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BACKGROUND: Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. CASE: We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. CONCLUSIONS: LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Feminino , alfa-Sinucleína/genética , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genéticaRESUMO
In this review, the role of innate and adaptive immunity in the pathogenesis of inflammatory bowel diseases (IBD) is reported. In IBD, an altered innate immunity is often found, with increased Th17 and decreased Treg cells infiltrating the intestinal mucosa. An associated increase in inflammatory cytokines, such as IL-1 and TNF-α, and a decrease in anti-inflammatory cytokines, such as IL-10, concur in favoring the persistent inflammation of the gut mucosa. Autoinflammation is highlighted with insights in the role of inflammasomes, which activation by exogenous or endogenous triggers might be favored by mutations of NOD and NLRP proteins. Autoimmunity mechanisms also take place in IBD pathogenesis and in this context of a persistent immune stimulation by bacterial antigens and antigens derived from intestinal cells degradation, the adaptive immune response takes place and results in antibodies and autoantibodies production, a frequent finding in these diseases. Inflammation, autoinflammation and autoimmunity concur in altering the mucus layer and enhancing intestinal permeability, which sustains the vicious cycle of further mucosal inflammation.
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OBJECTIVES: Antibodies against glutamic acid decarboxylase isoform 65 (GAD-Ab) have been found in different severe neurological conditions associated with altered synthesis of γ-aminobutyric acid (GABA). Serum GAD-Ab can be found in up to 90â¯% of patients with type 1 diabetes mellitus (T1DM), mostly at relatively low concentrations, while high concentrations of GAD-ab are thought to be more frequently associate to a neurological condition, with levels 100-folds higher than those found in T1DM. Although CSF testing is recommended when suspecting a GAD-associated neurological syndrome, no commercial immunoassay is validated for this use and no cut-off is internationally recognized to support the diagnosis. METHODS: In this study we validated CSF testing of GAD-Ab on an automated chemiluminescence (CLIA) immunoassay that had previously shown good agreement with ELISA on serum. RESULTS: We tested 43 CSF from patients with typical GAD-associated neurological disorders and patients with other neurological conditions, identifying a clinical cut-off of 18â¯kIU/L that discriminated GAD-disease with an area under the curve (AUC) of 0.921. CLIA showed good analytical performances on repeatability and recovery tests in CSF and confirmed an excellent agreement with ELISA. CONCLUSIONS: GAD-Ab associated neurological disorders are rare but CSF testing for GAD-Ab is a common request for neurologists when suspecting an insidious autoimmune central nervous system disease. CLIA platforms are expected to be increasingly adopted in clinical laboratories due to their flexibility and reliability, therefore studies on decisional levels should be implemented for improving the interpretation and utilization of laboratory data.
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Diabetes Mellitus Tipo 1 , Doenças do Sistema Nervoso , Humanos , Autoanticorpos , Síndrome , Diabetes Mellitus Tipo 1/diagnóstico , Luminescência , Reprodutibilidade dos Testes , Doenças do Sistema Nervoso/diagnóstico , Glutamato DescarboxilaseRESUMO
OBJECTIVES: SARS-CoV-2 serology presents an important role in several aspects of COVID-19 pandemic. Immunoassays performances have to be accurately evaluated and correlated with neutralizing antibodies. We investigated the analytical and clinical performances of a SARS-CoV-2 RBD IgG assay, automated on a high throughput platform, and the correlation of the antibodies (Ab) levels with the plaque reduction neutralization (PRNT50) Ab titers. METHODS: A series of 546 samples were evaluated by SARS-CoV-2 RBD IgG assay (Snibe diagnostics), including 171 negative and 168 positive SARS-CoV-2 subjects and a further group of 207 subjects of the COVID-19 family clusters follow-up cohort. RESULTS: Assay imprecision ranged from 3.98 to 12.18% being satisfactory at low and medium levels; linearity was excellent in all the measurement range. Considering specimens collected after 14 days post symptoms onset, overall sensitivity and specificity were 99.0 and 92.5%, respectively. A total of 281 leftover samples results of the PRNT50 test were available. An elevated correlation was obtained between the SARS-CoV-2 RBD IgG assay and the PRNT50 titer at univariate (ρ=0.689) and multivariate (ρ=0.712) analyses. CONCLUSIONS: SARS-CoV-2 S-RBD IgG assay shows satisfactory analytical and clinical performances, and a strong correlation with sera neutralizing activity.
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Anticorpos Neutralizantes/imunologia , Imunoglobulina G/imunologia , Testes de Neutralização/métodos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/patologia , COVID-19/virologia , Criança , Feminino , Humanos , Imunoensaio/métodos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Subunidades Proteicas/imunologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Adulto JovemRESUMO
The differential diagnosis between acquired inflammatory demyelinating syndromes of the central nervous system (CNS), such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and acute disseminated encephalomyelitis (ADEM) can be very challenging at onset. Apart from cerebrospinal fluid oligoclonal bands and anti-aquaporin-4 antibodies (AQP4-Ab), definite diagnostic biomarkers are lacking. Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) have been increasingly described in children with AQP4-seronegative NMOSD, ADEM and other inflammatory demyelinating CND syndromes; despite partial overlaps with AQP4-Ab disease, a novel "MOG-Ab-disorder" phenotype has been suggested. In this study, we tested the presence of MOG-Ab and AQP4-Ab in 57 children at first onset of acute neurological symptoms; three clinical subgroups were identified: 12 patients had acquired inflammatory demyelinating CNS syndromes, 11 had other autoimmune/immune-mediated disorders of the central and peripheral nervous system and 34 had non-immune-mediated CNS disorders. MOG-Abs were found positive only in a subset of cases in the subgroup with acquired inflammatory demyelinating CNS syndromes (in 2/12 patients, both with non-MS phenotype) and in none of the patients with other autoimmune and immune-mediated disorders of the central and peripheral nervous system or with non-immune-mediated disorders of the CNS.Data from the literature review support clinical and analytical observations.
