PubMed was performed for articles mentioning the cutaneous association in MA and published between 1994 and October 2020. CONCLUSION: The present review summarizes the cutaneous associations as well as the coincidental dermatological findings seen in MA patients. Those include changes in the epidermis, dermis, or skin appendages for example café-au-lait spots, hypomelanosis of Ito, livedo racemosa, hemangiomas, premature graying of hair, chilblains etc.
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Trastornos Cerebrovasculares , Enfermedad de Moyamoya , Enfermedades de la Piel , Encéfalo , Humanos , Enfermedad de Moyamoya/complicaciones , PielRESUMEN
BACKGROUND: The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients. OBJECTIVE: This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya. METHODS: Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs. RESULTS: Two de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced. CONCLUSION: The recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.
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Proteínas de Unión al ADN/genética , Dosificación de Gen/genética , Predisposición Genética a la Enfermedad , Enfermedad de Moyamoya/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Adolescente , Niño , Preescolar , Cromosomas Humanos X/genética , Femenino , Duplicación de Gen/genética , Genoma Humano/genética , Humanos , Lactante , Masculino , Enfermedad de Moyamoya/diagnóstico , Enfermedad de Moyamoya/patología , Polimorfismo de Nucleótido Simple/genética , Secuenciación del ExomaRESUMEN
OBJECTIVE: In Europe, MMA is a very rare non-inflammatory vasculopathy. MMA is an important differential diagnosis of cerebral vasculitis. Systemic manifestations, such as livedo racemosa or renal artery stenosis, associated with Moyamoya variants suggest the involvement also of non-cerebral vessels. Hypothetically, capillary microscopy could be a promising non-invasive screening method to visualize microcirculation, for example prior to cerebral angiography. METHODS: Standardized capillary microscopic images were taken in European patients with MMA and subsequently evaluated in a blinded analysis, using data obtained from a large NP cohort and a large SLE cohort by the same blinded Investigator as controls. RESULTS: Twenty-four European MMD patients and 14 healthy accompanying controls were included in this study. The results were compared to 116 SLE patients and 754 NP subjects. In MMD patients, no capillary morphological differences were found in comparison with NP, in particular no density reduction or increased neoangiogenesis. The pattern observed in the SLE cohort was clearly distinct from NP and MMD with regard to vascular density, vascular damage, and neoangiogenesis. CONCLUSIONS: MMD is not associated with microvascular changes of the nailfold capillaries. In this respect, it is clearly distinct from SLE.
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Capilares , Microcirculación , Angioscopía Microscópica , Enfermedad de Moyamoya , Adulto , Anciano , Capilares/patología , Capilares/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/patología , Enfermedad de Moyamoya/fisiopatologíaRESUMEN
PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. METHODS: Exome sequencing from 39 trios were analyzed. RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
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Trastornos Cerebrovasculares/genética , Enfermedad de Moyamoya/genética , Adulto , Proteínas de Ciclo Celular/genética , Trastornos Cerebrovasculares/metabolismo , Niño , Preescolar , ADN Helicasas/genética , Discapacidades del Desarrollo/genética , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Metiltransferasas/genética , Metiltransferasas/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Persona de Mediana Edad , Mutación/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Secuenciación del Exoma/métodosRESUMEN
INTRODUCTION: Clinical spectrum of Moyamoya angiopathy (MMA) differs across populations with different ethnicity. This study, the largest one done among Indian population was undertaken to assess clinico-radiological profile of MMA patients in eastern India. METHODS: A single centre cross-sectional study was undertaken among 76 MMA cases. Each patient was evaluated for epidemiological, clinical and radiological characteristics. SPSS 25 was used for statistical analysis. P < 0.05 was taken as statistically significant. RESULTS: 36 (47.4%) were children without gender preponderance. There were female predominance among adults (male:femaleâ¯=â¯1:2.33). Mean age at onset of first neurological symptoms for children was 4.2 ± 2.0years, followed by 34.9 ± 58.2months of latency with final diagnosis at the mean age of 7.4 ± 3.5years. For adults, mean age of onset of first neurological symptoms was 31.5 ± 12.3years, followed by 14.7 ± 41.7months time gap and diagnosed at the mean age of 33.5 ± 12.5years. There was a statistically significant difference between child and adult regarding the diagnostic latency (pâ¯=â¯0.035). Fixed motor weakness (FMW) was the predominant symptom across the whole disease course. Among children predominant first neurological symptom was fixed motor weakness (FMW) (52.8%), followed by seizures (22.2%). FMW was predominant (55%) first neurological complaint, followed by headache (22.5%) among adults. Seizure was more prevalent among children both as first (pâ¯=â¯0.002) and presenting symptom at the time of diagnosis (pâ¯=â¯0.048). Over the course of the disease seizure was more common among children (pâ¯=â¯0.001), while headache was more common among adults (pâ¯=â¯0.017). Recurrence of symptoms was more common among children (pâ¯=â¯0.059). Infarcts were more common among children (91.7%) than adults (72.5%), while hemorrhage was seen only among adults (25%) (pâ¯=â¯0.004). Isolated cerebral cortex was involved more commonly among children (59.4%) than adults (36.1%), while isolated subcortical involvement was seen only among adults (19.4%) (pâ¯=â¯0.016). Majority of the MMA cases were of Suzuki stage 4 (39.5%) and 5 (27.6%). Brain atrophy was associated with diagnostic latency (pâ¯=â¯0.009). CONCLUSION: Indian Moyamoya presents similar to disease presentation in Caucasian and Japanese patients. It is a frequently overlooked cause of stroke in young, often with various non-motor presentations, failure to recognize which leads to delay in diagnosis. Radiological burden disproportionate to number of acute vascular events, with subtle neurological manifestations like headache or seizure, often with cognitive decline, should raise suspicion of MMA.
