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1.
Clin Immunol ; 210: 108316, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31770611

RESUMO

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

2.
RMD Open ; 5(2): e001041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673420

RESUMO

Objectives: The aims of this study were to update the evidence on the incidence and prevalence rates of vaccine preventable infections (VPI) in patients with autoimmune inflammatory rheumatic diseases (AIIRD) and compare the data to the general population when available. Methods: A literature search was performed using Medline, Embase and Cochrane library (October 2009 to August 2018). The primary outcome was the incidence or prevalence of VPI in the adult AIIRD population. Meta-analysis was performed when appropriate. Results: Sixty-three publications out of 3876 identified records met the inclusion criteria: influenza (n=4), pneumococcal disease (n=7), hepatitis B (n=10), herpes zoster (HZ) (n=29), human papillomavirus (HPV) infection (n=13). An increased incidence of influenza and pneumococcal disease was reported in patients with AIIRD. HZ infection-pooled incidence rate ratio (IRR) was 2.9 (95% CI 2.4 to 3.3) in patients with AIIRD versus general population. Among AIIRD, inflammatory myositis conferred the highest incidence rate (IR) of HZ (pooled IRR 5.1, 95% CI 4.3 to 5.9), followed by systemic lupus erythematosus (SLE) (pooled IRR 4.0, 95% CI 2.3 to 5.7) and rheumatoid arthritis (pooled IRR 2.3, 95% CI 2.1 to 2.6). HPV infection-pooled prevalence ratio was 1.6, 95% CI 0.7 to 3.4 versus general population, based on studies mainly conducted in the SLE population in Latin America and Asia. Pooled prevalence of hepatitis B surface antigen and hepatitis B core antibody in patients with AIIRD was similar to the general population, 3%, 95% CI 1% to 5% and 15%, 95% CI 7% to 26%, respectively. Conclusion: Current evidence shows an increased risk of VPI in patients with AIIRD, emphasising that prevention of infections is essential in these patients.

3.
RMD Open ; 5(2): e001035, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565247

RESUMO

Aim: To present a systematic literature review (SLR) on efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD), aiming to provide a basis for updating the EULAR evidence-based recommendations. Methods: An SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Outcome was determined by efficacy, immunogenicity and safety of vaccination in adult patients with AIIRD, including those receiving immunomodulating therapy. Furthermore, a search was performed on the effect of vaccinating household members of patients with AIIRD on the occurrence of vaccine-preventable infections in patients and their household members (including newborns). The literature search was performed using Medline, Embase and the Cochrane Library (October 2009 to August 2018). Results: While most investigated vaccines were efficacious and/or immunogenic in patients with AIIRD, some were less efficacious than in healthy control subjects, and/or in patients receiving immunosuppressive agents. Adverse events of vaccination were generally mild and the rates were comparable to those in healthy persons. Vaccination did not seem to lead to an increase in activity of the underlying AIIRD, but insufficient power of most studies precluded arriving at definite conclusions. The number of studies investigating clinical efficacy of vaccination is still limited. No studies on the effect of vaccinating household members of patients with AIIRD were retrieved. Conclusion: Evidence on efficacy, immunogenicity and safety of vaccination in patients with AIIRD was systematically reviewed to provide a basis for updated recommendations.

4.
Gesundheitswesen ; 2019 Oct 15.
Artigo em Alemão | MEDLINE | ID: mdl-31614384

RESUMO

OBJECTIVE: The aim of the article was to describe the development of a training program to enhance the health literacy of patients with immunodeficiency. In addition, patient satisfaction and acceptance of the training will be evaluated. METHODS: Patients' needs were identified with a questionnaire (N=238). Additionally, interviews with clinical immunologists (N=5) and patients with common variable immunodeficiency (CVID) (N=9) were conducted. On this basis, the authors developed a manual for the intervention. It focuses on active communication with physicians as well as health-related communication at the workplace. The evaluation of patient satisfaction with the intervention was based on a questionnaire (N=49). RESULTS: The results show that the ratings of the patients were in the good to very good range (M=1.77; SD=0.38). From the analysis of the free text, hints for training improvement could be derived. CONCLUSION: Evaluation of the intervention showed that the new training was accepted and patients considered it comprehensible and relevant.

5.
Scand J Immunol ; : e12811, 2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31378960

RESUMO

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B-cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.

6.
Front Immunol ; 10: 1272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379802

RESUMO

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

7.
Ann Rheum Dis ; 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413005

RESUMO

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

9.
Front Immunol ; 10: 951, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114586

RESUMO

The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.

10.
Front Immunol ; 10: 568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057532

RESUMO

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.

