The HFE H63D is a single-nucleotide polymorphism in the HFE gene (c.187C>G, rs1799945), which results  the substitution of  aspartic acid for  histidine at amino acid position 63 of the HPE protein (p.His63Asp). The protein participates in the regulation of iron absorption. Homozygous H63D variant is rarely the cause of hemochromatosis , however it is also associated with the occurrence of other conditions like hypotransferrinemia, liver dysfunction, bone and joint issues, diabetes mellitus, heart disease, hormone imbalances, porphyria cutanea tarda (PCT), infertility, stroke, neurodegenerative and brain damages, some cancers, venous and peripheral artery disease. Brain iron accumulation The most relevant risk associated with the H63D variant is for brain damagedue to iron accumulation which causes oxidation processes within the affected cells(chronic oxidative stress) and, as a consequence, leading to cell death (scarring of brain tissue) with severely disturbed neurotransmitter activity. These incurable processes include increased cellular iron, oxidative stress (free radical activity), brain glutamate dysbalance, and abnormal levels of tau proteins and alpha-synuclein which both may result in dementias and parkinson ’s disease, or similar conditions. Scientists found that patients homozygous for  H63D  show a higher risk of earlier signs of cognitive impairment and earlier onset of dementias compared to individuals with normal HFE genes or H63D heterozygous mutation . Cardiac iron accumulation Some individuals with the homozygous H63D variant may show signs of heart disease, cardiomyopathies  and disturbances in the calcium channels in particular. Liver disorders The homozygous H63D variant is an indication of an Iron Metabolism Disorder known as Hemochromatosis (Iron Overload) and may increase the risk to develop a fatty liver , cryptic (nonspecific) liver dysfunctions, metabolic syndrome and, in patients with a cirrhotic or a liverdamaged due to alcohol also the rates of liver cancer.
The HFE H63D is a single-nucleotide polymorphism in the HFE gene (c.187C>G, rs1799945), which results in the substitution of an aspartic acid for a histidine at amino acid position 63 of the HPE protein (p.His63Asp). HFE participates in the regulation of iron absorption. Homozygous H63D variant can occasionally be the cause of hemochromatosis . It is also associated with the occurrence of other conditions like hypotransferrinemia, liver dysfunction, bone and joint issues, diabetes mellitus, heart disease, hormone imbalances, porphyria cutanea tarda (PCT), infertility, stroke, neurodegenerative and brain damages, some cancers, venous and peripheral artery disease. Health impacts The primary risk associated with the H63D mutation is brain damage, as iron accumulation can cause oxidation within affected cells, ultimately leading to cell death and scarring of the brain tissue. Another potential consequence is abnormal levels of tau proteins and alpha-synuclein , which play a role in conditions like Alzheimer's, Lewy body dementia, and Parkinson ’s ; patients homozygous for the H63D mutation show a higher risk of earlier signs of cognitive impairment and earlier onset of dementias compared to individuals with normal or heterozygous genotypes . Some individuals with the homozygous H63D variant may show signs of heart disease, cardiomyopathies , and disturbances in the calcium channels in particular. The homozygous H63D variant is an indicator of the iron metabolism disorder hemochromatosis, which may increase the risk of developing a fatty liver . In patients with a cirrhotic liver, the mutation can increase the rate of liver cancer.
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