Inborn Errors Research Articles

Диагностика врожденных дефектов иммунитета в многопрофильном стационаре: обзор клинических наблюдений

Inborn errors of immunity (IEI) are rare heterogeneous diseases with a wide range of clinical manifestations that makes its diagnosis difficult for practitioners of different specialties. The purpose of this research was to describe a series of clinical case reports of primary immunodeficiencies (PIDs) diagnosis using the TREC/KREC assay in a multidisciplinary hospital. In order to verify the diagnosis, TREC/KREC determination, immunophenotyping and molecular genetic studies were performed. Thirty-nine patients with alarming signs of PIDs were examined within a period of 18 months. Primary immunodeficiencies were identified in 6 (31.6%) children with congenital malformations, in 5 (50%) with resistant cytopenias and in 3 (30%) with severe infections. Syndromal IDs were diagnosed in 8 (57.1%), combined immunodeficiency in a single patient (7.1%), immune regulation defects in 2 (14.3%) and antibody formation disorders in 3 (21.5%). Abnormal TREC/KREC values were established in 9 (64.3%) patients with IEI at the early stages of diagnostic search. Thus, TREC/KREC assay is an effective method for IEI diagnosis within a multidisciplinary hospital.

Customizing subcutaneous immunoglobulin administration in primary antibody deficiency: patient-centric care perspectives.

This report delves into the challenges and potential solutions associated with flexible, customized subcutaneous immunoglobulin (SCIG) infusion regimens for patients with primary antibody deficiency disease (PAD). Advances in the treatment of inborn errors of immunity, particularly PAD, have converted fatal diseases into chronic, complex, long-term conditions that make adherence to treatment a critical issue. Conventional SCIG infusion regimens, while clinically effective, may not always align with the varied lifestyles, changing lifestyles and commitments of patients which can lead to missed doses, diminishing adherence thus posing potential health risks and compromising the overall effectiveness of treatment. For these reasons, it's important to develop flexible infusion regimens tailored to meet individual patient needs. Patient-centric strategies that promote shared decision-making and awareness of patient status not only promote medical efficacy but also enhance the overall patient experience. The authors of this report call attention for a need to shift toward more adaptable and individualized SCIG treatment plans for PAD patients whose needs may change over the long-term course of treatment.

Complications of the Bacillus Calmette-Guerin vaccine as an early warning sign of inborn errors of immunity: a report of 197 patients

BackgroundAccording to the WHO’s recommendation for developing countries, Bacillus Calmette-Guerin (BCG) vaccination has been implemented in some countries as part of national vaccination programs at birth. Although it is generally considered safe, some complications may occur; including BCGitis (local) or BCGosis (systemic), ranging from mild like local abscesses to fatal impediments like osteomyelitis and disseminated BCG infection. This study aimed to determine the spectrum of inborn errors of immunity (IEI) in BCG-vaccinated neonates experiencing local or systemic complications.MethodsIn this cross-sectional study, we investigated Iranian children referred to the Immunology, Asthma, and Allergy Research Institute (IAARI) between 2007-2023 for suspected immunodeficiency. Medical history was recorded, and primary screening tests for immunodeficiency were conducted for all cases. For suspected cases, more advanced immunologic investigations were performed to reach a definitive diagnosis. Furthermore, the study incorporated the documented genetic findings of the patients under investigation. All patients with inborn error of immunity who had a history of BCG vaccine complications within the first year of vaccination were enrolled in the study.ResultsWe investigated 3,275 cases suspected of IEI, identifying197 patients with both IEI and BCG vaccine complications. Among these, 127 (64.5%) were male. Symptoms began at or before 3 months of age in 64.8% of the cases, and parental consanguinity was reported in 79.2%. Genetic diagnoses were confirmed in 108 patients. Of the 197 patients, 108 (54.8%) had BCGitis, while 89 (45.2%) experienced systemic complications (BCGosis). A family history of IEI, BCG-related complications, and unexplained deaths were observed in 20.3%, 12.2%, and 29.9% of cases, respectively. Furthermore, 46.2% had at least one of these three risk factors in their history.ConclusionsEarly BCG vaccine complications may indicate an underlying immunodeficiency, particularly when there is a positive family history of BCG complications, immunodeficiency, or unexplained deaths. Nation-wide vaccination protocols should address this issue by delaying inoculation to allow for immunological screening of suspected immunodeficient patients, thereby preventing BCG vaccine-related morbidity and mortality.

