Angioedema hereditary D84.1

Knowledge of rare genetic diseases such as hereditary angioedema (HAE) has evolved in parallel with the development of new molecular tools. C1 inhibitor (C1-INH) deficiency has been recognized as the major cause of HAE (HAE-C1-INH) since the 1960s. Discovery of the broad spectrum of mutations affecting the C1-INH gene (SERPING1) was not possible until the late 1980s, when Sanger sequencing became available and more readily accessible worldwide.

However, the involvement of other genes in HAE was not discovered until 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. The knowledge gained through the new era of genomics has been crucial for the discovery of mutations in additional genes, improving or explaining the understanding of the complex pathogenesis of this phenotypically largely identical disease. In the last three years, advanced next-generation sequencing techniques have enabled the identification of mutations in five additional novel genes associated with hereditary angioedema variants with normal C1-INH (nC1-INH-HAE): ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).

Hereditary angioedema:

Type I hereditary angioedema , mutation in Serping1 (C1-INH deficiency).

Type II hereditary angioedema, mutation in Serping1 (C1-INH dysfunction)

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Type III Hereditary angioedema , mutation in factor XII (F12)

Type IV Hereditary angioedema , mutation in plasminogen (PLG)

Type V Hereditary angioedema , mutation in angiopoietin 1 (ANGPT1)

Type VI Hereditary angioedema , mutation in kininogen 1 (KNG1)

Type VII Hereditary angioedema , mutation in myoferlin (MYOF)

Type VIII Hereditary angioedema , mutation in heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6)

Type U Hereditary angioedema, genetic defect unknown

Basically, hereditary angioedema can be distinguished between:

• hereditary angioedema with mutation in the C1-esterase inhibitor gene(SERPING1): C1-INH-HAE (HAE type I/ HAE type II)

and

• hereditary angioedemawithout detectable mutation in SERPING1 gene: nC1-INH-HAE (HAE types III - VIII) with normal C1-INH (see below classification).

Note: Mutations in SERPING1, the gene encoding C1-INH (C1 esterase inhibitor), are responsible for the vast majority of cases of hereditary angioedema (85%). C1-esterase inhibitor (C1-INH) is an important regulator of critical enzymes involved in the cascades of bradykinin formation. These increase vascular permeability and allow the flow of fluids into the extracellular space. Disturbances in this cascade can lead to acute swelling conditions (angioedema).

Face, extremities (especially arms, less frequently legs), genitals; also lips, tongue, larnyx, abdomen (abdominal cramps). Laryngeal swelling is acutely life-threatening.

The treatment of hereditary angioedema should be individually tailored to the needs of those affected.

There are various treatment options:

Acute therapy: Depending on the age of the patient, there are various medications approved for treatment. The drugs:

^Berinert®, ^Cinryze® and Conestat alfa (^Ruconest® ) replace the missing C1 inhibitor.

The drugs Icatibant (Firazyr®^: blockade of the bradykinin B2 receptor) and Lanadelumab (^Takhzyro®: monoclonal antibody against plasma kallikrein) inhibit the effect of bradykininin different ways. Bradykinin is primarily responsible for the development of symptoms in HAE.

Alternative: Sebetralstat is an investigational oral plasma kallikrein inhibitor for the acute treatment of hereditary angioedema (HAE). Sebetralstat works by targeting the kallikrein-kinin system (KKS) cascade and selectively inhibiting the plasma kallikrein that triggers HAE attacks. Sebetralstat is administered orally (Riedl MA et al. 2024). In the neck and head region, each attack should be treated in all age groups.

In trial: NTLA-2002 is a CRISPR-based drug in clinical trials that targets the gene encoding kallikrein B1 (KLKB1). A single dose of NTLA-2002 can provide lifelong control of angioedema attacks.

• Therapy should start as early as possible
• Children < 6 years: All attacks (including gastrointestinal tract, arms and legs) should be treated
• Children > 6 years: Treatment should be considered for attacks outside the head/neck area (indication according to severity)
• Medication must be available at short notice at all times

Short-term prophylaxis: Short-term prophylaxis is recommended before head/neck surgery. This applies to an upcoming surgical medical procedure, e.g. dental treatment. Use of Berinert® (intravenous), alternatively: Cinryze®.

• Recommended for all tissue-traumatizing and surgical procedures in the head and neck area
• If short-term prophylaxis is not used, a C1 inhibitor concentrate should be kept to hand as an emergency medication
• Short-term prophylaxis should be administered as soon as possible before the procedure

Long-term prophylaxis: The aim of this is to prevent swelling attacks in the long term. The possibility of permanent, preventive treatment can be considered for patients in life situations that are associated with increased disease activity (assessed by frequency and severity of attacks). The disease burden as such can also be taken into account for prophylactic therapy. In addition, long-term prophylaxis is useful for patients who cannot be adequately treated with repeated on-demand treatments.

• Long-term prophylaxis is not standard for all patients. It depends on the age of the patient and the course of the disease. ^Cinryze® or ^Berinert® (s.c.) or Lanadelumab (^Takhzyro®) is recommended from the age of 12. When deciding on long-term prophylaxis, the frequency of the attacks, the individual burden of the disease and the impairment of the usual daily routine should be taken into account. As a rule, long-term prophylaxis is not given for fewer than two attacks per month.

Concomitant medication: For mild ventral attacks, it may be sufficient to prescribe only antispasmodic medication.

Treatment of laryngeal edema: Patients with HAE in the head with edema of the pharynx or larynx are an emergency due to the imminent risk of suffocation and should be hospitalized and monitored immediately. All affected patients must be treated as quickly as possible with a C1 inhibitor or ^Firazyr® . Intubation of the patient is necessary if there is a threat of respiratory distress (see also angioedema of the head and neck region)

Supportive measures: In order to enable rapid treatment of incipient swelling, older patients as well as parents, other relatives, teachers and other caregivers should be informed about the clinical picture. They should be able to recognize a life-threatening situation (e.g. laryngeal oedema) and act in a targeted manner (activate emergency preparedness).

• The patient should always carry an emergency plan with them, showing what action needs to be taken. All patients should also carry an emergency card.
• Patients with HAE due to C1-INH deficiency should always keep an emergency medication sufficient for two doses at home and carry it with them when traveling. The patient and the disease should be known at the nearest hospital.
• Teachers of school children should be informed that acute attacks can occur. Before dental operations, including tooth extractions, and other operations in the mouth and throat area, patients with HAE due to C1-INH deficiency should receive 20 units per kg body weight of C1-INH concentrate one hour before the operation (see short-term prophylaxis).

Home self-treatment: As HAE is a lifelong disease, there is the possibility of home self-treatment. This is only possible with the consent of the treating doctor and after the parents or the patients themselves have been trained by the doctor. Self-treatment means that an attack of swelling can be treated earlier and the severity of the swelling is usually less severe.

1. Hubiche T et al. (2005) Érythème annulaire réticulé annonciateur de crises d'œdème angioneurotique héréditaire chez un enfant. Ann Dermatol Venereol132: 249-251.
2. Rasmussen ER et al. (2016) Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema. Acta Derm-Venereol 96: 373-376.
3. Riedl MA et al. (2024) Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks. N Engl J Med 391:32-43
4. Santacroce R et al. (2021) The Genetics of Hereditary Angioedema: A Review. J Clin Med 10: 2023.
5. Veronez CL et al. (2021) The Expanding Spectrum of Mutations in Hereditary Angioedema. J Allergy Clin Immunol Pract 9: 2229-2234.