H63D syndrome (in some countries called Oslo Syndrom) is a rare genetic disorder that is often the result of a homozygous mutation of the HFE mutation H63D. This mutation can cause or promote numerous syndromes, but Oslo syndrome is specific to this homozygous variant. Typically, there is excessive transferrin saturation based on a relative deficiency of transferrin, resulting in free iron of the NTBI (labile iron pool) type being released into certain tissues (especially parenchyma and brain) or other organs, where it can cause the most severe damage at the cellular level. In addition, in many Oslo syndrome patients, there is also a nonspecific activation of the inert immune system, which, in addition to the iron-related organ damage, leads to autoimmune reactions.[1][2][3][4][5][6][7][8]
Variants[edit]
- H63D Syndrome Type-1 (synonyme: Oslo Syndrom)
- H63D Syndrome Type-2
- H63D Syndrome Type-3 (synonyme: Oshtoran Syndrome)
The three subtypes of H63D syndrome differ considerably from each other, but share as their main overlap the fact that patients usually have a homozygous mutation of the HFE gene H63D and very specific clinical abnormalities in iron metabolism.
Symptoms of H63D Syndrome Type-1[edit]
Because it is a storage disease, the course is slow, insidious, and chronic. Usually, the first symptoms appear in childhood or adolescence, but are so nonspecific that they are usually followed up seriously at first. Often, organs at highest risk of NTBI accumulation (brain, heart, liver, testes, skin) are already severely structurally damaged when the diagnosis is made due to significant symptoms.
Brain damage[edit]
The damage to the brains (degeneration) caused by NTBI in the context of H63D syndrome result from oxidative stress within the affected and subsequently leads to cell death (scarring of brain tissue) with severely impaired neurotransmitter activity. These incurable processes include increased cellular iron, free radical activity, disruption of dopamine and glutamate balance in the brain, and abnormal levels of tau proteins and alpha-synuclein, both of which lead to dementia, Parkinson's disease or similar disorders. The substantia nigra and basal ganglia with all their functions are particularly susceptible.[9][10][11][12][13][14][15].
Iron deposition in the heart[edit]
Many patients with Oslo syndrome suffer from conduction abnormalities, cardiomyopathies, arrhythmias, and especially calcium channel disorders.[16][17]
Liver symptoms[edit]
A fatty liver (even at normal weight) as well as cryptic (nonspecific) liver dysfunction and a metabolic syndrome are also typical of Oslo syndrome.[3][18][19]
Skin and other organs[edit]
Because NTBI iron cannot be stained in biopsies, iron deposition in skin, liver, etc., is not histologically detectable. However, deposits sometimes visible to the naked eye occur, as do impetigo-like skin changes, blistering, itching, etc., this rarely in the tissues of the eye. In males, Oslo syndrome often results in slightly reduced testes, sometimes with degenerative changes. If there is already significant damage to the substantia nigra, H63D patients also experience symptoms similar to those of the non-motor signs of Parkinson's disease. These include loss of sense of smell, slowing or partial paralysis of gastrointestinal passage, cataplexies, narcolepsy, dementia, etc. Sensory disorders such as hearing loss and eye disease may also occur at times.
Immune system[edit]
For reasons that are as yet completely unexplained, the inert immune system is overactive in many Oslo syndrome patients, in the sense of passager autoaggressive dysfunctions, which present themselves by a "colorful" symptom picture, occur highly acutely, can be dangerous in some cases, and regress after a certain time. A tipping point mechanism can be assumed, which is still completely unexplored.
Diagnosis and treatment of H63D Syndrome Type-1[edit]
Based on current research, individuals with a homozygous HFE H63D mutation should be evaluated for syndromic symptoms affecting the brain, nervous system, heart, liver, and, to a lesser extent, kidney function, skin disease, hemopoiesis, and other vulnerable organ systems. Signposts include too low transferrin value with much too high saturation and low ferritin.[20] No causative treatment is currently (as of 2019) available, as non-protein bound free iron (NTBI) cannot be removed from cells by phlebotomy or similar procedures. Thus, at best, some of the symptoms can be alleviated in the case of disease. Dietary control of iron intake in the case of a homozygous H63D mutation should only be done under the supervision of a medical nutritional counselor, as an overload of non-protein-bound iron (NTBI) in the body, such as due to hypotransferrinemia, may coexist with a deficiency of ferritin.[21][22][23]
Cure rate[edit]
As of 2022, Oslo syndrome is incurable. The various symptoms must each be treated by experienced specialists so that a patient with H63D syndrome does not suffer too much. In addition, a medically supervised reduction of iron intake is to be aimed at in order to slow down the progression somewhat, if necessary. To date, no studies exist on the effectiveness of this therapeutic approach.
