Haemochromatosis type 3

Haemochromatosis type 3 is a type of iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern.[2][3][4] The first confirmed case was diagnosed in 1865 by French doctor Trousseau. Later in 1889, the German doctor von Recklinghausen indicated that the liver contains iron, and due to bleeding being considered to be the cause, he called the pigment "Haemochromatosis."[5] In 1935, English doctor Sheldon's groundbreaking book titled, Haemochromatosis, reviewed 311 patient case reports and presented the idea that haemochromatosis was a congenital metabolic disorder.[5] Hereditary haemochromatosis is a congenital disorder which affects the regulation of iron metabolism thus causing increased gut absorption of iron and a gradual build-up of pathologic iron deposits in the liver and other internal organs, joint capsules and the skin.[5] The iron overload could potentially cause serious disease from the age of 40–50 years. In the final stages of the disease, the major symptoms include liver cirrhosis, diabetes and bronze-colored skin. There are four types of hereditary hemochromatosis which are classified depending on the age of onset and other factors such as genetic cause and mode of inheritance.[6]

Haemochromatosis type 3
Other namesTFR2-related hemochromatosis[1]
SpecialtyHematology

Signs and Symptoms

The presence of Haemochromatosis type 3 can be realized through its many signs and symptoms throughout bodily systems. Systems affected by Haemochromatosis type 3 include the skeletal, endocrine, cardiovascular, neurological, genitourinary, and integumentary systems.[7][8][9][10] There are also implications associated with a person's hematology, laboratory analysis results, and their liver.[11]

Those that inherit Haemochromatosis type 3 can be asymptomatic in up to 75% of cases.[12] The most common symptoms for those with symptoms can include severe fatigue (75%), impotence (45%), arthralgia (44%), hepatomegaly (13%), skin pigmentation, and arthritis.[12]

The specific diseases and conditions that show a correlation with Haemochromatosis type 3 are the following:

Systems Affected and Associated Symptoms[11]
System Symptom/Disease
Skeletal Arthritis
Hematology Anemia

Lymphopenia

Neutropenia

Thrombocytopenic Purpura

Genitourinary (Male) Impotence

Decreased Libido

Hypogonadism

Genitourinary (Female) Amenorrhea
Endocrine Diabetes
Neurologic Fatigue
Abdomen, Liver Cirrhosis

Fibrosis

Cardiovascular Cardiomyopathy
Integumentary Hyperpigmentation
Laboratory Abnormalities Increased Serum Ferritin

Increased Serum Iron

Increased Transferrin Saturation

Increased Liver Transaminases

Genetics

Inheritance Pattern

The disease haemochromatosis type 3 is inherited in an autosomal recessive manner. Individuals with this disease exhibit a mutation or pathogenic effect in both copies of the TFR2 in each cell. People with only one copy of TFR2 that is affected are labeled as carriers. Carriers typically do not exhibit signs or symptoms of the disease. This disease is shown to have reduced penetrance. Thus, some people with pathogenic variants of the TFR2 gene may never present symptoms related to the disease.[13]

Gene Involved

The gene involved with patients diagnosed with type 3 hemochromatosis is TFR2 ( or HFE3).

HFE is most often the cause of hereditary hemochromatosis.[14] The HFE gene provides instructions for producing a protein that is located on the surface of cells, primarily liver and intestinal cells. The HFE protein is also found on some immune system cells. The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. When the HFE protein is attached to a protein called transferrin receptor 1, the receptor cannot bind to a protein called transferrin. When transferrin receptor 1 is bound to transferrin, iron enters liver cells. So, it is likely that the HFE protein regulates iron levels in liver cells by preventing transferrin from binding to transferrin receptor 1. The HFE protein regulates the production of a protein called hepcidin. Hepcidin is produced by the liver, and it determines how much iron is absorbed from the diet and released from storage sites in the body. When the HFE protein is not bound to transferrin receptor 1, it binds to a group of other proteins that includes hepcidin. The formation of this protein complex triggers the production of hepcidin. So when the HFE protein is bound to transferring receptor 1, hepcidin production is turned off and when the HFE protein is not bound to transferring receptor 1, hepcidin production is turned on.[15]

The transferrin receptor 2 (TFR2) gene is responsible for encoding a single-pass type II membrane protein. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation.[16]

Type of Mutations

Majority of the cases of hemochromatosis are caused by mutations in the HFE gene.[17] More specifically, Type 3 HH is characterized by mutations in transferrin receptor 2.[18] HH type 3 is linked to mutations in a gene on chromosome 7q22, encoding TFR2.[19] A deletion in the DNA sequence at this location is associated with causing type 3 hemochromatosis.[19]

Location of the Chromosome

The heterozygous mutation in the transferrin receptor-2 gene (TFR2) and the mutation in the hemochromatosis type 3 gene (HFE3) are the causes of hemochromatosis type 3.[20] These mutations are found on chromosome 7q22.[20] The location of the genes affected are at 7:100,620,419 on the DNA chromosome.[21][22]

Effects on Gene Products

The gene product is a member of the major histocompatibility complex class I-like family and holds a mutation, Cys-292 to Tyr (C282Y), in 85% of patient chromosomes. The mutation eliminates the ability of HFE to prevent cell-surface expression. There are also other mutations that prevent association of the mutant HFE protein with transferrin receptor.

