1. Introduction
Hereditary angioedema (HAE) due to C1 Inhibitor (C1-INH) deficiency
(C1-INH-HAE) is a rare autosomal dominant disease caused by reduced
C1-INH plasma levels (C1-INH-HAE type I) or by the presence of a
dysfunctional C1-INH (C1-INH-HAE type II) [1]. C1-INH-HAE type I is
estimated to occur in approximately 85% of cases, type II occurs in the
remaining 15%. C4 is reduced in both C1-INH-HAE type I and II while C3
is normal [2]. The disease is caused by sequence variants in C1-INH
gene (SERPING1, OMIM #606860) that is located on chromosome 11
(11.q12-q13.1) and comprises of eight exons and seven introns
distributed over 17 kb, with introns containing 17 repetitive Alu
sequences (1,5,6). More than 560 different pathogenic variants inSERPING1 have been described to date, ranging from single
nucleotide substitutions, small insertions and/or deletions, large
deletions and duplications (HGMD® Professional,http://www.hgmd.cf.ac.uk/ac/index.php)
[3]. De novo variants, i.e. variants where parents have got a
normal C1-INH, can be identified in approximately 25% of the families
[4]. The deficiency of C1-INH results in uncontrolled activation of
the contact system and release of bradykinin, the mediator of increased
vascular permeability and angioedema manifestations [5,6].
C1-INH-HAE manifests with recurrent episodes of edema of the skin,
gastrointestinal tract and upper airway. The disease is disabling and
laryngeal edema can lead to asphyxiation and death if left untreated
[2]. Data on the prevalence of C1-INH-HAE are sparse. Globally, the
estimated frequency reported in literature varies from 1 every 10,000 to
1 every 150,000 people without racial or gender differences [7-9].
Focusing on European countries, the higher prevalence is reported in
England [10], Denmark [11,12], Italy [13], Hungary [14],
Norway [15], Sweden [16], and Switzerland [17], where the
calculated prevalence is 1:65,000 to 1:75,000 inhabitants. Lower rate is
reported in Greece [14], Serbia [18], Slovenia [19], and
Spain [20], where the prevalence has been evaluated to be
approximately 1:90,000 to 1:105,000 inhabitants.
Since C1-INH-HAE is a genetic disease, the deficiency of C1-INH is
present from birth. Nevertheless, a minority of patients have perinatal
angioedema symptoms. Patients typically begin to present clinical
manifestations in childhood and attacks frequency often increases during
puberty. Before the second decade of life the majority of patients
manifest symptoms of angioedema [21]. Due to the rarity of the
disease and to the fact that the clinical symptoms overlap with those of
other forms of angioedema, C1-INH-HAE is frequently misdiagnosed.
Consequently, C1-INH-HAE patients may experience considerable delay
between symptoms onset and diagnosis [21].
In a recent international observational study analysing data of patients
eligible to Icatibant treatment (Icatibant Outcome Survey, IOS)
conducted in 8 European countries, the mean delay in diagnosis of
C1-INH-HAE patients was 12.8 years [22].
Currently on-demand therapies (ODT) for the treatment of C1-INH-HAE
attacks are available: fresh frozen plasma, two plasma derived C1-INH
(Berinert®, Cinryze®), one recombinant C1-INH (Ruconest®) and the
bradykinin receptor antagonist Icatibant (Firazyr®) [23]. Clinical
guidelines recommend patients to treat all attacks at onset [23].
ODT reduce the duration of attacks and the risk of death due to
asphyxia. Patients who do not reach adequate disease control with ODT
can be switched to long-term prophylaxis (LTP) [23], with attenuated
androgens, subcutaneous preparation of plasma - derived C1-INH [24]
or subcutaneous Lanadelumab (Takhzyro®, a human monoclonal antibody to
kallikrein) [25].
Data regarding epidemiology, genetics, access to diagnosis and therapy
from states belonging to former Republics of the Union of Soviet
Socialist Republics are missing. This study analyses data from
C1-INH-HAE patients from Belarus, a country born in 1991, as an example
of the region.