Cindy Ma: Science is often not black and white, and the answer usually lies in the grey.

Professor Cindy Ma heads the Human Immune Disorders Laboratory at the Garvan Institute of Medical Research. She is a member of the Garvan Faculty, holds a conjoint appointment with UNSW Sydney (School of Clinical Medicine, Faculty of Medicine and Health), and is an NHMRC of Australia Investigator Grant Fellow (L1). Her research interests lie in the study of human diseases of the immune system such as primary immunodeficiencies due to inborn errors of immunity (IEI), resulting from disease-causing monogenic germline variants. Another area of research her laboratory is perusing is the pathways that cause severe allergies and atopic diseases such as atopic dermatitis and food anaphylaxis.

Training machine learning models to detect rare inborn errors of metabolism (IEMs) based on GC–MS urinary metabolomics for diseases screening

Training machine learning models to detect rare inborn errors of metabolism (IEMs) based on GC–MS urinary metabolomics for diseases screening

COVID-19 Vaccination in Patients With Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: A USIDNET Report

COVID-19 Vaccination in Patients With Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: A USIDNET Report

A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics

Methylmalonic aciduria and homocystinuria, CblC type, is an inborn error of intracellular vitamin B12 (cobalamin) metabolism caused, in the majority of cases, by mutations in the MMACHC gene. Five Cypriot patients (four males and one female) were diagnosed with a CblC defect. Age at diagnosis ranged from 10 days to 9 months. We present here the clinical, biochemical and molecular findings of these patients. Our retrospective study indicates that all patients were carriers of the known p.Arg91LysfsTer14 variant in either a homozygous or compound heterozygous state with other known MMACHC pathogenic variants. Out of three patients sharing the same genotype the one diagnosed and initiated treatment in the neonatal period displayed an improved clinical outcome.

Nutritional Management of Patients with Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) are a large group of single-gene disorders resulting from enzyme defects in biochemical and metabolic pathways [...]

Inborn errors of immunity reveal the molecular requirements for the generation and maintenance of human IL-9 expressing cells.

CD4+ T cells play essential roles in adaptive immunity. Distinct CD4+ T cell subsets - Th1, Th2, Th17, Th22, T follicular helper and regulatory T cells - have been identified and their contributions to host defence and immune regulation are increasingly well-defined. IL-9 producing Th9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human Th9 cells remain incompletely defined. Define signalling pathways that regulate IL-9 production by human CD4+ T cells. Human naive and memory CD4+ T cells were cultured under different conditions and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4+ T cells from a broad range of patients (n=92) with pathogenic variants in key immune genes (n=21) to differentiate into IL-9+ cells. We identified two culture conditions that yielded IL-9-expressing cells from naïve CD4+ T cells, and amplified IL-9 production by in vivo-generated memory CD4+ T cells: TGFβ plus IL-4 (i.e. Th9 polarising condition), and the combination of IL-21, IL-23, IL-6, IL-1β and TGFβ (i.e. Th17 polarising condition). Combining these conditions had a synergistic effect in generating IL-9+CD4+ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signalling via the TCR and STAT5. Importantly, IL-9 induction was restrained by IFNγ/STAT1 and IL-10. Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4+ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.

Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for the diagnosis of inborn errors of immunity (IEI)

BackgroundInborn errors of immunity (IEIs) are more than 500 different rare congenital disorders of the immune system characterized by susceptibility to infections and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High throughput sequencing techniques may allow a timely genetic definition. Guidelines for the use and the interpretation of genetic testing produced by the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) do not cover specificities for the application to IEIs. ObjectiveThe aim of this consensus study is to define the best approach to genetic testing for IEIs. MethodsA panel of experts in the context of the Italian Primary Immunodeficiency Network (IPINet) composed a list of statements that were evaluated using Delphi method. ResultsThe experts recommend that genetic testing for IEIs should be offered to selected patients with warning signs for IEIs and highlight the crucial role of thorough phenotyping and functional tests for the conclusive diagnosis of IEI. Comprehensive educational programs targeted to health care professionals and the public should be developed to increase IEIs awareness and reduce the diagnostic delay. Ethical issues should be pondered over the diagnostic advantages of genetic tests requested for diagnostic purposes. ConclusionAdherence to the guidelines on the use and interpretation of genetic testing for the diagnosis of IEIs should help limiting the inappropriate use of these techniques and reduce the risk of misdiagnosis and apprehension for inconclusive genetic results.

