Biology:HFE H63D gene mutation

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HFE

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]

General 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.[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

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]

Pathomechanism

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.

H63D syndrome symptoms

  • Variable motor dysfunction, possibly including Parkinson's symptoms late in the course.
  • Postural instability analogous to Parkinson's disease.
  • Narcolepsy, often with cataplexy - when manifestation of degenerative and irreversible brain damage has already occurred.
  • Cognitive dysfunction: Often highly severe and usually primarily obsessive in nature, compatible with dysfunction of the basal ganglia. They are often misrecognized - especially in the early phase of the disease - in the sense of a misdiagnosis as "mental suffering". If thought disorders are in the foreground, a timely diagnosis is therefore often delayed.
  • Tic disorders: variable Tourette's-like tics occurring with a strongly fluctuating course.
  • Hyperkinesias, sometimes with self-injuries.
  • Disturbance of REM sleep with risk of self-injury.
  • Dementia of varying severity from mild cognitive impairment to full-blown dementia, most compatible with Lewy body dementia. Clinically relevant changes occur in 30% to 60% of H63D patients, depending on the study. Variability is due to nonstandardized measurement procedures and cut-off values, especially in mild cognitive impairment.
  • Cognitive impairments: This aspect is often masked by performance reserves over time (months to years), especially in previously cognitively strong patients, but can lead to significant failures in daily and occupational functioning under high sensory and complex content input.
  • Decline in intelligence quotients despite preserved selective performance in areas that can be relatively well delineated diagnostically.
  • Impairment of executive functions with preserved long-term memory. The occurrence or worsening of narcolepsy with a decrease in tic symptomatology is indicative of progressive damage to brain tissue, mainly in the region of the substantia nigra.
  • Cardiac damage and dysfunction, especially conduction defects and arrhythmias, occasionally progressing to heart failure
  • Liver damage (even early in the course, often an unexplained steatosis).
  • Excessive episodes of the inert part of the immune system with highly variable autoimmune reactions, including periods of decreased defense of the adaptive immune system.
  • Fibrosis in various organ systems, including the skin.
  • Impaired motility in the digestive system, usually constipation, less commonly bloating.
  • Testicular atrophy, erectile dysfunction and degeneration of penile tissue degeneration (shrinking of the shaft) in male patients, sometimes with unspecific degenerative signs on sonography like calcifications.
  • Skin symptoms of variable nature (including impetigo, pruritus, hyper-responsiveness, hidradenitis suppurativa, etc.).
  • Rarely: kidney involvement, eye diseases due to NTBI-induced oxidative processes, hearing loss, etc.
  • Rather later in the course, with already structurally altered substantia nigra: urge incontinence in all its manifestations.
  • Chronic eosinophilia with possible structural damage to the heart.[27]
  • Disorders of adrenal and other endocrine organ function due to oxidative-related inflammatory processes with functional or structural organ damage caused by infiltration processes in the adrenal cortex region. (primary adrenal insufficiency).[28][29] Subsequently, there is clinically relevant dysfunction of the HPA axis as well as adrenaline synthesis in the adrenal medulla with erratic adrenaline excesses.[30] Due to the variety of symptoms, the syndrome is usually diagnosed relatively late, especially if all relevant parameters of iron metabolisms are not obtained by laboratory diagnosis.

Laboratory

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.

Imaging

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.

Pathohistology

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.

Therapies

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]

Impact on athletic performance in healthy individuals

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]

