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Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. Recent years altered this perception, as a growing number of leukodystrophies was described to have an onset at adult ages. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic Cerebral Amyloid Angiopathy that was found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid-old adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles, and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later on displayed severe degeneration and loss. In addition, despite loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of Cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.
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CSF1 receptor-related leukoencephalopathy is a rare genetic disorder presenting with severe, adult-onset white matter dementia as one of the leading symptoms. Within the central nervous system, the affected CSF1-receptor is expressed exclusively in microglia cells. Growing evidence implicates that replacing the defective microglia with healthy donor cells through hematopoietic stem cell transplant might halt disease progression. Early initiation of that treatment is crucial to limit persistent disability. However, which patients are suitable for this treatment is not clear, and imaging biomarkers that specifically depict lasting structural damage are lacking. In this study, we report on two patients with CSF1R-related leukoencephalopathy in whom allogenic hematopoietic stem cell transplant at advanced disease stages led to clinical stabilization. We compare their disease course with that of two patients admitted in the same timeframe to our hospital, considered too late for treatment, and place our cases in context with the respective literature. We propose that the rate of clinical progression might be a suitable stratification measure for treatment amenability in patients. Furthermore, for the first time we evaluate [18F] florbetaben, a PET tracer known to bind to intact myelin, as a novel MRI-adjunct tool to image white matter damage in CSF1R-related leukoencephalopathy. In conclusion, our data add evidence for allogenic hematopoietic stem cell transplant as a promising treatment in CSF1R-related leukoencephalopathy patients with slow to moderate disease progression.
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PURPOSE: The aim of the study was to investigate the feasibility and acceptability of a routine screening for peripartum depression (PD) by gynecologists and pediatricians. In addition, it was investigated whether two separate Plus Questions (PQ) of the "EPDS-Plus" are valid for screening experiences of violence or a traumatic birth and whether they can be associated with symptoms of PD. METHODS: Using the EPDS-Plus the prevalence of PD was investigated in 5235 women. The convergent validity of the PQ with the Childhood Trauma Questionnaire (CTQ) and Salmon's Item List (SIL) was assessed using correlation analysis. The association between the experience of violence and/or traumatic birth experience and PD was subjected to the chi-square test. Furthermore, a qualitative analysis for acceptance and satisfaction by the practitioners was performed. RESULTS: The prevalence was 9.94%/10.18% for antepartum/postpartum depression. The convergent validity of the PQ showed strong correlation with CTQ (p<0.001) and SIL (p<0.001). For violence and PD, a significant association was found. There was no significant association for traumatic birth experience and PD. There was a high level of satisfaction and acceptance of the EPDS-Plus questionnaire. CONCLUSION: Screening for peripartum depression is feasible in regular care and can help to identify depressed as well as potentially traumatized mothers, especially in preparing trauma-sensitive birth care and treatment. Therefore, specialized peripartum "psych" treatment for all affected mothers in all regions has to be implemented.
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Traumatismos do Nascimento , Depressão Pós-Parto , Gravidez , Feminino , Humanos , Criança , Depressão , Período Periparto , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/epidemiologia , Parto , Mães , Programas de RastreamentoRESUMO
BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.
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Imunoglobulinas Intravenosas , Miastenia Gravis , Adulto , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Método Duplo-Cego , Corticosteroides/uso terapêutico , Resultado do TratamentoRESUMO
Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.
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Insuficiência Adrenal , Adrenoleucodistrofia , Transplante de Células-Tronco Hematopoéticas , Recém-Nascido , Humanos , Masculino , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/terapia , Consenso , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Insuficiência Adrenal/diagnóstico , Triagem Neonatal/métodosAssuntos
Anormalidades do Olho , Deformidades Congênitas do Pé , Sindactilia , Anormalidades Dentárias , Adulto , Anormalidades Craniofaciais , Anormalidades do Olho/complicações , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/genética , Humanos , Sindactilia/complicações , Sindactilia/diagnóstico por imagem , Sindactilia/genética , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/genéticaRESUMO
Cerebral disease manifestation occurs in about two thirds of males with X-linked adrenoleukodystrophy (CALD) and is fatally progressive if left untreated. Early histopathologic studies categorized CALD as an inflammatory demyelinating disease, which led to repeated comparisons to multiple sclerosis (MS). The aim of this study was to revisit the relationship between axonal damage and myelin loss in CALD. We applied novel immunohistochemical tools to investigate axonal damage, myelin loss and myelin repair in autopsy brain tissue of eight CALD and 25 MS patients. We found extensive and severe acute axonal damage in CALD already in prelesional areas defined by microglia loss and relative myelin preservation. In contrast to MS, we did not observe selective phagocytosis of myelin, but a concomitant decay of the entire axon-myelin unit in all CALD lesion stages. Using a novel marker protein for actively remyelinating oligodendrocytes, breast carcinoma-amplified sequence (BCAS) 1, we show that repair pathways are activated in oligodendrocytes in CALD. Regenerating cells, however, were affected by the ongoing disease process. We provide evidence that-in contrast to MS-selective myelin phagocytosis is not characteristic of CALD. On the contrary, our data indicate that acute axonal injury and permanent axonal loss are thus far underestimated features of the disease that must come into focus in our search for biomarkers and novel therapeutic approaches.
