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Iron-refractory iron deficiency anaemia (IRIDA)
IRIDA results from changes in the TMPRSS6 gene, affecting the body's ability to properly absorb and utilise iron. Individuals with IRIDA often experience symptoms of anaemia despite standard iron treatments.
Overview
Iron-Refractory Iron Deficiency Anaemia (IRIDA) is a rare genetic disorder characterised by persistent iron deficiency anaemia that does not respond well to typical oral iron supplements. This condition is present from birth, though symptoms may become noticeable at different ages. It leads to the body having insufficient iron to produce haemoglobin, the protein in red blood cells that carries oxygen [PMID:34731309].
Individuals with IRIDA often require intravenous iron treatments to manage their anaemia because their bodies struggle to absorb iron effectively from the diet. The condition is distinct from other forms of iron deficiency anaemia that might be caused by blood loss or dietary insufficiency, as it has a specific genetic basis.
Symptoms & clinical features
The symptoms of IRIDA are primarily those of iron deficiency anaemia. These can include fatigue, weakness, paleness of the skin, shortness of breath, and reduced exercise tolerance. Children may also experience developmental delays or poor growth [PMID:24607738].
Other potential symptoms can include restless legs syndrome, brittle nails, and pica (a craving for non-food items like ice or dirt). The severity of these symptoms can vary between individuals, even within the same family, and may fluctuate depending on the degree of anaemia. These symptoms are often resistant to standard oral iron supplements, which is a key characteristic of IRIDA.
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Affected organs
IRIDA primarily affects the blood and the digestive system, specifically how iron is absorbed and regulated. The deficiency in iron impacts the bone marrow's ability to produce healthy red blood cells. The brain and muscles can also be affected due to reduced oxygen delivery, leading to fatigue and developmental issues in children. Overall, the condition affects the body's iron metabolism, a process crucial for various bodily functions.
Risks & severity
IRIDA is a lifelong condition, and its severity can vary. Without appropriate management, chronic anaemia can lead to complications affecting heart function and overall well-being. However, with effective iron therapy, many individuals with IRIDA can lead relatively normal lives [PMID:22081692].
The exact prevalence of IRIDA is not well established, but it is considered a rare disorder. The age of onset for symptoms can range from infancy to adulthood, with many individuals presenting in early childhood. Regular monitoring and tailored treatment are important to minimise the long-term impact of chronic iron deficiency.
Genetic causes
IRIDA is caused by pathogenic variants in the TMPRSS6 gene. This gene provides instructions for making a protein called matriptase-2. Matriptase-2 plays a critical role in regulating iron levels in the body by controlling the production of hepcidin, a hormone that reduces iron absorption from the diet and iron release from storage.
Pathogenic changes in TMPRSS6 lead to an overproduction of hepcidin. Elevated hepcidin levels restrict the amount of iron absorbed from food in the gut and also prevent iron from being released from the body's stores. This results in a functional iron deficiency, meaning there is iron in the body, but it cannot be properly accessed or utilised, leading to the characteristic anaemia that resists oral iron supplementation.
- TMPRSS6 transmembrane serine protease 6
Inheritance pattern
IRIDA is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the TMPRSS6 gene - one from each parent - to develop the condition. Individuals who inherit only one altered copy are carriers; they typically do not show symptoms of IRIDA but can pass the altered gene to their children.
If both parents are carriers of a TMPRSS6 gene variant, there is a 25% chance with each pregnancy that their child will inherit two altered copies and develop IRIDA. There is a 50% chance the child will be a carrier, and a 25% chance the child will inherit two unaffected copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
The diagnosis of IRIDA is usually suspected based on persistent iron deficiency anaemia that does not respond to oral iron treatment. Blood tests will typically show low iron levels, low transferrin saturation, and often inappropriately normal or high hepcidin levels, which is unusual for iron deficiency.
Definitive diagnosis involves genetic testing to identify pathogenic variants in the TMPRSS6 gene. Referrals for genetic testing would typically come from a haematologist or general practitioner, often through the NHS Genomic Medicine Service, using relevant R-codes for anaemia or iron metabolism disorders. Genetic counselling is offered to families undergoing testing to explain the implications of the results.
Management & lifestyle
Management of IRIDA focuses on correcting the iron deficiency and anaemia. Oral iron supplements are generally ineffective due to the underlying genetic mechanism. Therefore, treatment typically involves intravenous iron infusions to bypass the impaired intestinal absorption. The frequency and dosage of intravenous iron need to be carefully monitored by a haematologist.
Regular blood tests are essential to track iron levels, haemoglobin, and other relevant markers to guide treatment adjustments. Patients are often managed through specialist haematology clinics within the NHS. Genetic counsellors can provide support and information regarding the genetic basis of the condition and its implications for family planning.
UK care pathway
In the UK, individuals suspected of having a rare genetic condition like IRIDA are typically referred to specialist services. This journey often begins with a General Practitioner or a specialist, such as a haematologist, who suspects a genetic cause for the symptoms. Genetic testing for IRIDA, specifically targeting the TMPRSS6 gene, can be accessed through the NHS Genomic Medicine Service (GMS) pathways.
Genetic counsellors play a vital role in this pathway, offering support, information, and guidance to individuals and families throughout the diagnostic process and beyond. They can explain the inheritance patterns, implications of genetic test results, and discuss family planning options. Genetic testing within the GMS often uses specific R-codes for hereditary anaemias to ensure appropriate testing and interpretation.
Frequently asked questions
What makes IRIDA different from other iron deficiency anaemias?
IRIDA is unique because it's caused by a genetic change in the TMPRSS6 gene, leading to the body's inability to properly use dietary iron. Unlike other types of iron deficiency, it usually doesn't improve with standard oral iron supplements.
Can IRIDA be cured?
IRIDA is a lifelong genetic condition, meaning it cannot be cured. However, the symptoms, primarily anaemia, can be effectively managed with regular intravenous iron treatments to maintain healthy iron levels and improve quality of life.
What does it mean for my family if I have IRIDA?
IRIDA is inherited in an autosomal recessive pattern. This means family members might be carriers of the gene variant. Genetic counselling can help explain the risks for children and other relatives and discuss options for family planning.
Will I need to take iron medication forever?
For most individuals with IRIDA, ongoing iron therapy, typically via intravenous infusions, is necessary to manage the condition and prevent anaemia. The treatment plan is tailored to each individual by a specialist haematologist.
Where can I get support for IRIDA in the UK?
In the UK, support for IRIDA is typically provided through NHS specialist haematology clinics. Genetic counsellors can also offer information and support regarding the genetic aspects. Patient advocacy groups for rare anaemias might also provide community support.
References
- Fan S, Zhao T, Sun L. The global prevalence and ethnic heterogeneity of iron-refractory iron deficiency anaemia. Orphanet journal of rare diseases. 2023. PMID: 36604716