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Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.
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Dedos , Megalencefalia , Humanos , Megalencefalia/genética , Dedos/anormalidadesRESUMO
Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.
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Doenças Autoimunes , COVID-19 , Síndrome do Desconforto Respiratório , Doenças Reumáticas , Humanos , Doenças Autoimunes/tratamento farmacológico , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/epidemiologia , Antivirais/uso terapêuticoRESUMO
Hughes-Stovin syndrome is a rare disease characterized by thrombophlebitis and multiple pulmonary and/or bronchial aneurysms. The etiology and pathogenesis of HSS are incompletely known. The current consensus is that vasculitis underlies the pathogenic process, and pulmonary thrombosis follows arterial wall inflammation. As such, Hughes-Stovin syndrome may belong to the vascular cluster with lung involvement of Behçet syndrome, although oral aphtae, arthritis, and uveitis are rarely found. Behçet syndrome is a multifactorial polygenic disease with genetic, epigenetic, environmental, and mostly immunological contributors. The different Behçet syndrome phenotypes are presumably based upon different genetic determinants involving more than one pathogenic pathway. Hughes-Stovin syndrome may have common pathways with fibromuscular dysplasias and other diseases evolving with vascular aneurysms. We describe a Hughes-Stovin syndrome case fulfilling the Behçet syndrome criteria. A MYLK variant of unknown significance was detected, along with other heterozygous mutations in genes that may impact angiogenesis pathways. We discuss the possible involvement of these genetic findings, as well as other potential common determinants of Behçet/Hughes-Stovin syndrome and aneurysms in vascular Behçet syndrome. Recent advances in diagnostic techniques, including genetic testing, could help diagnose a specific Behçet syndrome subtype and other associated conditions to personalize the disease management.
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Aneurisma , Síndrome de Behçet , Vasculite , Humanos , Aneurisma/complicações , Aneurisma/diagnóstico , Aneurisma/patologia , Síndrome de Behçet/diagnóstico , Artéria Pulmonar/patologia , Vasculite/patologiaRESUMO
The coexistence of osteogenesis imperfecta and inflammatory arthritis has been very rarely described. Nevertheless, systemic inflammation has been found in osteogenesis imperfecta. The COL1A1 mutations may affect collagen synthesis as well as post-translational modifications, extracellular matrix interactions, and receptor-mediated signaling. Major collagen binding ligands forming the interactome, such as cytokines, cell adhesion molecules, matrix metalloproteinases, proteoglycans, and other molecules, are autoimmunity targets involved in rheumatoid arthritis pathogenesis. Cross-talk between bone remodeling and inflammatory pathways involving osteoclasts is important in osteogenesis imperfecta and rheumatoid arthritis. In osteogenesis imperfecta, the structural abnormalities and repeated traumatism, including fractures, could activate locally the innate immunity and trigger arthritis, similar to post-traumatic arthritis. Currently, the therapy of osteogenesis imperfecta is a suboptimally met need. Understanding the complex putative pathogenic links between osteogenesis imperfecta and inflammatory arthritis could hopefully lead to new therapeutic targets. Raising awareness regarding a possible association between osteogenesis imperfecta and arthritis could help improve the quality of life in these patients.
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Artrite Reumatoide , Osteogênese Imperfeita , Artrite Reumatoide/complicações , Colágeno Tipo I/genética , Citocinas , Humanos , Ligantes , Mutação , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Proteoglicanas , Qualidade de VidaRESUMO
OBJECTIVES: Due to the rarity of relapsing polychondritis (RP), no randomised clinical trial has been conducted to date and treatment remains empirical. We performed a systematic literature review to assess the efficacy of the main conventional immunosuppressants and biotherapies used in RP. METHODS: We searched MEDLINE for original articles without language restriction. Abstracts from American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) were also considered for inclusion. Observational studies and clinical trials reporting on the efficacy of conventional immunosuppressants and biotherapies in adult patients with RP were selected and pooled response rates for each treatment were computed. RESULTS: Of 304 articles and abstracts identified, 31 underwent full-text review, and 11 were included. The studies involved a total of 177 patients, exposed to a total of 247 lines of treatments. The main treatments studied (by number of lines) were: TNF inhibitors (TNFi), n=92; methotrexate (MTX), n=38; tocilizumab (TCZ), n=26; anakinra (ANA), n=21; rituximab (RTX), n=16; abatacept (ABT), n=14; cyclophosphamide (CYC), n=14; azathioprine (AZA), n=13. The pooled response rates across studies were: 72% [95% CI: 42-95] for ABT, 66% [95% CI: 49-82] for TCZ, 64% [95% CI: 53-74] for TNFi, 56% [95% CI: 37-73] for MTX, 47% [95% CI: 26-68] for ANA, 43% [95% CI: 20-68] for RTX. Based on more limited data, response rates for AZA and CYC ranged from 38 to 100% and from 25 to 100%, respectively. CONCLUSIONS: In this systematic review of available evidence regarding the treatment of relapsing polychondritis, ABT, TCZ and TNFi were the drugs associated with the best outcomes. ABT efficacy must be interpreted in light of the small number of patients treated. While MTX had slightly less efficacy, it is one of the drugs for which data are the most robust.