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Adrenoleucodistrofia , Esclerose Múltipla , Adrenoleucodistrofia/metabolismo , Axônios/metabolismo , Humanos , Masculino , Esclerose Múltipla/patologia , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismoRESUMO
X-linked adrenoleukodystrophy (X-ALD), the most frequent monogenetic disorder of brain white matter, is highly variable, ranging from slowly progressive adrenomyeloneuropathy (AMN) to life-threatening inflammatory brain demyelination (CALD). In this study involving 94 X-ALD patients and 55 controls, we tested whether plasma/serum neurofilament light chain protein (NfL) constitutes an early distinguishing biomarker. In AMN, we found moderately elevated NfL with increased levels reflecting higher grading of myelopathy-related disability. Intriguingly, NfL was a significant predictor to discriminate non-converting AMN from cohorts later developing CALD. In CALD, markedly amplified NfL levels reflected brain lesion severity. In rare cases, atypically low NfL revealed a previously unrecognized smoldering CALD disease course with slowly progressive myelin destruction. Upon halt of brain demyelination by hematopoietic stem cell transplantation, NfL gradually normalized. Together, our study reveals that blood NfL reflects inflammatory activity and progression in CALD patients, thus constituting a potential surrogate biomarker that may facilitate clinical decisions and therapeutic development.
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Adrenoleucodistrofia/metabolismo , Biomarcadores/metabolismo , Degeneração Neural/metabolismo , Proteínas de Neurofilamentos/metabolismo , Adolescente , Adrenoleucodistrofia/diagnóstico , Adulto , Biomarcadores/sangue , Criança , Estudos de Coortes , Progressão da Doença , Humanos , Filamentos Intermediários/metabolismo , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico , Proteínas de Neurofilamentos/sangueRESUMO
Muscle pain as a common symptom in daily practice frequently occurs as a non-specific accompanying symptom in multiple internal and neurological diseases. Primarily inflammatory or autoimmune muscular diseases are causing muscle pain. However, a number of non-inflammatory causes of pain can also be considered for differential diagnosis. These are presented in this article. In principle, a distinction must be made between focal and diffuse muscle pain. As an invasive diagnostic procedure, a muscle biopsy should only be performed as the last step in the diagnostic alogorithm. If diffuse muscle pain is only associated with slight muscle weakness or is completely absent, there is usually a primary rheumatic cause. Statins (HMG-CoA reductase inhibitors) can lead to rhabdomyolysis, muscle fiber atrophy and muscle necrosis by damaging the muscle fiber membrane. Myotonias are autosomal dominant or autosomal recessive inherited disorders of muscle function. The genetic defect leads to pronounced muscle stiffness. The cause of metabolic myopathies can be disorders of the carbohydrate, fat or purine metabolism. Fibromyalgia syndrome (FMS) is a non-inflammatory disease and, according to the current knowledge, recognized as the result of an exposure to physical, biological and psychosocial factors (biopsychological disease model). To help diagnosing FMS, pain regions and core symptoms (fatigue, sleep disturbances) can be detected using questionnaires (Widespread Pain Index [WPI] and Symptom Severity Scale [SSS]).
