Hereditāra angioedēma: klīniskā un ģenētiskā izpēte

Hereditary angioedema (HAE) is a rare, potentially life-threatening, autosomal
dominant disorder, the diagnosis and management of which continue to pose significant
challenges in both clinical practice and research. Despite increasing availability of molecular
diagnostic tools and targeted therapies, HAE is often diagnosed with delay or misclassified as
other types of angioedema. Due to the wide spectrum of clinical manifestations, underlying
genetic heterogeneity, and the need for a personalized management approach, research into
HAE remains of high relevance both in Latvia and internationally. The dissertation “Hereditary
angioedema: clinical and genetic research” is dedicated to the comprehensive characterization
of this disease within the Latvian patient population.
The pathogenesis of HAE primarily results from a quantitative and/or functional
deficiency of C1 esterase inhibitor (C1-INH), caused by pathogenic variants in genes such as
SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, or HS3ST6. Clinically, it presents with
recurrent angioedema of the skin, gastrointestinal tract, and airways. The primary aims of
the study were to characterize the clinical features of HAE, identify disease-causing genetic
variants, and explore potential biomarkers for improved diagnostics.
The study included all diagnosed HAE patients in Latvia, as well as individuals with
idiopathic angioedema and healthy controls. A comprehensive clinical and epidemiological
evaluation was performed, based on data extracted from medical records, structured interviews,
and patient-reported questionnaires. Standard genetic analysis was performed using Sanger
sequencing of the SERPING1 gene in patients with HAE type I/II and of the F12, PLG,
ANGPT1 gene regions in patients with suspected HAE with normal C1 inhibitor levels and
function (nC1-INH HAE). Advanced genetic analysis was conducted using genome sequencing
(GS) to identify rare non-coding and structural variants in HAE type I/II patients in whom no
pathogenic variant was detected by standard genetic testing, and using exome sequencing (ES)
for gene panel analysis in patients with suspected nC1-INH HAE. In both patient and control
groups, metabolomic profiling of blood samples was performed using liquid
chromatography-mass spectrometry (LC-MS) to identify novel biomarkers for HAE diagnosis.
The study revealed that the prevalence of HAE in Latvia is lower than reported in
the literature and in other countries. The clinical presentation of Latvian patients, including
edema localization, prodromal symptoms, and trigger factors, was largely consistent with
previously published data. However, a significant diagnostic delay from symptom onset to
confirmation was observed, highlighting underrecognition of the disease in clinical settings.
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Standard genetic testing using Sanger sequencing identified causative SERPING1
variants in HAE types I and II patients, whereas in the nC1-INH HAE cohort genetic
confirmation was achieved in one individual through detection of a pathogenic PLG variant.
Advanced genetic analysis, comprising GS and ES, yielded no additional pathogenic
findings. GS was unable to detect any rare noncoding or structural variants. These negative
findings nonetheless prompted a systematic reevaluation of clinical diagnoses, thereby
uncovering alternative causes of clinical symptoms. Furthermore, beyond its capacity to
identify novel genetic aberrations and to guide timely, precision-based therapies, GS –
as demonstrated by our study – serves an essential role in elucidating the pathogenesis of
angioedema and refining diagnostic determinations when extensive genetic screening fails to
reveal pathogenic variants.
Metabolomic analysis led to the identification of several potential biomarkers for HAE,
including isovalerylcarnitine, hydroxyproline and cystine, which may serve as novel indicators
for disease detection. Moreover, combinations of multiple metabolites – such as the ratio of
hydroxyproline and cystine to creatinine and isovalerylcarnitine (OH-Pro × Cys)/(Cr × IVC) –
may constitute an ancillary diagnostic biomarker for HAE.
In conclusion, this dissertation offers a comprehensive overview of the clinical
variability of HAE in Latvia, contributes to the understanding of its genetic basis, and
highlights the diagnostic value of extended genetic and metabolomic investigations. It supports
the advancement of early, accurate diagnosis and the development of personalized therapeutic
strategies, while also offering practical recommendations for future research directions and
improved patient care in hereditary angioedema.