Hemophilia genetic disorder

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Hemophilia: Genetic Disorder and Advances in Treatment

Hemophilia Genetic Basis

X-Linked Inheritance and Gene Mutations

Hemophilia is a genetic disorder primarily affecting males due to its X-linked inheritance pattern. The disorder is caused by mutations in the F8 gene (hemophilia A) or the F9 gene (hemophilia B), which code for coagulation factors VIII and IX, respectively 245. These mutations lead to insufficient production of these critical clotting factors, resulting in spontaneous and traumatic bleeding episodes 24.

Mutation Types and Detection

A variety of mutations can cause hemophilia, including deletions, point mutations, insertions, and inversions 147. Advances in genetic analysis, such as PCR, Sanger sequencing, and next-generation sequencing (NGS), have enabled the detection of these mutations in over 97% of patients with hemophilia B and a similar high percentage in hemophilia A 16. These techniques have also revealed that many mutations in severe hemophilia A are located outside the coding regions and splice junctions of the factor VIII gene .

Clinical Manifestations and Severity

Severity Levels

The clinical severity of hemophilia correlates with the level of clotting factor activity. Severe hemophilia is associated with less than 1% of normal factor activity, moderate with 2-5%, and mild with 6-50% . This variability in severity is due to the different types of mutations affecting the amount and functionality of the clotting factors produced .

Female Carriers and Symptomatic Females

While hemophilia predominantly affects males, carrier females with reduced factor levels can also experience bleeding symptoms. In rare cases, females can have hemophilia due to skewed X-chromosome inactivation or other genetic anomalies 19.

Advances in Treatment

Traditional Factor Replacement Therapy

Traditional treatment for hemophilia involves regular infusions of clotting factor concentrates derived from human plasma or recombinant sources. This therapy has significantly improved the life expectancy and quality of life for patients but comes with challenges such as the development of inhibitory antibodies and the risk of blood-borne infections 210.

Gene Therapy

Gene therapy has emerged as a promising treatment for hemophilia, aiming to provide a long-term solution by introducing functional copies of the defective genes into patients' cells. Recombinant adeno-associated viral (AAV) vectors are commonly used for this purpose, showing success in normalizing factor levels and reducing bleeding rates in clinical trials 25. However, challenges such as transient liver enzyme elevations and the need for long-term data on safety and efficacy remain .

Next-Generation Therapies

Next-generation gene therapies are focusing on improving the specificity and efficiency of viral constructs, reducing therapeutic doses, and minimizing cellular stress. These advancements aim to enhance the safety, durability, and efficacy of gene therapy for hemophilia and other blood clotting disorders .

Conclusion

Hemophilia is a complex genetic disorder with significant advancements in understanding its genetic basis and developing effective treatments. Traditional factor replacement therapy has been life-saving, but gene therapy offers the potential for a more permanent solution. Ongoing research and clinical trials continue to improve the prospects for patients with hemophilia, aiming for safer, more effective, and long-lasting treatments.

Sources and full results

Most relevant research papers on this topic

Hemophilia B: molecular pathogenesis and mutation analysis

Hemophilia B is an X-chromosome-linked bleeding disorder with genetic analysis enabling mutation detection in over 97% of patients, and inhibitory antibody development can be predicted in 2% of cases.

Highly Cited

2015·

94citations

·A. Goodeve

Hemophilia as a blueprint for gene therapy

Hemophilia gene therapy advances could guide future gene therapy advances for other inherited disorders.

2021·

12citations

·M. Ragni

Hemophilia A gene therapy: current and next-generation approaches

Gene replacement therapies offer safe, stable, and effective treatment for hemophilia A, with next-generation approaches incorporating chimeric DNA sequences to enhance clotting factor synthesis and secretion.

2021·

29citations

·S. Pipe et al.

Genetic Basis of Hemophilia A

Hemophilia A results from a variety of factor VIII gene mutations, with severity and activity varying within a family, and new mutations often occurring in previously unaffected families.

1991·

16citations

·J. Gitschier et al.

Advances and Challenges for Hemophilia Gene Therapy.

Hemophilia gene therapy shows promise in normalizing factor levels and improving bleed rate and quality of life, but long-term data is needed and healthcare services must evolve for equitable care.

Rigorous JournalHighly Cited

2019·

76citations

·P. Batty et al.

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative.

The My Life, Our Future (MLOF) project identified novel DNA variants in 924 hemophilia patients, revealing potential clinical implications and advancing our understanding of hemophilia.

Observational StudyHighly Cited

2017·

93citations

·J. Johnsen et al.

Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene.

Severe hemophilia A mutations are often found in DNA sequences outside the coding regions and splice junctions of the factor VIII gene, making detection difficult.

Observational StudyHighly Cited

1991·

151citations

·M. Higuchi et al.

Key Genes of the Immune System and Predisposition to Acquired Hemophilia A: Evidence from a Spanish Cohort of 49 Patients Using Next-Generation Sequencing

Two HLA cluster genes and rs1049174 in KLRK1 are linked to acquired hemophilia A, potentially improving diagnosis and prognosis for affected individuals.

Observational Study

2023·

2citations

·José Pardos-Gea et al.

Six molecular patterns leading to hemophilia A phenotype in 18 females from Poland.

Comprehensive molecular diagnostics is crucial for female hemophilia diagnosis, as it may change the diagnosis or reveal broader morbidities beyond coagulation disorders.

Observational Study

2020·

10citations

·S. Janczar et al.

State and Prospects of Gene Therapy for the Hemophilias

Gene therapy offers a promising alternative for treating hemophilia, potentially providing a permanent cure and enhancing life expectancy and quality of life.

1995·

18citations

·F. Fallaux et al.

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