RESUMO
PURPOSE: Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by pathogenic variants of genes encoding the enzyme complex NADPH oxidase. In countries where tuberculosis (TB) is endemic and the Bacillus Calmette-Guérin (BCG) vaccine is routinely administered, mycobacteria are major disease-causing pathogens in CGD. However, information on the clinical evolution and treatment of mycobacterial diseases in patients with CGD is limited. The present study describes the adverse reactions to BCG and TB in Mexican patients with CGD. METHODS: Patients with CGD who were evaluated at the Immunodeficiency Laboratory of the National Institute of Pediatrics between 2013 and 2024 were included. Medical records were reviewed to determine the clinical course and treatment of adverse reactions to BCG and TB disease. RESULTS: A total of 79 patients with CGD were included in this study. Adverse reactions to BCG were reported in 55 (72%) of 76 patients who received the vaccine. Tuberculosis was diagnosed in 19 (24%) patients. Relapse was documented in three (10%) of 31 patients with BGC-osis and six (32%) of 19 patients with TB, despite antituberculosis treatment. There was no difference in the frequency of BCG and TB disease between patients with pathogenic variants of the X-linked CYBB gene versus recessive variants. CONCLUSIONS: This report highlights the importance of considering TB in endemic areas and BCG complications in children with CGD to enable appropriate diagnostic and therapeutic approaches to improve prognosis and reduce the risk of relapse.
Assuntos
Vacina BCG , Doença Granulomatosa Crônica , NADPH Oxidase 2 , Tuberculose , Humanos , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/complicações , Vacina BCG/efeitos adversos , Masculino , Feminino , Criança , Tuberculose/epidemiologia , Tuberculose/imunologia , Pré-Escolar , Lactente , Adolescente , NADPH Oxidase 2/genética , Estudos de Coortes , Mycobacterium bovis , México/epidemiologia , Antituberculosos/uso terapêutico , NADPH Oxidases/genéticaRESUMO
PURPOSE: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children. METHODS: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method. RESULTS: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. CONCLUSION: DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.
Assuntos
Eczema , Hipersensibilidade , Síndrome de Job , Criança , Humanos , Lactente , Pré-Escolar , Estudos Retrospectivos , Síndrome de Job/genética , Eczema/epidemiologia , Eczema/genética , Mutação , Fatores de Troca do Nucleotídeo Guanina/genéticaRESUMO
Visual disturbances in Takayasu arteritis (TA) are common but tend to be late manifestations of the disease. However, its presence at diagnosis must alert TA to avoid sight disabilities. Herein, we present two children with TA that debuted with vision loss, and the results of the literature review displayed 58 subjects with vision loss before the diagnosis of TA. The world English literature was reviewed by searching the PubMed database of the National Library of Medicine for the terms "Takayasu Arteritis" and "Blindness" or "Amaurosis fugax", from 190 to 2021. Cases eligible must present vision loss before or at TA diagnosis. Our two patients who presented with amaurosis fulfilled the criteria for TA diagnosis. The first patient had a bilateral and transient visual loss, whereas the second had monocular and permanent amaurosis. Both patients were cursed with hypertension and demonstrated large vessel compromise; their clinical picture improved with corticosteroids and immunosuppressant therapy. We identified in the literature review sixteen patients with TA in case reports and 42 in case series, plus our two cases presented herein with monocular or bilateral vision loss at the time of diagnosis. Previous literature indicated that amaurosis represents a severely advanced disease. Herein, we reported two children with amaurosis as their pivotal symptom; they had significant head and neck vascular alterations, so prompt and aggressive treatment is needed to prevent disease progression and disability. Transient or permanent vision loss must alert the physician to include Takayasu arteritis in the differential diagnosis.
