Orphanet Journal of Rare Diseases | Clinical Features and Treatment Management of HAE-nC1INH Patients

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This study analyzed the clinical features and treatment responses of 163 French HAE-nC1INH patients, revealing differences in attack locations, hormone sensitivity, and treatment outcomes among various pathogenic gene variants. It provides important insights for clinical individualized therapy.

 

Literature Overview

The article titled 'Management of hereditary angioedema with normal C1Inh: a series of 163 French patients,' published in Orphanet Journal of Rare Diseases, reviews a national retrospective study conducted by the French Center for Rare Diseases (CREAK) on the clinical features and treatment management of HAE-nC1INH patients. The article highlights that F12 and PLG gene mutations are the primary causes of HAE-nC1INH, and these mutations differ in attack locations, hormone sensitivity, and treatment responses. The study included 287 patients with F12 mutations, 38 with PLG mutations, and 1 with a KNG1 mutation, of which 136 had clinical data. It emphasizes the genotype-phenotype associations and explores the efficacy and safety of current treatments in HAE-nC1INH patients.

Background Knowledge

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of vascular leakage and edema. HAE-nC1INH (C1-inhibitor activity normal) is primarily caused by mutations in the F12 and PLG genes. F12 mutations (p.Thr328Lys) increase the sensitivity of FXII to plasmin, leading to excessive bradykinin production. PLG mutations (p.Lys330Glu), on the other hand, bypass FXII activation by directly cleaving HMWK, thereby triggering bradykinin-mediated edema. These two mutation types significantly differ in age of onset, attack locations, and response to estrogen, providing a basis for personalized treatment. Current therapeutic strategies for HAE include B2 receptor antagonists (e.g., Icatibant), C1INH concentrates, and kallikrein inhibitors (e.g., Lanadelumab). However, the efficacy and safety of these treatments in HAE-nC1INH patients remain poorly evaluated. This study fills the gap by providing large-scale real-world data, which is valuable for optimizing treatment strategies and genetic counseling.

 

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Research Methods and Experimental Design

This was a national retrospective study conducted by the French Center for Rare Diseases (CREAK) network, including patients diagnosed with F12, PLG, and KNG1 mutations at the molecular biology laboratory of Grenoble University Hospital. All pathogenic mutations were confirmed by targeted Sanger sequencing. Clinical data, including attack locations, frequency, and treatment responses, were collected. Patients were defined as symptomatic if they had experienced at least one attack in their lifetime. Treatment efficacy was assessed by experts; an attack was considered effectively treated if its duration was reduced by at least 50% compared to untreated episodes. Non-parametric Fisher's exact and Wilcoxon-Mann-Whitney tests were used for statistical analysis.

Key Findings and Perspectives

• 49% of F12 mutation carriers exhibited estrogen dependency, while no such association was observed in PLG mutation patients (p < 0.01)
• HAE-PLG patients more frequently experienced tongue attacks (68.5%), whereas HAE-FXII patients mainly presented with facial, laryngeal, and abdominal attacks
• 91% of HAE-PLG patients had received at least one dose of Icatibant, with 100% efficacy; 67% of HAE-FXII patients used Icatibant or C1INH concentrate, primarily during pregnancy
• 12.6% of HAE-FXII patients and 47.4% of HAE-PLG patients required long-term prophylactic treatment; Tranexamic acid was more effective in PLG mutation patients (66.7% attack-free) compared to F12 mutation patients (37.5% attack-free)
• Kallikrein inhibitors (e.g., Lanadelumab) were highly effective in F12 mutation patients (100% symptom-free), but only 25% effective in PLG mutation patients
• Low-dose progestin-only contraceptives are safe for female HAE-nC1INH patients and do not exacerbate disease symptoms

Significance and Future Directions

This study provides critical evidence for the clinical management of HAE-nC1INH, demonstrating that current HAE-C1INH treatment strategies remain largely effective and safe in HAE-nC1INH patients. Future research should focus on optimizing treatment approaches for specific genotypes, particularly developing novel therapies for PLG mutation carriers. Additionally, due to the high estrogen sensitivity in HAE-nC1INH patients, further genotype-phenotype correlation studies are necessary to guide individualized hormone management.

 

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Conclusion

This study systematically analyzed the clinical and treatment data of 163 French HAE-nC1INH patients, revealing differences in clinical presentation and treatment responses between F12 and PLG mutations. HAE-FXII patients are predominantly female and highly estrogen-sensitive, while HAE-PLG patients more commonly experience tongue attacks. Icatibant and C1INH concentrates both demonstrated good efficacy and safety in acute attack management, but the effectiveness of long-term prophylaxis with Tranexamic acid and kallikrein inhibitors varied by genotype. The study underscores the importance of genetic testing in HAE diagnosis and recommends low-dose progestin-only contraceptives for female patients. Further large-scale studies are needed to validate treatment efficacy in specific genotypes and explore more precise molecular-targeted therapies.

 

Alexis Bocquet, Laurence Bouillet, Gaelle Hardy, Olivier Fain, and Delphine Gobert. Management of hereditary angioedema with normal C1Inh: a series of 163 French patients. Orphanet Journal of Rare Diseases.