Spectrum of Disease Severity

The disease can manifest itself without showing any symptoms, but these symptoms can emerge over time and the disease can therefore become more severe. Symptoms that emerge early on in the disease are generally less severe, and may include conditions such as fatigue, weakness, skin discoloration, loss of sex drive and joint pain. Late in the disease, people may experience liver disease as well as disease to other major organs as excess iron is deposited over time. People can also develop diabetes, heart problems, and abdominal pain.

Diagnosis

Like many genetic or rare diseases, diagnosis of haemochromatosis type 3 is challenging. In order to formulate a diagnosis healthcare professionals view medical history, symptoms, physical exam, and laboratory test results.[23]

Testing Resources

The Genetic Testing Registry provides information about genetic tests for haemochromatosis type 3. There are 62 different clinical tests available including two biochemical Genetics tests and 60 molecular genetics tests. There is also one research test available.

  • Clinical tests
    • Biochemical genetics tests (2)
      • Enzyme assay (2)
    • Molecular genetics tests (60)
      • Deletion/duplication analysis (22)
      • Sequence analysis of select exons (12)
      • Sequence analysis of the entire coding region (52)
      • Targeted variant analysis (9)
  • Research Tests
    • TFR2-Related Hereditary Haemochromatosis (1)[24]

Management

Treatment for hemochromatosis type 3 may include reducing iron levels by removing blood (phlebotomy), iron chelation therapy, diet changes, and treatment for complications of the disease. The purpose of the treatment is to reduce the amount of iron in the body to normal levels, prevent or delay organ damage from excess iron, and maintain normal amounts of iron throughout the lifetime.[25] Phlebotomy helps to remove excess iron from the body. Most treatment begins with weekly therapeutic phlebotomy, occasionally treatment is initially twice a week if iron levels are elevated. Maintenance phlebotomy usually involved treatment every 2–4 months. Iron chelation therapy may be recommended for people that have other health issues as well.[25] Dietary recommendations may include avoiding alcohol and red meat. People with hemochromatosis are not recommended to take iron or vitamin C supplements.[25]

Epidemiology

The prevalence in the ethnic Norwegian population of homozygous and heterozygous inheritance is 0.8% and 12-15% respectively, which makes haemochromatosis one of the most common hereditary diseases in Norway.[5] Type 1 hemochromatosis is one of the most common genetic disorders in the United States, affecting about 1 million people. It most often affects people of Northern European descent. The other types of hemochromatosis are considered rare and have been studied in only a small number of families worldwide.[6]