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Antirreumáticos , Artrite Reumatoide , Policondrite Recidivante , Abatacepte/uso terapêutico , Adulto , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Policondrite Recidivante/diagnóstico , Policondrite Recidivante/tratamento farmacológico , Rituximab/uso terapêutico , Inibidores do Fator de Necrose TumoralRESUMO
OBJECTIVES: Relapsing polychondritis (RP) evolves with variable and intermittent involvement of cartilage and proteoglycan-rich structures. Ocular manifestations are present in up to two-thirds of RP patients. Necrotising scleritis (NS) and peripheral ulcerative keratitis (PUK) may be inaugural and may lead to eye perforation and vision loss. We aimed to review NS and PUK in RP, in order to characterise them, to identify successful treatment options and unmet needs. METHODS: A systematic review of the currently available evidence in PubMed, EMBASE and Scopus was performed according to PRISMA, including observational studies, single case reports and case series of NS/PUK in RP. Study design, number of patients, age, gender, treatment and outcome, were extracted. Two RP patients also provided their opinion. RESULTS: Five case reports and two case series were eligible for inclusion. We identified 10 RP patients with eye-threatening complications (NS and/or PUK), 9 adults (2 males, 7 females, aged 35-72, median age 57.6 years) and one paediatric patient (F, 11 years). Apart from glucocorticoids, cyclophosphamide was effective in 4 patients; infliximab, high-dose immunoglobulins, dapsone, or cyclosporine were also successfully employed in a case each. Surgical repair was reported in 2 cases. CONCLUSIONS: Ocular inflammation is often bilateral and recurring in RP; NS/PUK are rare complications. All patients who develop NS/PUK should be specifically questioned for RP signs and symptoms. Early institution of immunosuppressive therapies is mandatory. Increasing awareness, physicians' and patients' education and a multidisciplinary approach may help improve the prognosis of these serious complications of RP.
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Úlcera da Córnea , Policondrite Recidivante , Esclerite , Adulto , Criança , Úlcera da Córnea/diagnóstico , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/etiologia , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Policondrite Recidivante/complicações , Policondrite Recidivante/diagnóstico , Policondrite Recidivante/tratamento farmacológico , Esclerite/diagnóstico , Esclerite/tratamento farmacológico , Esclerite/etiologiaRESUMO
OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.
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Dermatomiosite , Doenças Pulmonares Intersticiais , Autoanticorpos , Dermatomiosite/complicações , Feminino , Humanos , Helicase IFIH1 Induzida por Interferon , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Inclusion body myositis (IBM) is an acquired, late-onset inflammatory myopathy, with both inflammatory and degenerative pathogenesis. Although idiopathic inflammatory myopathies may be associated with malignancies, IBM is generally not considered paraneoplastic. Many studies of malignancy in inflammatory myopathies did not include IBM patients. Indeed, IBM is often diagnosed only after around 5 years from onset, while paraneoplastic myositis is generally defined as the co-occurrence of malignancy and myopathy within 1 to 3 years of each other. Nevertheless, a significant association with large granular lymphocyte leukemia has been recently described in IBM, and there are reports of cancer-associated IBM. We review the pathogenic mechanisms supposed to be involved in IBM and outline the common mechanisms in IBM and malignancy, as well as the therapeutic perspectives. The terminally differentiated, CD8+ highly cytotoxic T cells expressing NK features are central in the pathogenesis of IBM and, paradoxically, play a role in some cancers as well. Interferon gamma plays a central role, mostly during the early stages of the disease. The secondary mitochondrial dysfunction, the autophagy and cell cycle dysregulation, and the crosstalk between metabolic and mitogenic pathways could be shared by IBM and cancer. There are intermingled subcellular mechanisms in IBM and neoplasia, and probably their co-existence is underestimated. The link between IBM and cancers deserves further interest, in order to search for efficient therapies in IBM and to improve muscle function, life quality, and survival in both diseases.