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Terapia de Imunossupressão , Arterite de Takayasu , Estados Unidos , Humanos , Criança , Cegueira/diagnóstico , Progressão da Doença , Arterite de Takayasu/tratamento farmacológico , Diagnóstico DiferencialRESUMO
BACKGROUND: Information on anaphylaxis among recipients of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains scarce. OBJECTIVE: To identify the observed incidence of anaphylaxis in recipients of different anti-SARS-CoV-2 vaccines. METHODS: A nationwide observational study among recipients of 61,414,803 doses of seven different anti-SARS-CoV-2 vaccines, describing the incidence and characteristics of adult patients (age ≥ 18 years) who developed anaphylaxis as an adverse event following immunization (AEFI) against SARS-CoV-2 vaccines between December 24, 2020, and October 15, 2021, in Mexico. RESULTS: Sixty-six patients developed anaphylaxis as an AEFI, for an overall observed incidence of 1.07 cases per 1,000,000 (95% CI 0.84-1.37) administered doses. Eighty-six percent of the patients were female, consistent with previous reports of AEFI to COVID-19 vaccines. mRNA-based vaccine recipients had the highest frequency of anaphylaxis, followed by adenovirus-vectored vaccines and inactivated virus recipients, with an observed incidence of 2.5, 0.7, and 0.2 cases per 1,000,000 doses administered, respectively. Only 46% of the patients received correct treatment with epinephrine as the first-line treatment through the appropriate route and dose. We detected one case of anaphylactic reaction-related death occurring 5 min following immunization with ChAdOx1 nCov-19 for a mortality rate of 1.5% among those who developed this AEFI. CONCLUSIONS: In our population, anaphylactic reactions were infrequent. Our study provides further evidence supporting the security of these newly developed vaccines.
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Anafilaxia , Vacinas contra COVID-19 , COVID-19 , Adolescente , Adulto , Feminino , Humanos , Masculino , Anafilaxia/induzido quimicamente , Anafilaxia/epidemiologia , ChAdOx1 nCoV-19/efeitos adversos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , México/epidemiologiaRESUMO
BACKGROUND AND OBJECTIVES: Glucose-6-phosphate catalytic subunit 3 (G6PC3) deficiency is characterized by severe congenital neutropenia with recurrent pyogenic infections, a prominent superficial venous pattern and cardiovascular and urogenital malformations caused by an alteration of glucose homeostasis, with increased endoplasmic reticulum stress and cell apoptosis. METHODS: We reviewed our patients with G6PC3 deficiency diagnosed along the last decade in Mexico; we also searched the PubMed/Medline database for the terms ('G6PC3 deficiency' OR 'Dursun syndrome' OR 'Severe congenital neutropenia type 4'), and selected articles published in English from 2009 to 2020. RESULTS: We found 89 patients reported from at least 14 countries in 4 continents. We describe five new cases from Mexico. Of the 94 patients, 56% are male, 48% from Middle East countries and none of them had adverse reactions to live vaccines; all presented with at least 1 severe infection prior to age 2. Seventy-five per cent had syndromic features, mainly atrial septal defect in 55% and prominent superficial veins in 62%. CONCLUSIONS: With a total of 94 patients reported in the past decade, we delineate the most frequent laboratory and genetic features, their treatment and outcomes, and to expand the knowledge of syndromic and non-syndromic phenotypes in these patients.
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Glucose-6-Fosfatase , Neutropenia , Domínio Catalítico , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Humanos , Masculino , Neutropenia/congênito , Neutropenia/genéticaRESUMO
BACKGROUND: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. OBJECTIVE: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. RESULTS: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. CONCLUSIONS: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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COVID-19/epidemiologia , Doenças Genéticas Inatas/epidemiologia , Síndromes de Imunodeficiência/epidemiologia , SARS-CoV-2 , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS). A group of previously unrecognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here, we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two variants that had not been associated with immunodeficiency. This study represents the first case series of RAG1- or RAG2-deficient patients from Mexico and Latin America.
