Functional Complement Analysis Can Predict Genetic Testing Results and Long-Term Outcome in Patients With Complement Deficiencies

Abstract

BackgroundPrevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries.ObjectiveThe purposes of our study were to confirm CD and define complete and partial CD in registered patients in Slovenia, to evaluate frequency of clinical manifestations, and to assess the risk for characteristic infections separately for subjects with complete and partial CD.MethodsCD was confirmed with genetic analyses in patients with C2 deficiency, C8 deficiency, and hereditary angioedema or with repeated functional complement studies and measurement of complement components in other CD. Results of genetic studies (homozygous subjects vs. heterozygous carriers) and complement functional studies were analyzed to define complete (complement below the level of heterozygous carriers) and partial CD (complement above the level of homozygous patients). Presence of characteristic infections was assessed separately for complete and partial CD.ResultsGenetic analyses confirmed markedly higher prevalence of CD in Slovenian PID registry (26% of all PID) than in other national and international PID registries (0.5–6% of all PID). Complement functional studies and complement component concentrations reliably distinguished between homozygous and heterozygous CD carriers. Subjects with partial CD had higher risk for characteristic infections than previously reported.ConclusionResults of our study imply under-recognition of CD worldwide. Complement functional studies and complement component concentrations reliably predicted risk for characteristic infections in patients with complete or partial CD. Vaccination against encapsulated bacteria should be advocated also for subjects with partial CD and not limited to complete CD.

European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management

“…Similar methodology was also developed for assessment of the lectin pathway [33]. A Slovenian study showed that patients with C2 or C8 deficiencies present with CH50 values below the lower limit of the reference range, that homozygous mutations are associated with lower CH50 values than heterozygous mutations and that patients with infections have lower CH50 values than those not exhibiting infections [34]. Patients with homozygous C2 mutations consistently present with CH50 below the lower limit of the reference range and also significantly lower CH50 than carriers of heterozygous mutations causing C2 deficiency [34].…”

“…2). In recent years, diagnosis by genetic testing has become more common [34], and it offers an alternative option where detailed functional assays are not available or not easily accessible. However, the genetic diagnosis of complement deficiencies is complicated and potentially confounded by copy number variations, point mutations and the presence of pseudogenes [37].…”

“…Complement deficiencies make up 1-10% of all reported PIDs, according to international registry data [1]; however, in some national registries, the proportion is significantly higher [34]. Table 1 outlines known complement deficiencies and associated symptoms/disorders.…”

Das Komplementsystem: von den Grundlagen zur klinischen Bedeutung

“…Defekte des Komplementsystems machen etwa 5 % aller primären Immundefekte aus, wie aus der aktuellen Auswertung des Registers der Europäischen Gesellschaft für Immundefekte (ESID) hervorgeht (https://cci-reporting.uniklinik-freiburg.de/#/; Stand 21.02.2020). Sie können jedoch, wie einige nationale Studien belegen, auch deutlich höhere Prävalenzen aufweisen [19,21], was nicht zuletzt auf unterschiedliche diagnostische Möglichkeiten zurückzuführen ist. Ohne Berücksichtigung des Mangels an Mannose-bindendem Lektin (MBL), der bei ca.…”

Genetic bases of C7 deficiency: systematic review and report of a novel deletion determining functional hemizygosity

“…Primary complement (C) deficiencies represent approximately 1-10% of all reported primary immunodeficiencies (PIDs) ( 1 ), even though markedly higher numbers were documented in specific national registries ( 2 ). The most prevalent C deficiencies affect mannose-binding lectin (MBL), which is estimated to occur in more than 10% of the Caucasian population, and C2 ( 3 ).…”