12.
Front Immunol ; 10: 297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941118

RESUMO

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

13.
Clin Immunol ; 203: 59-62, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004792

RESUMO

Some patients diagnosed with common variable immunodeficiency (CVID) actually suffer from combined immunodeficiency (CID) and therefore may require a different, CID-adapted treatment. Several CD4 T-cell-based criteria have been proposed in the past to identify patients with CID within the cohort of adult CVID patients. In this monocentric study, we used retrospective immunological and clinical data of 238 CVID patients to compare four different proposals of how to define CID among CVID patients. We demonstrate that none of the current definitions sufficiently separates CID from CVID patients and that the relative reduction of naïve CD4 T cells <10% has the highest sensitivity of all tested markers for patients with clinical complications often associated with CID. Thus, a very low percentage of naïve CD4 T cells in any adult CVID patient should raise suspicion, but is not sufficient to define CID among CVID patients.

16.
J Clin Immunol ; 39(1): 45-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30547383

RESUMO

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.


Assuntos
Brônquios/patologia , Síndromes de Imunodeficiência/patologia , Parede Torácica/patologia , Adolescente , Adulto , Idoso , Bronquiectasia/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Feminino , Humanos , Lactente , Masculino , Espirometria/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
17.
Front Immunol ; 9: 2012, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250467

RESUMO

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.

18.
Front Immunol ; 9: 1730, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083170

RESUMO

DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells and a wide spectrum of antibody deficiencies or dysgammaglobulinemia, presumably due to impaired germinal center responses. We set out to evaluate circulating follicular helper T cells (cTFHs) in DiGeorge syndrome, as markers of T-B interaction in the germinal centers in a cohort of 17 patients with partial DiGeorge and 21 healthy controls of similar age. cTFHs were characterized as CXCR5+CD45RA- CD4+ T cells using flow cytometry. We verify previous findings that the population of memory CD4+ T cells is relatively increased in diGeorge patients, corresponding to low naïve T cells and impaired T cell production in the thymus. The population of CXCR5+ memory CD4+ T cells (cTFHs) was significantly expanded in patients with DiGeorge syndrome, but only healthy controls and not DiGeorge syndrome patients showed gradual increase of CXCR5 expression on cTFHs with age. We did not observe correlation between cTFHs and serum IgG levels or population of switched memory B cells. There was no difference in cTFH numbers between DiGeorge patients with/without thrombocytopenia and with/without allergy. Interestingly, we show strong decline of PD1 expression on cTFHs in the first 5 years of life in DiGeorge patients and healthy controls, and gradual increase of PD1 and ICOS expression on CD4- T cells in healthy controls later in life. Thus, here, we show that patients with DiGeorge syndrome have elevated numbers of cTFHs, which, however, do not correlate with autoimmunity, allergy, or production of immunoglobulins. This relative expansion of cTFH cells may be a result of impaired T cell development in patients with thymic dysplasia.

19.
Front Immunol ; 9: 1656, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30072997

RESUMO

Background: A significant amount of common variable immunodeficiency (CVID) patients manifest with autoimmunity. Particularly, autoimmune thrombocytopenia (AITP) is commonly seen. Intravenous immunoglobulins (IVIG) are an established treatment option for both, CVID and AITP. Nonetheless, due to fewer systemic side effects, immunoglobulins are increasingly applied subcutaneously (SCIG). Objective: To compare the efficacy and safety of IVIG and SCIG treatment in patients with both CVID and clinical relevant thrombocytopenia in the prevention of AITP bouts. Methods: Patients with both CVID and AITP were enrolled at the Centre for Chronic Immunodeficiency in Freiburg, Germany and at the Royal Free Hospital, London, UK. Clinical and laboratory features of patients were collected and analyzed. Results: This retrospective study recruited 61 adult patients between 19 and 71 years of age who had a diagnosis of CVID and at least one bout of thrombocytopenia defined as a platelet count of <50,000/µl if bleeding episodes occurred, or a platelet count of <20,000/µl without bleeding. Thirty patients received immunoglobulin through IVIG, and 31 patients were on SCIG replacement. One patient of the IVIG-group was excluded, because of a diffuse large B-cell lymphoma. We did not find a higher occurrence of thrombocytopenic events in CVID patients who received SCIG, compared to CVID patients who had IVIG, but we identified a low IgG through level as a risk factor for AITP bouts. Conclusion: SCIG is at least as safe as IVIG for patients with CVID and concomitant AITP. However, an IgG through level under 7 g/l is a key factor for the development of AITP.

20.
Clin Immunol ; 195: 82-87, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30075290

RESUMO

Signaling via the CD19-complex, consisting of CD19, CD81, CD21 and CD225, is critically important for B-cell development, differentiation and maturation. In this complex, each protein has its own distinct function. Over the past decade, 15 patients with antibody deficiency due to deficiencies in the CD19-complex have been described. These patients have deficiencies in different complex-members, all caused by either homozygous or compound heterozygous mutations. Although all patients had antibody deficiencies, the clinical phenotype was different per deficient protein. We aimed to provide an overview of what is known about the function of the different complex-members, knowledge from mouse-studies and to summarize the clinical phenotypes of the patients. Combining this knowledge together can explain why deficiencies in different members of the same complex, result in disease phenotypes that are alike, but not the same.

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