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Mialgia/etiologia , Contratura/classificação , Contratura/diagnóstico , Contratura/etiologia , Diagnóstico Diferencial , Fibromialgia/classificação , Fibromialgia/diagnóstico , Fibromialgia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Cãibra Muscular/classificação , Cãibra Muscular/diagnóstico , Cãibra Muscular/etiologia , Debilidade Muscular/classificação , Debilidade Muscular/diagnóstico , Debilidade Muscular/etiologia , Doenças Musculares/classificação , Doenças Musculares/diagnóstico , Doenças Musculares/etiologia , Mialgia/classificação , Mialgia/diagnóstico , Miotonia/classificação , Miotonia/diagnóstico , Miotonia/etiologia , Fatores de Risco , Espasmo/classificação , Espasmo/diagnóstico , Espasmo/etiologiaRESUMO
OBJECTIVE: To identify a pharmacological compound targeting macrophages, the most affected immune cells in inflammatory X-linked adrenoleukodystrophy (cerebral X-ALD) caused by ABCD1 mutations and involved in the success of hematopoietic stem cell transplantation and gene therapy. METHODS: A comparative database analysis elucidated the epigenetic repressing mechanism of the related ABCD2 gene in macrophages and identified the histone deacetylase (HDAC) inhibitor Vorinostat as a compound to induce ABCD2 in these cells to compensate for ABCD1 deficiency. In these cells, we investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFAs) and their differentiation status. We investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFA) and differentiation status. Three advanced cerebral X-ALD patients received Vorinostat and CSF and MRI diagnostics was carried out in one patient after 80 days of treatment. RESULTS: Vorinostat improved the metabolic defects in X-ALD macrophages by stimulating ABCD2 expression, peroxisomal ß-oxidation, and ameliorating VLCFA accumulation. Vorinostat interfered with pro-inflammatory skewing of X-ALD macrophages by correcting IL12B expression and further reducing monocyte differentiation. Vorinostat normalized the albumin and immunoglobulin CSF-serum ratios, but not gadolinium enhancement upon 80 days of treatment. INTERPRETATION: The beneficial effects of HDAC inhibitors on macrophages in X-ALD and the improvement of the blood-CSF/blood-brain barrier are encouraging for future investigations. In contrast with Vorinostat, less toxic macrophage-specific HDAC inhibitors might improve also the clinical state of X-ALD patients with advanced inflammatory demyelination.
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Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/deficiência , Subfamília D de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Adrenoleucodistrofia/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Vorinostat/farmacologia , Doença Aguda , Adrenoleucodistrofia/líquido cefalorraquidiano , Adrenoleucodistrofia/diagnóstico por imagem , Coenzima A Ligases/efeitos dos fármacos , Humanos , Imageamento por Ressonância Magnética , Avaliação de Resultados em Cuidados de Saúde , PeroxissomosRESUMO
The adult cerebral form of X-linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic hematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), 8 with stable cognition and 7 of them with stable motor function (estimated event-free survival 36 ± 17%). Death after transplantation occurred within the first year after HSCT and was caused either primarily by infection (N = 3) or due to disease progression triggered by infection (N = 1). Patients with minor myelopathic symptoms (N = 4) or with no or mild cerebral symptoms pre-transplant (N = 7) had an excellent outcome. In contrast, no patient with major neurological symptoms associated with an extensive involvement of pyramidal tract fibres in the internal capsule (N = 5) survived without cognitive deterioration. Notably, early leukocyte recovery was associated with dismal outcome for yet unknown reasons. All 10 tested survivors showed a reduction of plasma hexacosanoic acid (C26:0) in the absence of Lorenzo's oil. Over time, the event-free survival could be improved from 2 out of 8 patients (25%) before 2013 to 5 out of 7 patients (71%) thereafter. Therefore, allogeneic HSCT appears to be a suitable treatment option for carefully selected ACALD patients when transplanted from matched donors after myeloablative, busulfan-based conditioning.
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Adrenoleucodistrofia/terapia , Progressão da Doença , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Adrenoleucodistrofia/mortalidade , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy that only in rare cases arrests spontaneously. These findings emphasize monocytes/macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy.
