Deficiency of intrinsic factor
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Deficiency of Intrinsic Factor: Genetic Insights and Clinical Implications
Genetic Polymorphisms and Mutations in Intrinsic Factor Deficiency
Congenital Intrinsic Factor Deficiency and Genetic Polymorphisms
Congenital intrinsic factor (IF) deficiency is a genetic disorder characterized by megaloblastic anemia due to the absence of gastric intrinsic factor. A significant genetic polymorphism associated with this condition is the g.68A>G variant in the coding region of the gastric intrinsic factor gene (GIF). This variant changes the amino acid sequence from glutamine to arginine at the fifth codon position, which has been identified in several affected individuals. The inheritance pattern is autosomal recessive, with most parents of affected individuals being heterozygous for this mutation.
Novel Mutations in the GIF Gene
Recent studies have identified additional mutations in the GIF gene that contribute to hereditary intrinsic factor deficiency. For instance, a novel compound heterozygous mutation involving a c.776delA frame shift in exon 6 and a c.585C>A nonsense mutation in exon 5 was reported in a Chinese patient. These mutations result in the dysfunction of the gastric intrinsic factor protein, leading to severe anemia and cobalamin deficiency. Another study identified a 4-base deletion (c183_186delGAAT) in exon 2 of the GIF gene, causing premature termination of translation and absence of functional intrinsic factor.
Clinical Manifestations and Diagnosis
Symptoms and Presentation
Patients with intrinsic factor deficiency typically present with symptoms of severe megaloblastic anemia, growth retardation, and neurological dysfunction. These symptoms are due to the inability to absorb vitamin B12 (cobalamin) effectively, which is essential for red blood cell production and neurological function. The age of onset can vary significantly, with some cases being diagnosed in adulthood despite being congenital.
Diagnostic Approaches
Diagnosis of intrinsic factor deficiency involves several approaches. The Schilling test, which measures the absorption of vitamin B12, can indicate a failure to absorb cobalamin that is corrected by coadministration of intrinsic factor. Genetic testing to identify mutations in the GIF gene is also crucial for confirming the diagnosis. Additionally, the absence of intrinsic factor in gastric juice, despite normal acid secretion, is a key diagnostic indicator .
Treatment and Management
Vitamin B12 Supplementation
The primary treatment for intrinsic factor deficiency is the administration of vitamin B12. Patients typically respond well to intramuscular injections of cyanocobalamin, which can normalize hemoglobin levels and alleviate symptoms of anemia and neurological dysfunction .
Monitoring and Long-term Care
Long-term management involves regular monitoring of vitamin B12 levels and ongoing supplementation to prevent recurrence of symptoms. Genetic counseling may be recommended for affected families to understand the inheritance pattern and risks for future offspring .
Conclusion
Intrinsic factor deficiency, primarily caused by genetic mutations in the GIF gene, leads to severe cobalamin deficiency and megaloblastic anemia. Early diagnosis through genetic testing and appropriate treatment with vitamin B12 supplementation are essential for managing this condition and preventing long-term complications. Understanding the genetic basis and clinical manifestations of intrinsic factor deficiency can improve patient outcomes and guide future research in this area.
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