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Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Mutação/genética , Mutação/imunologia , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Adolescente , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Lactente , Linfócitos/imunologia , Masculino , México , FenótipoRESUMO
INTRODUCTION: Patients with inborn errors of immunity (IEI) have a compromised or inappropriate immune response. Although they might be considered a high-risk group for severe SARS-CoV-2 infection, the reported impact of COVID-19 in these patients has been reassuring, while the differential susceptibility of distinct types of IEI remains unclear. OBJECTIVE: We aimed to describe the findings and outcomes of our known patients with IEI who were diagnosed with COVID-19. METHODS: In a retrospective study from March 2020 to February 2021, four centers in Mexico collected clinical, laboratory, and genetic data from pediatric and adult patients with known diagnoses of IEI who presented with COVID-19, based on compatible symptoms and positive SARS-CoV-2 testing or known household exposure. RESULTS: We report 31 patients with known IEI from Mexico who presented with SARS-CoV-2 infection. Seventy-four percent were male, 52% were pediatric, and 81% survived. Their ages ranged from 5 months to 56 years, with a median of 17 years. Sixty-five percent had predominant antibody deficiencies, 48% were hospitalized, and 26% required ICU. Pediatric patients had a higher hospital admission rate than adults. Inpatient mortality was 40%, and ICU mortality rate was 63%. Forty-eight percent developed pneumonia, while 36% had evidence of hyperinflammation (4 adults and 7 children). Predominant laboratory features were lymphopenia and thrombocytopenia, seen in 70 and 44% of patients, respectively. The serum D-dimer median value was 2.6 (0.5-20.6) µg/mL, and the median highest ferritin value was 1015 (32-10,303) ng/mL. Intravenous immunoglobulin was used in 80% of patients. Other treatments included macrolides (39%) and corticosteroids (29%). Six patients died from secondary infection or uncontrolled systemic inflammation. DISCUSSION: Although impaired immunity due to IEI may be a predisposing factor for severe COVID-19, most of our patients with IEI who acquired the SARS-CoV-2 infection developed a well-tolerated infection and survived, as have more than 80% of worldwide reported patients to date. An impaired immune or inflammatory response may be a predisposing factor for some and a protective factor for others. A systematic review of the literature could help identify those patients at risk of severe disease and complications. Healthcare-associated infections should be aggressively prevented.
Assuntos
COVID-19/diagnóstico , Doenças da Imunodeficiência Primária/diagnóstico , SARS-CoV-2/fisiologia , Adolescente , Adulto , COVID-19/epidemiologia , COVID-19/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária/epidemiologia , Doenças da Imunodeficiência Primária/mortalidade , Estudos Retrospectivos , Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Adulto JovemRESUMO
Griscelli syndrome (GS) is a rare autosomal recessive disease with characteristic pigment distribution, and there are currently 3 types according to the underlying genetic defect and clinical features. We present the case of a girl born from consanguineous parents who presented with predominant neurologic symptoms, silvery hair and granulomatous skin lesions. Cerebral magnetic resonance revealed diffuse white matter lesions, and central nervous system (CNS) lymphocytic infiltration was suspected. The patient underwent haematopoietic stem cell transplantation with graft failure and autologous reconstitution. She developed elevated liver enzyme with a cholestatic pattern. Multiple liver biopsies revealed centrilobular cholestasis and unspecific portal inflammation that improved with immunomodulatory treatment. She was revealed to have an impaired cytotoxicity in NK cells and a decreased expression of RAB27A. However, no variants were found in the gene. All types of GS present with pigment dilution and irregular pigment clumps that can be seen through light microscopy in hair and skin biopsy. Dermic granulomas and immunodeficiency with infectious and HLH predisposition have been described in GS type 2 (GS2). Neurologic alterations might be seen in GS type 1 (GS1) and GS type 2 (GS2), due to different mechanisms. GS1 presents with neurologic impairment secondary to myosin Va role in neuronal development and synapsis. Meanwhile, GS2 can present with neurologic impairment secondary to SNC HLH. Clinical features and cytotoxicity might aid in differentiating GS1 and GS2, especially since treatment differs.