Assessment of quality of life in families affected by maple syrup urine disease: a cross sectional study.

Maple syrup urine disease (MSUD) is considered one of the intoxication-type inborn errors of metabolism (IT-IEM). Patients with MSUD are afflicted with a chronic illness, and the disease and its management have both physical and psychological consequences for the patients and their families. The aim of this study was to assess the quality of life (QoL) and its main determining factors for patients with MSUD and their families under follow-up in Sohag University Hospital. Parents of 36 patients with MSUD participated in a questionnaire translated into Arabic to assess their QoL. Subsequently, a file review was conducted to identify any key factors that could potentially influence the parents' QoL. The results of the study indicated that 27 (75 %) of the MSUD patients exhibited poor QoL, while only 9 (25 %) patients reported good QoL across all studied aspects. Significant differences were observed between the two groups in terms of the disease onset, whether acute or asymptomatic (diagnosed before acute metabolic decompensation) (p=0.001) and the type of screening employed (p=0.007). There is a paucity of data on the QoL of pediatric patients with IT-IEM, including MSUD. The methodological approaches and assessment instruments utilized in existing studies are inconsistent. Identifying the factors that affect QoL would be beneficial for improving patient care, evaluating outcomes and treatments, and planning effective social and psychological interventions to enhance the patients' QoL.

The RAG1 Mutation Presenting as Early Onset SLE in an Iranian Patient

It has been established that mutations of the Recombinase Activating Genes (RAG1 and RAG2) are responsible for classic T-B-NK+ severe combined immunodeficiency (SCID). On the other hand, it has now become evident that certain mutations within these genes can also lead to other forms of combined immunodeficiency, antibody deficiency, and even autoimmunity. In this report, we present a case involving a 9-month-old female patient who presents with clinical and laboratory findings indicative of systemic lupus erythematosus (SLE). Following the diagnosis of early- onset SLE and considering the presence of concurrent infections, it was considered necessary to investigate potential underlying monogenic disorders associated with inborn errors of immunity. Immunological evaluations demonstrated a combined immunodeficiency and whole exome sequencing confirmed that the patient has a mutation in the RAG1 gene.

ILAE neonatal seizure framework to aide in determining etiology.

To employ the neonatal seizure framework developed by the International League Against Epilepsy (ILAE) Neonatal Task force to assess its usefulness in determining the etiology of neonatal seizures. The members of the ILAE Neonatal Task Force evaluated 157 seizures from 146 neonates to determine internal validity and associations between semiology and a specific etiology. Provoked neonatal electrographic and electroclinical seizures were due to multiple etiologies. For electroclinical seizures, unilateral clonic seizures were typically seen with vascular etiologies, focal tonic seizures and sequential seizures with genetic etiologies, and myoclonic seizures with inborn errors of metabolism. Electrographic seizures were often seen in hypoxic-ischemic encephalopathy or vascular etiologies. These data suggest that the ILAE neonatal seizure classification may be used as a bedside tool to aid and guide workup to determine the etiology of seizures.

Lipid storage myopathy associated with sertraline treatment is an acquired mitochondrial disorder with respiratory chain deficiency