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Miosite de Corpos de Inclusão , Miosite , Neoplasias , Autoanticorpos/metabolismo , Humanos , Músculo Esquelético/metabolismo , Miosite/patologia , Miosite de Corpos de Inclusão/etiologia , Miosite de Corpos de Inclusão/terapia , Neoplasias/metabolismoRESUMO
Parotid non-Hodgkin lymphoma (NHL) in primary Sjögren syndrome (pSS) has no specific biomarker for diagnosis. Salivary glands ultrasound (US) is largely used, but its contribution in detecting parotid NHL has not been established. The aim of our study was to determine the added value of bidimensional shear wave elastography (2D-SWE) in pSS diagnosis and to determine its accuracy in identifying parotid NHL. Grey-scale US (GSUS) and 2D-SWE of salivary glands were performed in 35 patients with pSS and 35 healthy controls. The GSUS scores were calculated and the mean of three SWE consecutive measurements was used to appreciate the gland stiffness. SWE increase the diagnostic rate at a cut-off of 6.45 kPa (from 88.6 to 94.2%, p < 0.001) only if applied in patients with insufficient GSUS criteria for pSS diagnosis. The parotid glands with NHL (8 patients, all mucosa-associated lymphoid tissue type) had hyperechoic bands in more than half of the glandular parenchyma (in 68.75% of the glands), large hypoechoic area > 20 mm (all glands), traced gland area over 5 cm2 (all glands), parotid US score greater than 13 (in 68.75% of the glands), and high stiffness (elasticity modulus 13.9 ± 4.08 vs 6.32 ± 2.24) (all p < 0.001). These findings give high sensitivity (92.3%), specificity (100%), and positive (100%) and negative predictive values (98.3%) for NHL identification. The rest of GSUS findings did not correlate with the classic risk factors for lymphoma development (all p > 0.05). 2D-SWE had added value for pSS diagnosis in cases where GSUS aspect is normal or nonspecific. The higher stiffness of parotid NHL can be used for early diagnosis, biopsy guidance, and, possible, for treatment monitoring.
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Linfoma não Hodgkin/diagnóstico por imagem , Neoplasias Parotídeas/diagnóstico por imagem , Síndrome de Sjogren/fisiopatologia , Idoso , Estudos de Casos e Controles , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Parotídeas/etiologia , Neoplasias Parotídeas/patologia , Síndrome de Sjogren/complicações , UltrassonografiaRESUMO
OBJECTIVE: To compare the European League Against Rheumatism (EULAR) recommendations for the management of NPSLE with usual care in two tertiary centres and to detect potential pitfalls in their use for diagnosis and treatment. METHODS: A chart-based review of NPSLE manifestations was conducted in two European centres. Diagnostic and treatment decisions were compared against the EULAR recommendations for general NPSLE and specific manifestations. RESULTS: We studied a total of 94 patients who experienced 123 lupus-related neuropsychiatric events over 10 years. In 80% of the events, at least one EULAR-defined risk factor (previous NPSLE, generalized disease activity or aPL positivity) was present. Overall, there was good concordance between clinical care and recommendations for diagnosis and treatment (68.7% and 62.7% of events, respectively). Brain MRI was performed in the absence of a clear EULAR recommendation in 42.9% of events; therein, it was more frequently normal compared with imaging performed according to the recommendations (52.4% vs 18.5%, P = 0.008), and it did not influence management. Among patients reporting cognitive dysfunction, only 27.8% underwent the recommended neuropsychological assessment. In line with the recommendations, immunosuppressants were more frequently given in events suggestive of an inflammatory process (80.5% vs 47.6% in non-inflammatory events, P < 0.001). Notably, 52% of cerebrovascular events were managed with combined immunosuppressive/antithrombotic therapy due to either coexisting generalized lupus activity or recurrence despite prior antithrombotic treatment. CONCLUSION: Despite good concordance between EULAR recommendations for NPSLE and usual clinical practice, we identified a number of issues (such as overutilization of brain MRI, suboptimal evaluation of cognitive dysfunction, and frequent use of immunosuppressives in cerebrovascular disease) that need to be investigated further.