References

  1. ↑ "Hereditary hemochromatosis in the post-HFE era". Hepatology 48 (3): 991–1001. September 2008. doi:10.1002/hep.22507. PMID 18752323. 
  2. ↑ "Hemochromatosis: Causes". Mayo Foundation for Medical Education and Research (MFMER). http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=3. 
  3. ↑ "HGVS Recommendations for the Description of Sequence Variants: 2016 Update". Human Mutation 37 (6): 564–9. June 2016. doi:10.1002/humu.22981. PMID 26931183. 
  4. ↑ "Non-prescription supplement-induced hepatitis with hyperferritinemia and mutation (H63D) in the HFE gene". Hepatology Research 38 (3): 319–23. 2008. doi:10.1111/j.1872-034X.2007.00266.x. PMID 17944940. 
  5. ↑ "H63/H63D genotype and the H63D allele are associated in patients with hyperferritinemia to the development of metabolic syndrome". Eur. J. Intern. Med. 72: 106–107. 2019. doi:10.1016/j.ejim.2019.11.021. PMID 31796245. 
  6. ↑ 6.0 6.1 "HFE gene mutations in patients with alcoholic liver disease. A prospective study from northwestern Poland". Polish Archives of Internal Medicine 120 (4): 127–31. 2010. doi:10.20452/pamw.905. PMID 20424537. 
  7. ↑ "HFE Genotype, Parenchymal Iron Accumulation, and Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease". Gastroenterology 138 (3): 905–12. 2010. doi:10.1053/j.gastro.2009.11.013. PMID 19931264. 
  8. ↑ "Hereditary hemochromatosis genotypes and risk of ischemic stroke". Neurology 68 (13): 1025–31. 2007. doi:10.1212/01.wnl.0000257814.77115.d6. PMID 17389307. 
  9. ↑ "Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability". J. Biol. Chem. 286 (15): 13161–70. 2011. doi:10.1074/jbc.M110.170944. PMID 21349849. 
  10. ↑ "HFE polymorphisms affect cellular glutamate regulation". Neurobiol. Aging 32 (6): 1114–23. 2011. doi:10.1016/j.neurobiolaging.2009.05.016. PMID 19560233. 
  11. ↑ "H63D - The Other Mutation". 2010. http://www.irondisorders.org/Websites/idi/files/Content/854268/ST%20H63D%20APR%202010.pdf. 
  12. ↑ "HFE Gene Variants Affect Iron in the Brain". J. Nutr. 141 (4): 729S–739S. 2011. doi:10.3945/jn.110.130351. PMID 21346098. 
  13. ↑ "Prolyl-peptidyl isomerase, Pin1, phosphorylation is compromised in association with the expression of the HFE polymorphic allele, H63D". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1802 (4): 389–95. 2010. doi:10.1016/j.bbadis.2010.01.004. PMID 20060900. https://hal.archives-ouvertes.fr/hal-00566735/file/PEER_stage2_10.1016%252Fj.bbadis.2010.01.004.pdf. 
  14. ↑ "Prevalent Iron Metabolism Gene Variants Associated with Increased Brain Ferritin Iron in Healthy Older Men". J. Alzheimer's Dis. 20 (1): 333–41. 2010. doi:10.3233/JAD-2010-1368. PMID 20164577. 
  15. ↑ "Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort". BMC Neurology 6 (24): 24. 2006. doi:10.1186/1471-2377-6-24. PMID 16824219. 
  16. ↑ "Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism". Neurosci. Lett. 348 (2): 117–9. 2003. doi:10.1016/S0304-3940(03)00713-4. PMID 12902032. 
  17. ↑ "Association study between iron-related genes polymorphisms and Parkinson's disease". J. Neurol. 249 (7): 801–4. 2002. doi:10.1007/s00415-002-0704-6. PMID 12140659. 
  18. ↑ "Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra". Neurosci. Lett. 407 (1): 16–9. 2006. doi:10.1016/j.neulet.2006.07.070. PMID 16935420. 
  19. ↑ "H63D CG genotype of HFE is associated with increased risk of sporadic amyotrophic lateral sclerosis in a single population". Journal of Integrative Neuroscience 19 (3): 495–499. September 2020. doi:10.31083/j.jin.2020.03.131. PMID 33070529. 
  20. ↑ "HFE C282Y Homozygosity Is Associated With Lower Total and Low-Density Lipoprotein Cholesterol: The Hemochromatosis and Iron Overload Screening Study". Circ. Cardiovasc. Genet. 2 (1): 34–7. 2009. doi:10.1161/CIRCGENETICS.108.813089. PMID 20031565. 
  21. ↑ "Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment". Am. J. Hematol. 81 (3): 202–9. 2006. doi:10.1002/ajh.20493. PMID 16493621. 
  22. ↑ "Impact of H63D mutations, magnetic resonance and metabolic syndrome among outpatient referrals for elevated serum ferritin in the Basque Country". Annals of Hepatology 14 (3): 333–9. 2015. doi:10.1016/S1665-2681(19)31272-4. PMID 25864213. 
  23. ↑ "Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis". J. Exp. Clin. Cancer Res. 29 (1): 18. 2010. doi:10.1186/1756-9966-29-18. PMID 20196837. 
  24. ↑ "Iron homeostasis and H63D mutations in alcoholics with and without liver disease". World Journal of Gastroenterology 15 (1): 106–11. 2009. doi:10.3748/wjg.15.106. PMID 19115475. 
  25. ↑ Kelley et al Iron overload is rare in patients homozygous for the H63D mutation Can J Gastroenterol Hepatol 2014
  26. ↑ Preprint: Incidence of a clinically relevant H63D syndrome in carriers of a homozygous mutation of HFE gene H63D, accessed 09/05/2022
  27. ↑ Séguéla et al Eosinophilic cardiac disease: Molecular, clinical and imaging aspects Arch Cardiovasc Dis 2015
  28. ↑ Banaszkiewicz et al. Endocrine disorders in patients with hereditary hemochromatosis European Journal of Translational and Clinical Medicine, 2018
  29. ↑ Charmandari et al. Adrenal insufficiency The Lancet 2014
  30. ↑ Lazar, M., Seideman D., Schuster G., Diamandis, C. (2022). Endocrinology: Patients suffering from H63D syndrome are at high risk to develop clinically relevant endocrine abnormalities affecting their adrenal glands as well as their HPA and SAM axes. https://doi.org/10.5281/zenodo.7269988
  31. ↑ [Wirkstoff aktuell - Eine Information der KBV im Rahmen des § 73 (8) SBG V in Zusammenarbeit mit der Arzneimittelkommission der Deutschen Ärzteschaft: Deferasirox (Exjade)], Ausgabe 5-2008 (in German]p)
  32. ↑ Seideman et al. Preprint: Injury protection strategies for H63D syndrome patients suffering from cataplexy 2021
  33. ↑ "The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis". European Journal of Applied Physiology 120 (3): 665–673. March 2020. doi:10.1007/s00421-020-04306-8. PMID 31970519. 

External sources



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