Lipid storage myopathies are considered inborn errors of metabolism affecting the fatty acid metabolism and leading to accumulation of lipid droplets in the cytoplasm of muscle fibers. Specific diagnosis is based on investigation of organic aids in urine, acylcarnitines in blood and genetic testing. An acquired lipid storage myopathy in patients treated with the antidepressant drug sertraline, a serotonin reuptake inhibitor, has recently emerged as a new tentative differential diagnosis. We analyzed the muscle biopsy tissue in a group of 11 adult patients with muscle weakness and lipid storage myopathy which developed at a time when they were on sertraline treatment. This group comprise most patients with lipid storage myopathies in western Sweden during the recent nine-year period. By enzyme histochemistry, electron microscopy, quantitative proteomics, immunofluorescence of the respiratory chain subunits, western blot and genetic analyses we demonstrate that muscle tissue in this group of patients exhibit a characteristic morphological and proteomic profile. The patients also showed an acylcarnitine profile in blood suggestive of multiple acyl-coenzyme A dehydrogenase deficiency, but no genetic explanation was found by whole genome or exome sequencing. By proteomic analysis the muscle tissue revealed a profound loss of Complex I subunits from the respiratory chain and to some extent also deficiency of Complex II and IV. Most other components of the respiratory chain as well as the fatty acid oxidation and citric acid cycle were upregulated in accordance with the massive mitochondrial proliferation. The respiratory chain deficiency was verified by immunofluorescence analysis, western blot analysis and enzyme histochemistry. The typical ultrastructural changes of the mitochondria included pleomorphism, dark matrix and frequent round osmiophilic inclusions. Our results show that lipid storage myopathy associated with sertraline treatment is a mitochondrial disorder with respiratory chain deficiency and is an important differential diagnosis with characteristic features.

Anaesthetic management of an infant with MEGD(H)EL syndrome undergoing cochlear implant

BackgroundThe syndrome has these features: 3-methylglutaconic aciduria (MEG), deafness(D), encephalopathy (E), Leigh-like syndrome (L). This disorder is caused by biallelic mutations in serine active site-containing protein 1 (SERAC1) gene. When these patients experience hepatopathy (H) in addition to the above manifestations, the syndrome is referred to as MEGD(H)EL. The pathology of this syndrome shares features with diverse types of inborn errors of metabolism.Case presentationWe discussed the anaesthetic management of an infant 2-year-old suffering from MEGD(H)EL syndrome undergoing cochlear implant. We discuss the pathology, genetics and significant aspects of this sporadic disease which is important for anaesthesiologist.ConclusionsThe usage of dexmedetomidine as the main anaesthetic drug might have the benefit of a non-triggering anaesthetic agent in patients with a mitochondrial disease. Mixture of dexmedetomidine and ketamine provide an effective combination for procedural sedation, predominantly in select populations who are at a high risk of perioperative complications due to underlying co-morbid conditions.

HCT in the widening spectrum of congenital immunodeficiencies.

Hematopoietic stem cell transplantation (HSCT) and inborn errors of immunity (IEI) have been closely linked since transplantation was first used to cure severe combined immunodeficiency (SCID) in 1968. Since then, novel genes and diseases have been continually added to the ongoing list of IEI, and new data on indications and outcomes have emerged. We review recent data and progress in the field of hematopoietic cell transplantation (HCT) for IEI including new diseases and complications. Emerging data from haploidentical transplants, newborn screening results, and multicentric studies reveals promising outcomes for IEI. Immune dysregulation diseases deserve special attention regarding disease control and may require additional drugs pretransplant. Female carriers of X-linked Chronic granulomatous may present with a severe phenotype warranting the need for HCT. Insights from infectious complications and long-term comorbidities should help guide decisions to treat IEI patients. From classical indications to recently described diseases, HCT for immunodeficiencies is a rapidly growing field. Novel data regarding alternative donor transplants, results from large cohorts, and long-term complications provide valuable knowledge for clinical practice.

Quantitative Assessment of Core Fucosylation for Congenital Disorders of Glycosylation.