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Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/imunologia , Macrófagos/metabolismo , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/fisiologia , Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/fisiopatologia , Adulto , Plasticidade Celular/genética , Plasticidade Celular/fisiologia , Doenças Desmielinizantes/metabolismo , Humanos , Macrófagos/fisiologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/fisiologia , Bainha de Mielina/metabolismo , População Branca , Sequenciamento do Exoma/métodosRESUMO
The leukodystrophies are a group of inherited white matter disorders with a heterogeneous genetic background, considerable phenotypic variability and disease onset at all ages. This Review focuses on leukodystrophies with major prevalence or primary onset in adulthood. We summarize 20 leukodystrophies with adult presentations, providing information on the underlying genetic mutations and on biochemical assays that aid diagnosis, where available. Definitions, clinical characteristics, age of onset, MRI findings and treatment options are all described, providing a comprehensive overview of the current knowledge of the various adulthood leukodystrophies. We highlight the distinction between adult-onset leukodystrophies and other inherited disorders with white matter involvement, and we propose a diagnostic pathway for timely recognition of adulthood leukodystrophies in a routine clinical setting. In addition, we provide detailed clinical information on selected adult-onset leukodystrophies, including X-linked adrenoleukodystrophy, metachromatic leukodystrophy, cerebrotendinous xanthomatosis, hereditary diffuse leukoencephalopathy with axonal spheroids, autosomal dominant adult-onset demyelinating leukodystrophy, adult polyglucosan body disease, and leukoencephalopathy with vanishing white matter. Ultimately, this Review aims to provide helpful suggestions to identify treatable adulthood leukodystrophies at an early stage in the disease course.
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Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Leucoencefalopatias , Adulto , Idade de Início , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/fisiopatologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/terapia , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Leucoencefalopatias/terapiaRESUMO
Importance: Allogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized. Objectives: To identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes. Design, Setting, and Participants: This case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charité Universitätsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score. Main Outcomes and Measures: Overall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients' clinical symptoms, demyelination patterns, and stem cell source were stratified. Results: Of the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (50%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6). Conclusions and Relevance: All patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.
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Adrenoleucodistrofia/cirurgia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Humanos , Masculino , Transtornos Neurocognitivos/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Tempo , Transplante HomólogoRESUMO
The adult cerebral inflammatory form of X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disease, as devastating as childhood cerebral adrenoleukodystrophy. Allogeneic haematopoietic stem cell transplantation has been demonstrated to provide long-term neurological benefits for boys with the childhood cerebral form, but results in adults are sparse and inconclusive. We analysed data from 14 adult males with adult cerebral adrenoleukodystrophy treated with allogeneic haematopoietic stem cell transplantation on a compassionate basis in four European centres. All presented with cerebral demyelinating lesions and gadolinium enhancement. Median age at diagnosis of adult cerebral adrenoleukodystrophy was 33 years (range 21-48 years). In addition to cerebral inflammation, five patients had established severe motor disability from adrenomyeloneuropathy affecting only the spinal cord and peripheral nerves (Expanded Disability Status Scale score ≥ 6). Eight patients survived (estimated survival 57 ± 13%) with a median follow-up of 65 months (minimum 38 months). Death was directly transplant-/infection-related (n = 3), due to primary disease progression in advanced adult cerebral adrenoleukodystrophy (n = 1), or secondary disease progression (n = 2) after transient multi-organ failure or non-engraftment. Specific complications during stem cell transplantation included deterioration of motor and bladder functions (n = 12) as well as behavioural changes (n = 8). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all eight survivors, but deterioration of motor function occurred in the majority (n = 5). Limited motor dysfunction (Expanded Disability Status Scale score < 6) prior to transplantation was associated with significantly improved survival [78 ± 14% (n = 9) versus 20 ± 18%(n = 5); P < 0.05] and maintenance of ambulation (Expanded Disability Status Scale score < 7) post-transplant (78% versus 0%; P = 0.021). In contrast, bilateral involvement of the internal capsule on brain MRI was associated with poorer survival [20 ± 18% (n = 5) versus 78 ± 14% (n = 9); P < 0.05]. This study is the first to support the feasibility, complications and potential long-term neurological benefit of allogeneic haematopoietic stem cell transplantation in adult cerebral adrenoleukodystrophy. Further studies are warranted to attempt to improve outcomes through patient selection and optimization of transplantation protocols.