References
  1. RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Hemochromatosis type 3". www.orpha.net. Retrieved 8 June 2019.
  2. Roetto A, Totaro A, Piperno A, et al. (May 2001). "New mutations inactivating transferrin receptor 2 in hemochromatosis type 3". Blood. 97 (9): 2555–60. doi:10.1182/blood.V97.9.2555. PMID 11313241.
  3. Roetto A, Daraio F, Alberti F, et al. (2002). "Hemochromatosis due to mutations in transferrin receptor 2". Blood Cells Mol. Dis. 29 (3): 465–70. doi:10.1006/bcmd.2002.0585. PMID 12547237.
  4. Roetto A, Camaschella C (June 2005). "New insights into iron homeostasis through the study of non-HFE hereditary haemochromatosis". Best Pract Res Clin Haematol. 18 (2): 235–50. doi:10.1016/j.beha.2004.09.004. PMID 15737887.
  5. Johan Ulvik, Rune (20 December 2016). "Hereditary haemochromatosis through 150 years". Tidsskrift for den Norske Legeforening. 136 (23–24): 2017–2021. doi:10.4045/tidsskr.15.1003. PMID 28004554. Retrieved 26 April 2021.{{cite journal}}: CS1 maint: url-status (link)
  6. "Hereditary hemochromatosis". MedlinePlus. 1 February 2019.{{cite web}}: CS1 maint: url-status (link)
  7. Camaschella, C.; Fargion, S.; Sampietro, M.; Roetto, A.; Bosio, S.; Garozzo, G.; Arosio, C.; Piperno, A. (May 1999). "Inherited HFE-unrelated hemochromatosis in Italian families". Hepatology. 29 (5): 1563–1564. doi:10.1002/hep.510290509. ISSN 0270-9139. PMID 10216143. S2CID 25671765.
  8. Camaschella, C.; Roetto, A.; Calì, A.; De Gobbi, M.; Garozzo, G.; Carella, M.; Majorano, N.; Totaro, A.; Gasparini, P. (May 2000). "The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22". Nature Genetics. 25 (1): 14–15. doi:10.1038/75534. ISSN 1061-4036. PMID 10802645. S2CID 9227077.
  9. Griffiths, W.; Cox, T. (October 2000). "Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism". Human Molecular Genetics. 9 (16): 2377–2382. doi:10.1093/hmg/9.16.2377. ISSN 0964-6906. PMID 11005792.
  10. Mattman, Andre; Huntsman, David; Lockitch, Gillian; Langlois, Sylvie; Buskard, Noel; Ralston, Diana; Butterfield, Yaron; Rodrigues, Pedro; Jones, Steven; Porto, Graça; Marra, Marco (2002-08-01). "Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation". Blood. 100 (3): 1075–1077. doi:10.1182/blood-2002-01-0133. hdl:10400.16/826. ISSN 0006-4971. PMID 12130528.
  11. Camaschella, Clara; Roetto, Antonella; Calì, Angelita; De Gobbi, Marco; Garozzo, Giovanni; Carella, Massimo; Majorano, Nunzia; Totaro, Angela; Gasparini, Paolo (May 2000). "The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22". Nature Genetics. 25 (1): 14–15. doi:10.1038/75534. ISSN 1546-1718. PMID 10802645. S2CID 9227077.
  12. "Hemochromatosis: Practice Essentials, Background, Pathophysiology". 2019-11-21. Retrieved 2021-04-29.{{cite web}}: CS1 maint: url-status (link)
  13. "Hemochromatosis type 3 | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-04-26.
  14. "Hemochromatosis". Mayo Clinic. Retrieved 26 April 2021.{{cite web}}: CS1 maint: url-status (link)
  15. "HFE gene homeostatic iron regulator". MedlinePlus. Retrieved 26 April 2021.{{cite web}}: CS1 maint: url-status (link)
  16. "TRF2 transferring receptor 2 [ Homo sapiens (human) ]". NCBI. 10 April 2021. Retrieved 26 April 2021.{{cite web}}: CS1 maint: url-status (link)
  17. Crawford, Darrell H. G. (2014). "Hereditary hemochromatosis types 1, 2, and 3". Clinical Liver Disease. 3 (5): 96–97. doi:10.1002/cld.339. ISSN 2046-2484. PMC 6448708. PMID 30992896.
  18. Crawford, Darrell (2014). "Hereditary Hemochromatosis Types 1, 2, and 3". Clinical Liver Disease. 3 (5): 96–97. doi:10.1002/cld.339. PMC 6448708. PMID 30992896.
  19. Girelli, Domenico; Bozzini, Claudia; Roetto, Antonella; Alberti, Federica; Daraio, Filomena; Colombari, Romano; Olivieri, Oliviero; Corrocher, Roberto; Camaschella, Clara (2002-05-01). "Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene". Gastroenterology. 122 (5): 1295–1302. doi:10.1053/gast.2002.32984. ISSN 0016-5085. PMID 11984516.
  20. Roychoudhury, A. K. (1977-12-29). "Gene diversity in Indian populations". Human Genetics. 40 (1): 99–106. doi:10.1007/BF00280836. ISSN 0340-6717. PMID 604250. S2CID 10350768.
  21. "Genome Data Viewer - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-04-26.
  22. Feder, John N.; Penny, David M.; Irrinki, Alivelu; Lee, Vince K.; Lebrón, José A.; Watson, Nicole; Tsuchihashi, Zenta; Sigal, Elliott; Bjorkman, Pamela J.; Schatzman, Randall C. (1998-02-17). "The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding". Proceedings of the National Academy of Sciences of the United States of America. 95 (4): 1472–1477. Bibcode:1998PNAS...95.1472F. doi:10.1073/pnas.95.4.1472. ISSN 0027-8424. PMC 19050. PMID 9465039.
  23. "Hemochromatosis type 3 | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-04-26.
  24. "Hemochromatosis type 3 - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-04-26.
  25. "Hemochromatosis type 3". Genetics and Rare Diseases Information Center. 15 February 2018.{{cite web}}: CS1 maint: url-status (link)
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.