Congenital disorders of glycosylation (CDG) include a group of diseases characterized by defects of N-glycan fucosylation. The analytical molecule of choice for the diagnosis of CDG affecting N-glycosylation is serum transferrin: approximately 10% of the glycans attached to transferrin are fucosylated via an α1,6 linkage at the innermost N-acetylglucosamine residue, termed "core fucosylation." Isoelectric focusing (IEF) of transferrin is often used for diagnosis, but IEF is ineffective in detecting abnormal fucosylation. Here, we present mass spectrometry (MS) methods for detecting fucosylation disorders. First, the level of core fucosylation of the glycan attached to Asn630 of transferrin can be measured by the signal intensity ratio of tryptic peptide ions containing fucosylated and nonfucosylated biantennary oligosaccharides. The core fucosylation level at this glycosylation site in the 0- to 32-year-old group (n = 68) was 7.9 ± 1.7 (%, mean ± SD), and nearly null for SLC35C1-CDG caused by defects in the GDP-fucose transporter. More simply, fucosylation levels can be measured by quadrupole time-of-flight (QTOF) MS of intact transferrin. The fucosylation levels of intact transferrin measured by MS with a Q-mass analyzer, which is currently used as an instrumental standard for newborn screening for inborn errors of metabolism and has a lower resolution than the QTOF analyzer, correlated well with the values obtained by glycopeptide analysis. These methods, namely the analysis of glycopeptides or intact transferrin by Q MS, can also be used on dried blood spots and are expected to help facilitate the diagnosis of CDG affecting N-glycan fucosylation.

Inborn Error of WAS Presenting with SARS-CoV-2-Related Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) has been reported in patients with inborn errors of immunity (IEI), providing insights into disease pathogenesis. Here, we present the first case of MIS-C in a child affected by Wiskott-Aldrich syndrome (WAS) gene mutation, elucidating underlying predisposing factors and the involved inflammatory pathways. Genetic analysis revealed a frameshift truncating variant in the WAS gene, resulting in WAS protein expression between mild and severe forms, despite a clinical phenotype resembling X-linked thrombocytopenia (XLT). IL-1β secretion by LPS-stimulated peripheral blood mononuclear cells from patient during MIS-C was lower compared to healthy subjects but increased during follow-up. Conversely, the percentage of ASC (apoptosis-associated speck-like protein containing a CARD) specks in the patient's circulating monocytes during the acute phase was higher than in healthy subjects. The type I interferon (IFN) signature during MIS-C was normal, in contrast to the raised IFN signature measured far from the acute event. This case supports the association of IEI with MIS-C, potentially linked to delayed immune responses to SARS-CoV-2. The XLT phenotype underlies a subclinical immunodysregulation involving the NLRP3 inflammasome and the type-I IFN response.

Acute metabolic decompensation after liver transplant in a patient with maple syrup urine disease

AbstractMaple syrup urine disease (MSUD) is an inborn error of metabolism characterized by the accumulation of branched‐chain amino acids (leucine, isoleucine, and valine) caused by a defect in the branched‐chain alpha‐keto acid dehydrogenase complex. Liver transplant is an effective therapy for MSUD, and patients can usually tolerate a regular diet after transplant without symptomatic metabolic decompensation. Most post‐transplant patients do not follow a sick‐day diet. We report a case of a 7‐year‐old male with MSUD Type IA, status post‐liver transplant at 2 years of age, who presented with profound encephalopathy following poor oral intake and vomiting for 3 days. Broad laboratory workup was significant for hyperleucinosis and an unrevealing infectious workup. We conducted a review of eight post‐liver transplant MSUD patients followed at Washington University in St. Louis. The review revealed that plasma amino acids were generally not checked during intercurrent illnesses in this patient cohort. While most of our patients have not had documented encephalopathy, one of the patients with epilepsy had a seizure during a gastrointestinal illness. Based on the review of the literature and from our center's experience, acute metabolic decompensation with intercurrent illnesses in MSUD patients after liver transplant appears to be rare. This case report raises awareness that patients with MSUD are still at risk of developing metabolic crisis post‐liver transplant and provides additional insight into the risk factors associated with metabolic decompensation in this patient cohort.

Common variable immunodeficiency: autoimmune cytopenias and advances in molecular diagnosis.

Common variable immunodeficiency (CVID) is one of the most common groups of human inborn errors of immunity. In addition to infections resulting from insufficient levels of immunoglobulins and antibodies, a significant proportion of patients develop autoimmune cytopenias, especially immune thrombocytopenia, hemolytic anemia, or neutropenia. They may be the initial manifestation of CVID in a patient who has not had significant infections, and similar episodes may recur at intervals over time. Treatment of these hematologic complications includes the use of corticosteroids or other medications, often including rituximab; splenectomy is discouraged. Here we outline the overall occurrence of these blood cytopenias in a cohort of 408 patients, as well as the clinical and genetic associations noted in these individuals.