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Adrenoleucodistrofia/terapia , Progressão da Doença , Transplante de Células-Tronco Hematopoéticas/métodos , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/etiologia , Índice de Gravidade de Doença , Adrenoleucodistrofia/mortalidade , Adrenoleucodistrofia/patologia , Adrenoleucodistrofia/fisiopatologia , Adulto , Assistência ao Convalescente , Estudos de Viabilidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/fisiopatologia , Adulto JovemRESUMO
Whereas innate immune cells, such as NK and innate lymphoid cells (ILCs), have been characterized in different human tissues, knowledge on the thymic CD56-expressing cell subsets is limited. In this study, the rare subpopulations of thymic CD56+CD3- cells from samples of >100 patients have been successfully analyzed. The results revealed fundamental differences between thymic and peripheral blood (PB) CD56+CD3- cells. Thymic tissues lacked immunoregulatory CD56highCD16dim NK cells but showed two Eomes+CD56dim subsets on which common NK cell markers were significantly altered. CD56dimCD16high cells expressed high amounts of NKG2A, NKG2D, and CD27 with low CD57. Conversely, CD56dimCD16dim cells displayed high CD127 but low expression of KIR, NKG2D, and natural cytotoxicity receptors (NCRs). Thymic CD56+CD3- cells were able to gain cytotoxicity but were especially immunoregulatory cells, producing a broad range of cytokines. Finally, one population of thymic CD56+ cells resembled conventional NK cells, whereas the other represented a novel, noncanonical NK subset.
Assuntos
Antígeno CD56/análise , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Timo/imunologia , Adulto , Envelhecimento/imunologia , Antígenos CD/análise , Degranulação Celular , Separação Celular , Criança , Citocinas/biossíntese , Citotoxicidade Imunológica , Citometria de Fluxo , Humanos , Imunofenotipagem/métodos , Células Matadoras Naturais/classificação , Microscopia Confocal , Microscopia de Fluorescência , Receptores de Células Matadoras Naturais/análise , Timo/citologia , Timo/crescimento & desenvolvimentoRESUMO
X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the ABCD1 gene, encoding a member of the peroxisomal ABC transporter family. The ABCD1 protein transports CoA-activated very long-chain fatty acids (VLCFAs) into peroxisomes for degradation via ß-oxidation. In the severest form, X-ALD patients suffer from inflammatory demyelination of the brain. As the extent of the metabolic defect in the main immune cells is unknown, we explored their phenotypes concerning mRNA expression pattern of the three peroxisomal ABC transporters, VLCFA accumulation and peroxisomal ß-oxidation. In controls, ABCD1 expression was high in monocytes, intermediate in B cells and low in T cells; ABCD2 expression was extremely low in monocytes, intermediate in B cells and highest in T cells; ABCD3 mRNA was equally distributed. In X-ALD patients, the expression patterns remained unaltered; accordingly, monocytes, which lack compensatory VLCFA transport by ABCD2, displayed the severest biochemical phenotype with a 6-fold accumulation of C26:0 and a striking 70% reduction in peroxisomal ß-oxidation activity. In contrast, VLCFA metabolism was close to control values in B cells and T cells, supporting the hypothesis that sufficient ABCD2 is present to compensate for ABCD1 deficiency. Thus, the vulnerability of the main immune cell types is highly variable in X-ALD. Based on these results, we propose that in X-ALD the halt of inflammation after allogeneic hematopoietic stem cell transplantation relies particularly on the replacement of the monocyte lineage. Additionally, these findings support the concept that ABCD2 is a target for pharmacological induction as an alternative therapeutic strategy.
Assuntos
Adrenoleucodistrofia/metabolismo , Ácidos Graxos/metabolismo , Linfócitos/metabolismo , Monócitos/metabolismo , Subfamília D de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adrenoleucodistrofia/genética , Adulto , Estudos de Casos e Controles , Células Cultivadas , Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Oxirredução , Peroxissomos/metabolismoRESUMO
OBJECTIVE: Fabry disease is a rare X-linked inherited lysosomal storage disorder affecting multiple organ systems. It includes central nervous system involvement via micro- and macroangiopathic cerebral changes. Due to its clinical symptoms and frequent MRI lesions, Fabry disease is commonly misdiagnosed as multiple sclerosis. We present an overview of cases from Fabry centres in Germany initially misdiagnosed with multiple sclerosis and report the clinical, MR-tomographical, and laboratory findings. METHODS: Eleven Fabry patients (one male, ten females) initially diagnosed with multiple sclerosis were identified from 187 patient records (5.9%) and analyzed for presenting symptoms, results of the initial diagnostic workup, and the clinical course of the disease. RESULTS: Four patients were identified as having a "possible" history of MS, and 7 patients as "definite" cases of multiple sclerosis (revised McDonald criteria). On average, Fabry disease was diagnosed 8.2 years (±9.8 years) after the MS diagnosis, and 12.8 years after onset of first symptoms (±10.3 years). All patients revealed white matter lesions on MRI. The lesion pattern and results of cerebrospinal fluid examination were inconsistent and non-specific. White matter lesion volumes ranged from 8.9 mL to 34.8 mL (mean 17.8 mL±11.4 mL). There was no association between extra-neurological manifestations or enzyme activity and lesion load. CONCLUSION: There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging, ectatic vertebrobasilar arteries, proteinuria, or lack of intrathecally derived immunoglobulin synthesis.
