The HFE H63D is a single-nucleotide polymorphism in the HFE gene (c.187C>G, rs1799945), which results in the substitution of a histidine for an aspartic acid at amino acid position 63 of the HFE protein (p.His63Asp). HFE participates in the regulation of iron absorption.[1][2][3]
Homozygous H63D variant can occasionally be the cause of hemochromatosis. It is also associated with the occurrence of other conditions like hypotransferrinemia,[4][5] liver dysfunction,[6][7] bone and joint issues, diabetes mellitus, heart disease, hormone imbalances, porphyria cutanea tarda (PCT), infertility, stroke,[8] neurodegenerative and brain damages,[9] some cancers, venous and peripheral artery disease.[10][11]
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.[12][13] Another potential consequence is abnormal levels of tau proteins and alpha-synuclein, which play a role in conditions like Alzheimer's,[14] Lewy body dementia, and Parkinson’s;[15][16][17][18] 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.[citation needed] A study in 2020 predicted that the H63D variant may be a risk factor for incidental amyotrophic lateral sclerosis in a Han Chinese population.[19] Some individuals with the homozygous H63D variant may show signs of heart disease, cardiomyopathies, and disturbances in the calcium channels in particular.[20][21] The homozygous H63D variant is an indicator of the iron metabolism disorder hemochromatosis, which may increase the risk of developing a fatty liver.[22] In patients with a cirrhotic liver, the mutation can increase the rate of liver cancer.[6][23][24]
H63D syndrome is a very rare clinical phenotype based on a homozygous mutation of the HFE gene. This mutation is associated with diverse health issues, however H63D syndrome is the only known specific expression of a homozygous HFE-H63D mutation to date. The homozygous HFE-H63D mutation is the cause of classic and treatable hemochromatosis in only 6.7% of its carriers.[25] H63D syndrome is independently a distinct entity, and the incidence in homozygous carriers of the H63D mutation is approximately 10%.[26]
Typically, laboratory tests show an excessive and static transferrin saturation based on a relative deficiency of transferrin. The transferrin value is pre- and postprandial static low. Thus, the body does not respond to nutritive iron supplementation by providing more transferrin. This allows free iron of non-transferrin bound type (NTBI, labile iron pool) can enter various parenchymal tissues and trigger degenerative changes there by oxidation cascades. Iron overload primarily affects nerve cells in the substantia nigra and basal ganglia. Here, a slowly progressive degeneration occurs. In addition, many H63D syndrome patients experience nonspecific activation of the inert immune systems, which can additionally lead to spontaneously occurring, passive autoimmune reactions of variable type and severity.
The typical constellation of findings is indicative: The patients show a postprandial non-responsive and too low and static transferrin level (hypotransferrinemia) with high transferrin saturation (usually > 55 %) and low ferritin value. Multiple tests are obligatory due to physiologically induced fluctuations. Mild persistent eosinophilia and basophilia are sometimes found in parallel.
On transcranial sonography, the substantia nigra presents as in Parkinson's disease hyperechogenic, but the symptoms need not be identical. With rare exceptions, MRI remains unremarkable. The scintigraphy (DAT scan) may also be abnormal. Due to radiation exposure and advances in the field of sonography, DAT scans are now mostly used only in the context of clinical trials for this condition.
There is deposition of free iron in the brain and other tissues. NTBI iron cannot be stained in histology (e.g., with the (Berlin Blue staining). This is a common source of error or reason for false-negatives.
No causal treatment for H63D syndrome is currently (2023) available. Free iron not bound to proteins cannot be removed from the body by phlebotomy and related procedures. Instead, the patient would merely suffer a further drop in his already usually low ferritin level. Consequently, dialysis and iron chelators are also ineffective and are more likely to provoke lethals side effects than to improve the clinical picture.[31] Various drugs can be used to alleviate some symptoms - some in off-label use. In addition, medical assistive devices such as orthotics, hard hats, walkers, or wheelchairs are useful.[32]
A 2020 study revealed that the homozygous H63D variant (as well as the heterozygous one) is significantly higher in elite endurance athletes comparing to ethnically-matched controls in Russian and Japanese populations, and is associated with high V̇O2max in male athletes.[33]