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Enfermedad de Moyamoya/diagnóstico , Sistema Nervioso/fisiopatología , Examen Neurológico , Evaluación de Síntomas , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Estudios Transversales , Diagnóstico Tardío , Femenino , Humanos , India/epidemiología , Lactante , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/epidemiología , Enfermedad de Moyamoya/fisiopatología , Sistema Nervioso/diagnóstico por imagen , Valor Predictivo de las Pruebas , Prevalencia , Pronóstico , Factores de Riesgo , Adulto JovenRESUMEN
Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.
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Adenosina Trifosfatasas/genética , Predisposición Genética a la Enfermedad , Enfermedad de Moyamoya/diagnóstico , Mutación , Ubiquitina-Proteína Ligasas/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Alelos , Niño , Europa (Continente) , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/genética , Linaje , Fosfoproteínas Fosfatasas/genética , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare complication of patients treated with fingolimod. CASE PRESENTATION: Routine MRI eventually led to diagnosis of asymptomatic early PML that remained stable after discontinuation of fingolimod. As blood lymphocyte counts normalized, signs of immune reconstitution inflammatory syndrome (IRIS) and renewed MS activity developed. Both, advanced laboratory and ultrahigh field MRI findings elucidated differences between PML and MS. CONCLUSIONS: In our case, early discontinuation of fingolimod yielded a good outcome, lymphocyte counts reflected immune system activity, and paraclinical findings helped to differentiate between PML-IRIS and MS.
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Clorhidrato de Fingolimod/efectos adversos , Síndrome Inflamatorio de Reconstitución Inmune/diagnóstico por imagen , Inmunosupresores/efectos adversos , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/diagnóstico por imagen , Adulto , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
Moyamoya angiopathy is a rare vasculopathy with stenosis and/or occlusion of bilateral intracranial parts of internal carotid arteries and/or proximal parts of middle and anterior cerebral arteries. PHACE syndrome is characterized by large segmental hemangiomas in the cervical-facial region. Both conditions are known to be associated in rare cases. Recently, it was discussed in the literature that RNF213 variants could be etiologically involved in this association. Here, we describe a childhood case with this rare co-occurrence in which we did not identify any rare RNF213 variant. The clinical and genetic backgrounds are discussed.
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Adenosina Trifosfatasas/genética , Coartación Aórtica/complicaciones , Anomalías del Ojo/complicaciones , Enfermedad de Moyamoya/complicaciones , Síndromes Neurocutáneos/complicaciones , Ubiquitina-Proteína Ligasas/genética , Adulto , Coartación Aórtica/diagnóstico por imagen , Coartación Aórtica/genética , Encéfalo/diagnóstico por imagen , Anomalías del Ojo/diagnóstico por imagen , Anomalías del Ojo/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/genética , Síndromes Neurocutáneos/diagnóstico por imagen , Síndromes Neurocutáneos/genéticaRESUMEN
BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome. METHODS: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis. RESULTS: We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up. CONCLUSIONS: These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.
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Mutación de Línea Germinal , Enfermedad de Moyamoya/enzimología , Enfermedad de Moyamoya/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Adolescente , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Enfermedad de Moyamoya/diagnóstico , Enfermedad de Moyamoya/patología , Secuenciación del ExomaRESUMEN
Background Headache is common in patients with Moyanoya angiopathy (MMA), but usually underestimated in its management and not well characterized. Methods A validated self-administered headache screening questionnaire and a telephone interview were used in order to investigate headache characteristics, frequency and pain intensity in a large cohort of 55 German patients with MMA. Results Thirty-seven patients (67.3%) had suffered from headache in the past year. Headache intensity was rated 3.2 ± 1.3 on a verbal rating scale from 0 to 10. Seventeen patients (47.9%) reported migraine-like headache, 10 patients (27.0%) reported tension type-like headache and 10 patients (27.0%) had a combination of both. The majority of patients with migraine-like headache ( n = 10, 58.8%) described migrainous aura. Headache frequency and intensity improved significantly after revascularization surgery; however, nine patients developed new-onset headache postoperatively. Conclusion Headache is very common in MMA, often with a migraine-like phenotype. Tension type-like headache was also found in 27% of patients, which is a new finding that has not been reported before.
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Cefalea/diagnóstico , Cefalea/epidemiología , Enfermedad de Moyamoya/diagnóstico , Enfermedad de Moyamoya/epidemiología , Población Blanca , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
White matter lesions (WML) in younger patients might be due to a variety of neurological disorders. Fabry disease (FD), an x-linked inherited lysosomal storage disorder, happens to be misdiagnosed as multiple sclerosis (MS). In two middle-aged female patients, presenting bilateral WML, diagnosis of MS turned out to be doubtful. Human genetic analysis presented the Fabry mutation D313Y, in which clinical impact is still unclear. Disease manifestations outside the central nervous system were not detected. Our findings support the suspicion that Fabry mutation D313Y may be involved in neural damage resulting in WML.