Assuntos
Erros de Diagnóstico , Doença de Fabry/diagnóstico , Esclerose Múltipla/diagnóstico , Adulto , Idoso , Encéfalo/patologia , Análise Mutacional de DNA , Diagnóstico Tardio , Diagnóstico Diferencial , Doença de Fabry/líquido cefalorraquidiano , Doença de Fabry/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Esclerose Múltipla/líquido cefalorraquidiano , alfa-Galactosidase/genéticaRESUMO
Myasthenic crisis is the most serious life-threatening event in Myasthenia gravis patients, affecting up to 27% within the first two years after onset of disease. Extracorporeal removal of circulating autoantibodies against the nicotinic acetylcholine receptor (AChRAb) by methods of therapeutic apheresis, e.g. plasma exchange (PE) and immunoadsorption (IA) had been demonstrated as effective treatment especially in acute situations of myasthenic crisis. However, controlled data comparing clinical safety and efficacy of both methods in a clinical study were not available. Here the results of a prospective randomized controlled clinical trial are presented, investigating 19 patients with myasthenic crisis, who were randomized to receive either PE (n = 10) or IA (n = 9) in addition to combined drug treatment. Patients received 3 to 5 (mean 3.5 for PE, and 3.4 for IA) treatments over a period of 7 days with a predefined treatment volume of 1.5 l plasma (i.e., 20-25 ml/kg plasma representing 0.5-0.6 patients' plasma volumes). Clinical courses were monitored using disease specific clinical scores. After initiation of IA or PE the mean value of Myasthenia scores decreased equally until Day 14 of the post-treatment phase. Patients from both treatment groups improved to a stable clinical status of Oosterhuis Classes 1 and 2. Substantial reduction of AChRAb was documented after each session of PE or IA. In the treatment period 16 adverse effects (seven serious adverse events, SAE) in the PE and 10 (1 SAE) in the IA group were observed. In conclusion, IA proved to be equally effective compared with PE treatment in patients with myasthenic crisis. Three to five treatment sessions using low plasma volume dosage of 20-25 ml/kg were adequate to improve clinically relevant symptoms significantly in most patients.
Assuntos
Técnicas de Imunoadsorção , Miastenia Gravis/terapia , Troca Plasmática , Idoso , Autoanticorpos/sangue , Terapia Combinada , Feminino , Humanos , Técnicas de Imunoadsorção/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/imunologia , Troca Plasmática/efeitos adversos , Troca Plasmática/métodos , Estudos Prospectivos , Receptores Nicotínicos/imunologia , Resultado do TratamentoRESUMO
INTRODUCTION: For more than 50 years the acetylcholinesterase inhibitor pyridostigmine bromide has been the drug of choice in the symptomatic therapy for myasthenia gravis. The sustained-release dosage form of pyridostigmine (SR-Pyr) is only available in a limited number of countries (e.g. in the United States and Germany). Astonishingly, the therapeutic usefulness of SR-Pyr has not yet been evaluated. METHODS: In this non-interventional prospective open-label trial, 72 patients with stable myasthenia gravis were switched from instant-release dosage forms of pyridostigmine bromide to SR-Pyr. The results from the 37 patients younger than 60 years were separately analyzed. RESULTS: The initial daily dose of SR-Pyr was 288.1 ± 171.0mg. The drug switch was unproblematic in all patients. The number of daily doses was significantly reduced from 4.3 to 3.6 (p=0.011). The switch to SR-Pyr ameliorated the total quantified myasthenia gravis (QMG) score from 0.9 ± 0.5 to 0.6 ± 0.4 (p<0.001) in all patients and in the younger subgroup. This was accompanied by a significant improvement in the quality of life parameters. The health status valued by EuroQoL questionnaire improved from 0.626 ± 0.286 to 0.782 ± 0.186 (p<0.001). After switching to SR-Pyr, 28 adverse reactions disappeared and 24 adverse reactions occurred less frequent or weaker, however, 17 new adverse reactions were documented. CONCLUSIONS: Our results support the usefulness of SR-Pyr in an individualized therapeutic regimen to improve quality of life regardless of the patient's age in myasthenia gravis.