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Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/terapia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Piebaldismo/diagnóstico , Piebaldismo/terapia , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/terapia , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/terapia , Biomarcadores , Biópsia , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Perda Auditiva Neurossensorial/etiologia , Humanos , Linfo-Histiocitose Hemofagocítica/etiologia , Mutação , Fenótipo , Piebaldismo/etiologia , Transtornos da Pigmentação/etiologia , Doenças da Imunodeficiência Primária/etiologia , PrognósticoRESUMO
Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. KD can be complicated with macrophage activation syndrome. The optimal treatment for this KD complication has not been established, and a variety of treatments have been used. Infliximab, a chimeric monoclonal antibody that binds tumor necrosis factor, has proved to be efficacious in IV gammaglobulin resistant KD. We present 2 cases of KD complicated with macrophage activation syndrome, including 1 patient with DiGeorge syndrome successfully treated with a combined treatment of IV gammaglobulin, corticosteroids, cyclosporine, and infliximab.
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Fármacos Dermatológicos/uso terapêutico , Infliximab/uso terapêutico , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Corticosteroides/uso terapêutico , Adulto , Pré-Escolar , Ciclosporina/uso terapêutico , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Ativação Macrofágica/complicações , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Adulto JovemRESUMO
BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis that predominantly affects patients younger than 5 years. In the absence of an available, affordable diagnostic test, detailed clinical history and physical examination are still fundamental to make a diagnosis. METHODS: We present five representative cases with KD-like presentations: systemic onset juvenile idiopathic arthritis, mycoplasma-induced rash and mucositis, staphylococcal scalded skin syndrome, BCGosis, and the recently described multisystemic inflammatory syndrome in children (MIS-C) associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) virus. RESULTS: Rash, fever, and laboratory markers of inflammation can be present in several childhood diseases that may mimic KD. CONCLUSION: The term 'Kawasaki syndrome' instead of 'Kawasaki disease' may be more appropriate. Physicians should consider an alternative diagnosis that may mimic KD, particularly considering MIS-C during the present pandemic, as an aggressive diagnostic and therapeutic approach is needed.
Assuntos
COVID-19 , Síndrome de Linfonodos Mucocutâneos , Criança , Humanos , Síndrome de Linfonodos Mucocutâneos/diagnóstico , RNA Viral , SARS-CoV-2 , Síndrome de Resposta Inflamatória SistêmicaRESUMO
PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.
Assuntos
Doença Granulomatosa Crônica/imunologia , Mutação/genética , Infecções por Mycobacterium/epidemiologia , Mycobacterium/fisiologia , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Adolescente , Autoimunidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genes Ligados ao Cromossomo X , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Recém-Nascido , Inflamação , Masculino , México/epidemiologiaAssuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/deficiência , COVID-19/complicações , Síndromes de Imunodeficiência/complicações , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Anti-Infecciosos/uso terapêutico , COVID-19/genética , COVID-19/terapia , Hospitalização , Humanos , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , SARS-CoV-2 , Resultado do TratamentoRESUMO
Background: G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Objective: The G6PC3 c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it. Methods: Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date. Results: Based on the length of haplotypes shared amongst ten carriers of the G6PC3 c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency. Conclusion: The G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.
RESUMO
G6PC3 deficiency is a monogenic immunometabolic disorder that causes syndromic congenital neutropenia. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican origin. Based on the shared haplotypes amongst carriers of the c.210delC mutation, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it originated in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived cells. G6PC3 pathology is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the variant c.210delC impacts glycolysis by performing extracellular flux assays on patient-derived cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3 deficient patients reported in the literature to date, and we found that c.210delC carriers display all prominent clinical features observed in prior G6PC3 deficient patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.
RESUMO
Most patients with X-linked agammaglobulinemia are susceptible to infections, while some cases also suffer from inflammatory or autoimmune complications. We describe a patient with progressive encephalitis who improved after the use of immunomodulatory treatment with corticosteroids, fluoxetine, and nitazoxanide. In most of the cases the evolution of the progressive encephalitis is complicated and catastrophic. Based on our experience and the review of the literature, we propose the use of this combined treatment to control this devastating complication.