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Gerenciamento Clínico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/terapia , Guias de Prática Clínica como Assunto , Centros de Atenção Terciária , Adulto , Encéfalo/patologia , Europa (Continente) , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The ubiquitous RNA-processing molecule TDP-43 is involved in neuromuscular diseases such as inclusion body myositis, a late-onset acquired inflammatory myopathy. TDP-43 solubility and function are disrupted in certain viral infections. Certain viruses, high viremia, co-infections, reactivation of latent viruses, and post-acute expansion of cytotoxic T cells may all contribute to inclusion body myositis, mainly in an age-shaped immune landscape. The virally induced senescent, interferon gamma-producing cytotoxic CD8+ T cells with increased inflammatory, and cytotoxic features are involved in the occurrence of inclusion body myositis in most such cases, in a genetically predisposed host. We discuss the putative mechanisms linking inclusion body myositis, TDP-43, and viral infections untangling the links between viruses, interferon, and neuromuscular degeneration could shed a light on the pathogenesis of the inclusion body myositis and other TDP-43-related neuromuscular diseases, with possible therapeutic implications.
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Proteínas de Ligação a DNA , Miosite de Corpos de Inclusão , Viroses , Miosite de Corpos de Inclusão/virologia , Humanos , Viroses/imunologia , Viroses/virologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
VEXAS syndrome is a recently described condition characterized by systemic inflammation, predisposition to hematologic malignancy and a high rate of venous thrombosis. Here we report the case of an elderly male with erythema nodosumlike lesions, ankle arthralgia, and general symptoms. B-mode and Doppler ultrasound of the subcutis diagnosed superficial thrombophlebitis of the lower limbs, which turned out to be the manifestation of a paucisymptomatic VEXAS syndrome. VEXAS should be considered in any patient who presents with unexplained superficial thrombophlebitis, macrocytic anemia and unexplained systemic inflammation.
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We report on a patient with Lyme disease who presented with chronic bilateral otitis media and cranial neuropathy with rapid progressive hearing loss. After ceftriaxone and high-dose intravenous immunoglobulins, the disease was controlled only with methylprednisolone and cyclophosphamide. The relationship between Lyme disease and granulomatous vasculitis is discussed. Lyme disease should be kept in mind in the differential diagnosis of various otolaryngological and neurological presentations.
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Granuloma/complicações , Perda Auditiva Bilateral/etiologia , Doença de Lyme/complicações , Otite Média/complicações , Anti-Inflamatórios/administração & dosagem , Doença Crônica , Doenças dos Nervos Cranianos/complicações , Ciclofosfamida/administração & dosagem , Progressão da Doença , Evolução Fatal , Perda Auditiva Bilateral/diagnóstico , Humanos , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Otoscopia , Perfuração da Membrana Timpânica/complicações , Vasculite/complicaçõesRESUMO
Objective: The aim of this study is to describe a group of Romanian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. Materials: This consisted of 39 children diagnosed with PFAPA syndrome according to Thomas' criteria (eight patients with an age at diagnosis <1 year and 31 patients with an age at diagnosis >1 year). Methods: Retrospective analysis of the patients with PFAPA syndrome was focused on clinical features, laboratory findings and therapeutic methods. Comparison between the two groups divided by age at onset was also investigated. Results: Median age at onset was 1.58 years, and median age at diagnosis was 2.97 years. The mean interval between episodes was 35.5 days and the mean duration per febrile episode was 4.1 days. The median diagnosis delay was 2.42 years. The patients presented pharyngitis (100%), adenitis (94.8%) and aphthous lesions (66.7%). The frequency of febrile attacks was higher in children with an age at diagnosis under 1 year (p = 0.0287). Younger age was associated with the presence of aphthae. The mean value of C-reactive protein (CRP) was 7.9mg/dl and the mean value of leucocytes was 14,839/mm3. In 95% of patients given oral corticosteroids, remission of symptoms was reported within 24 h. In three patients, tonsillectomy was performed with complete remission of the disease. Conclusion: We present a cohort of children with PFAPA syndrome, with clinical and laboratory features similar to those described in the literature. Febrile attacks had a higher incidence in children with younger age at the onset of the disease. The patients had a favorable response to corticosteroids.