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Encefalomielite Aguda Disseminada , Esclerose Múltipla , Neuromielite Óptica , Aquaporina 4 , Autoanticorpos , Criança , Encefalomielite Aguda Disseminada/diagnóstico , Humanos , Glicoproteína Mielina-Oligodendrócito , Neuromielite Óptica/diagnósticoAssuntos
Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/metabolismo , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/diagnóstico , Pneumonia Viral/metabolismo , Idoso , Betacoronavirus , COVID-19 , Humanos , Itália/epidemiologia , Linfopenia , Masculino , Pandemias , SARS-CoV-2RESUMO
Serum biomarkers that might detect clinical progression are currently lacking for Spinal and bulbar muscular atrophy (SBMA), thus limiting the effectiveness of possible future pharmacological trials. Elevation of cardiac troponin T (cTnT) unrelated to myocardial damage in a motor neuron (MN) disease as amyotrophic lateral sclerosis (ALS) was associated to disease severity. We enrolled 47 SBMA patients and 5 Spinal muscular atrophy (SMA) type 3 adult patients as control group; each SBMA patient was evaluated at baseline and at one-year follow-up visit. Demographic and clinical data including functional scores (SBMAFRS) were collected; serum was collected as standard of care and tested for cardiac troponins. Levels of cTnT but not cTnI were increased in SBMA with respect to reference values; unlike other neuromuscular diseases, SMA patients had overall normal cTnT values. Median cTnT concentrations did not change after one year and values were correlated to motor function, particularly with lower limb subdomain, at baseline only. Variations of cTnT and of SBMAFRS were unrelated. The cautiously promising results of cTnT as potential biomarker should undergo a more extensive clinical validation, including studies with longer follow-up period. When evaluating SBMA patients for a potential cardiac damage cTnI testing should be coupled or preferred to cTnT.
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Esclerose Lateral Amiotrófica , Atrofia Bulboespinal Ligada ao X , Atrofia Muscular Espinal , Doenças Neuromusculares , Atrofias Musculares Espinais da Infância , Adulto , Humanos , Troponina T , Atrofia Muscular Espinal/diagnóstico , BiomarcadoresRESUMO
OBJECTIVE: To identify the potential prognostic value of lymphocyte subsets in COVID-19 patients, where lymphopenia is a common finding. METHODS: In 353 COVID-19 inpatients and 40 controls T cell subsets with markers of senescence and exhaustion were studied by flow cytometry. RESULTS: In severe illness, total lymphocytes B, NK, and all T subsets were dampened. Senescent CD4+, but mainly CD8+â T cells, increased in patients with respect to controls. The most significant index predicting fatal outcome was neutrophils/CD3+â T ratio. CONCLUSION: In conclusion, an altered T cell pattern underlies COVID-19 severity and is involved in predicting the outcome.
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COVID-19 , Humanos , Subpopulações de Linfócitos , Subpopulações de Linfócitos T , Linfócitos T CD8-Positivos , Senescência CelularRESUMO
Peripherin (PRPH), a type III intermediate filament, assembles with neurofilaments in neurons of the peripheral nervous system, including lower motor neurons (LMN). To evaluate the role of PRPH in LMN degeneration, we assessed PRPH and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum of 91 patients with motor neuron diseases (MND) and 69 controls. Overall, we found PRPH to be more concentrated in serum than in CSF. Serum PRPH resulted significantly increased in MND patients but it was unrelated to CSF-NfL or survival in the amyotrophic lateral sclerosis (ALS) subset. PRPH might represent a marker of LMN involvement.
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Doença dos Neurônios Motores/metabolismo , Proteínas de Neurofilamentos/metabolismo , Periferinas/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Humanos , Estudos Longitudinais , Doença dos Neurônios Motores/sangue , Doença dos Neurônios Motores/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Periferinas/sangue , Periferinas/líquido cefalorraquidiano , Estudos RetrospectivosRESUMO
Ves-Matic CUBE 200 is an automated erythrocyte sedimentation rate (ESR) analyser based on the modified Westergren principle of measurement. In this study, we aimed to assess its analytical performance following the key points addressed by the International Council for Standardization in Haematology and the comparability with the gold standard Westergren method. Comparison of the two methods yielded a correlation coefficient of 0.852, no significant bias and a small constant difference between compared results. Intrarun coefficients of variation (CV) ranged from 2.2% to 22.2%, the higher being for lower ESR values, while inter-run CVs were 19.7% for the normal range and 3.0% for the abnormal range. This study proved the analytical validity of the Ves-Matic CUBE 200 and its high comparability with the Westergren method, showing obvious improvements in the technology applied for automated determination of ESR and a valuable step forward in standardisation of ESR methods.