National survey on clinical and genetic characteristics of patients with hereditary angioedema in Latvia

Abstract Background Hereditary angioedema (HAE) is a rare and life-threatening inborn error of immunity. HAE is mostly caused by pathogenic variations in the serine protease inhibitor gene 1 (SERPING1), leading to deficient or dysfunctional C1-inhibitor (C1-INH), overproduction of bradykinin, and development of recurrent subcutaneous and/or submucosal oedema. The prevalence of HAE is 1 in 50,000 − 100000 people worldwide. We aimed to describe the clinical features and genetic spectrum of hereditary angioedema with C1-INH deficiency (C1-INH-HAE) in Latvia. Methods All patients from Latvia diagnosed with HAE (types I/II) from 2006 to March 2022 were included in the study. Laboratory tests and clinical data were analysed, and genetic tests with Sanger sequencing and whole genome sequencing were performed. Results The study identified 10 C1-INH-HAE patients (nine females, one male) from eight families. The point prevalence of HAE in Latvia is 0.53 per 100 000 inhabitants. Of all patients, seven (70%) had HAE type I and three (30%) had HAE type II. The median age of patients was 54 years and the median age at onset of symptoms was 15 years. A significant delay (median 20.5 years) until diagnosis was observed, and 60% of patients had a positive family history of angioedema. All HAE patients have been hospitalised a median two times during their lifetime. Skin (100%), abdominal (80%), and airway (80%) oedema were the most frequent symptoms. Triggering factors (60%) and prodromal symptoms (90%) were referred. Attacks were severe in 50% of patients, moderate in 10%, and mild in 40%. Pathogenic variations of SERPING1 were identified in eight patients (six families), confirming the diagnosis molecularly. In two patients (two families), no pathogenic variations in the genes were found even after whole genome sequencing. Conclusions Current data shows a significant delay and clear underdiagnosis of HAE in Latvia. Higher awareness and better information and communication between doctors would improve the diagnosis and management of HAE; as would screening of family members, patients with recurrent angioedema unresponsive to antihistamines and glucocorticoids, and patients with recurrent episodes of severe, unexplained abdominal pain

Table_1_Exploring disease-specific metabolite signatures in hereditary angioedema patients.xlsx

IntroductionHereditary angioedema (HAE) is a rare, life-threatening autosomal dominant genetic disorder caused by a deficient and/or dysfunctional C1 esterase inhibitor (C1-INH) (type 1 and type 2) leading to recurrent episodes of edema. This study aims to explore HAE patients’ metabolomic profiles and identify novel potential diagnostic biomarkers for HAE. The study also examined distinguishing HAE from idiopathic angioedema (AE).MethodsBlood plasma samples from 10 HAE (types 1/2) patients, 15 patients with idiopathic AE, and 20 healthy controls were collected in Latvia and analyzed using LC-MS based targeted metabolomics workflow. T-test and fold change calculation were used to identify metabolites with significant differences between diseases and control groups. ROC analysis was performed to evaluate metabolite based classification model.ResultsA total of 33 metabolites were detected and quantified. The results showed that isovalerylcarnitine, cystine, and hydroxyproline were the most significantly altered metabolites between the disease and control groups. Aspartic acid was identified as a significant metabolite that could differentiate between HAE and idiopathic AE. The mathematical combination of metabolites (hydroxyproline * cystine)/(creatinine * isovalerylcarnitine) was identified as the diagnosis signature for HAE. Furthermore, glycine/asparagine ratio could differentiate between HAE and idiopathic AE.ConclusionOur study identified isovalerylcarnitine, cystine, and hydroxyproline as potential biomarkers for HAE diagnosis. Identifying new biomarkers may offer enhanced prospects for accurate, timely, and economical diagnosis of HAE, as well as tailored treatment selection for optimal patient care.</p