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The oral microbiome, forming a biofilm that covers the oral structures, contains a high number of microorganisms. Biofilm formation starts from the salivary pellicle that allows bacterial adhesion-colonization-proliferation, co-aggregation and biofilm maturation in a complex microbial community. There is a constant bidirectional crosstalk between human host and its oral microbiome. The paper presents the fundamentals regarding the oral microbiome and its relationship to modulator factors, oral and systemic health. The modern studies of oral microorganisms and relationships with the host benefits are based on genomics, transcriptomics, proteomics and metabolomics. Pharmaceuticals such as antimicrobials, prebiotics, probiotics, surface active or abrasive agents and plant-derived ingredients may influence the oral microbiome. Many studies found associations between oral dysbiosis and systemic disorders, including autoimmune diseases, cardiovascular, diabetes, cancers and neurodegenerative disorders. We outline the general and individual factors influencing the host-microbial balance and the possibility to use the analysis of the oral microbiome in prevention, diagnosis and treatment in personalized medicine. Future therapies should take in account the restoration of the normal symbiotic relation with the oral microbiome.
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The majority of patients with anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis present with psychiatric symptoms and subsequently develop neurological features. However, isolated psychiatric episodes occur in <5% of affected individuals, less frequent at disease onset (<1%) compared to relapse (4%). We report the case of a previously healthy 24-year-old female who presented with psychotic symptoms and behavioral alterations. Despite therapy, she showed no improvement and subsequently developed catatonic features. While the ancillary tests were normal, the clinical warning signs raised the suspicion of anti-NMDAR encephalitis which we later confirmed. Given its strong association with underlying tumors, we screened the patient and found an ovarian teratoma. Once removed, the patient displayed a substantial improvement in the mental status. Besides being extremely rare, this case illustrates the need to maintain clinical suspicion of anti-NMDAR encephalitis even in the absence of neurological features or paraclinical anomalies.
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Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood-brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes' Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.
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Recent years have brought about new understandings regarding the pathogenesis of anemia in sports. From hemodilution and redistribution considered to contribute to the so-called "sports anemia" to iron deficiency caused by increased demands, dietary restrictions, decreased absorption, increased losses, hemolysis, and sequestration, to genetic determinants of different types of anemia (some related to sport), the anemia in athletes deserves a careful and multifactorial approach. Dietary factors that reduce iron absorption (e.g., phytate, polyphenols) and that augment iron's bioavailability (e.g., ascorbic acid) should be considered. Celiac disease, more prevalent in female athletes, may underlie an unexplained iron deficiency anemia. Iron loss during exercise occurs in several ways: sweating, hematuria, gastrointestinal bleeding, inflammation, and intravascular and extravascular hemolysis. From a practical point of view, assessing iron status, especially in the athletes at risk for iron deficiency (females, adolescents, in sports with dietary restrictions, etc.), may improve the iron balance and possibly the performance. Hemoglobin and serum ferritin are measures that are easily employable for the evaluation of patients' iron status. Cutoff values should probably be further assessed with respect to the sex, age, and type of sport. A healthy gut microbiome influences the iron status. Athletes at risk of iron deficiency should perform non-weight-bearing, low-intensity sports to avoid inducing hemolysis.
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A 57-year female patient diagnosed with Behçet's disease, on azathioprine, was noticed to have at a routine examination antinuclear and antiphospholipid antibodies. An overlapping lupus-like syndrome was diagnosed; hydroxychloroquine and aspirin were added. Three years later, the patient presented with dyspnea and sweating, with no fever. A cardiac bruit was noted; a giant vegetation was detected by echocardiography. Laboratory revealed severe thrombocytopenia, antiphospholipid antibodies and low complement. Blood cultures were positive for Abiotrophia defectiva serology and also revealed a chronic Coxiella burnetii infection. Antibiotic therapy, low-dose anticoagulation and control of the underlying disease mildly improved the platelet count, which fully recovered only after cardiac valve replacement. However, the Behçet's disease, initially quiescent, flared after the therapy of infections. We discuss potential links between Behçet's disease and the occurrence of antinuclear and antiphospholipid antibodies and Coxiella endocarditis in this setting. We also highlight the differences between the endocarditis in Behçet's disease, antiphospholipid syndrome, Coxiella burnetii and Abiotrophia defectiva infection, respectively. Intracellular infections may modify the presentation of autoimmune diseases. Confounding clinical features of Coxiella persistent infection and non-bacterial thrombotic endocarditis in Behçet's disease warrant further insight.