Web links[edit]
- Brain damage caused by a homozygous H63D mutation
- Short scientific summery
- Independent Research group’s non-profit website
- H63D on SoundCloud (Podcasts)
Literature[edit]
- Wint Nandar, James R. Connor: HFE Gene Variants Affect Iron in the Brain. The Journal of Nutrition, Volume 141, Issue 4, April 2011, 729S-739S.
- P. Adams, P. Brissot, L. W. Powell: EASL International Consensus Conference on Haemochromatosis. Journal of Hepatology 2000;33:485-504.
- K. Bridle, T. K. Cheung, T. Murphy, M. Walters, G. Anderson, D. G. Crawford, L. M. Fletcher: Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res 2006;30:106-112.
- Anastasios Papadopoulos et al.: H63D Syndrome renamed Oslo Syndrome. Zenodo Publishing Geneva, 2022
Individual references[edit]
- ↑ Castiella, Urreta, Zapata et al: H63/H63D genotype and the H63D allele are associated in patients with hyperferritinemia to the development of metabolic syndrome. Eur J Intern Med. 2019 Nov 30. doi:10.1016/j.ejim.2019.11.021.
- ↑ Ellervik C, Tybjaerg-Hansen A, Appleyard M, Sillesen H, Boysen G, Nordestgaard BG. Hereditary hemochromatosis genotypes and risk of ischemic stroke. Neurology. 2007;68:1025-1031.
- ↑ 3.0 3.1 Raszeja-Wyszomirska J, Kurzawski G, Zawada I, Suchy J, Lubinski J, Milkiewicz P.: HFE gene mutations in patients with alcoholic liver disease. A prospective study from northwestern Poland. Pol Arch Med Wewn. 2010, 120(4):127-131; PMID 20424537.
- ↑ Valenti L, Fracanzani AL, Bugianesi E, Dongiovanni P, Galmozzi E, Vanni E, Canavesi E, Lattuada E, Roviaro G, Marches G, Fargion S.: HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2010 Mar;138(3):905-912.
- ↑ Fujii H, Takagaki N, Yoh T, Morita A, Ohkawara T, Yamaguchi K, Minami M, Sawa Y, Okanoue T, Ohkawara Y, Itoh Y: Non-prescription supplement-induced hepatitis with hyperferritinemia and mutation (H63D) in the HFE gene. Hepatol Res. 2008 Mar;38(3):319-323.
- ↑ Mitchell RM, Lee SY, Simmons Z, Connor JR: HFE polymorphisms affect cellular glutamate regulation. Neurobiol Aging. 2009.
- ↑ Iron Disorders Institute nanograms: H63D - The Other Mutation, April 2010.
- ↑ Yiting Liu, Sang Y. Lee, James R. Connor, et al: Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability. J Biol Chem. 2011 Apr 15; 286(15): 13161-13170. doi:10.1074/jbc.M110.170944.
- ↑ Bartzokis G, Lu PH, Tishler TA, Peters DG, Kosenko A, Barrall KA, Finn JP, Villablanca P, Laub G, Altshuler LL, Geschwind DH, Mintz J, Neely E, Connor JR: Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men. J Alzheimers Dis. 2010 Apr;20(1):333-341.
- ↑ Hall EC, Lee SY, Simmons Z, Neely EB, Nandar W, Connor JR: Prolylpeptidyl isomerase, Pin 1 phosphorylation is compromised in association with the expression of the HFE polymorphic allele, H63D. Biochim Biophys Acta. 2010 Apr;1802(4):389-395.
- ↑ Wint Nandar, James R. Connor: HFE Gene Variants Affect Iron in the Brain. The Journal of Nutrition, Volume 141, Issue 4, April 2011, 729S-739S, doi:10.3945/jn.110.130351.
- ↑ Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, 120. Morgadinho AS, Ribeiro MH, Hardy J, Singleton A, et al: Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort. BMC Neurol. 2006;6:24.
- ↑ Dekker MC, Giesbergen PC, Njajou OT, van Swieten JC, Hofman A, 127 Breteler MM, van Duijn CM. Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism. Neurosci Lett. 2003;348:117-119.
- ↑ Borie C, Gasparini F, Verpillat P, Bonnet AM, Agid Y, Hetet G, Brice A, Durr A, Grandchamp B.: Association study between iron-related genes polymorphisms and Parkinson's disease. J Neurol. 2002; 249: 801-804.
- ↑ Akbas N, Hochstrasser H, Deplazes J, Tomiuk J, Bauer P, Walter U, Behnke S, Riess O, Berg D.: Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra. Neurosci Lett. 2006;407:16-19.
- ↑ P. C. Adams, J. S. Pankow, J. C. Barton, R. T. Acton, C. Leiendecker-Foster, G. D. McLaren, M. Speechley, J. H. Eckfeldt: The hemochromatosis and iron overload screening study. Circ Cardiovasc Genet. 2009 Feb;2(1):34–37.
- ↑ M. Franchini, Hereditary iron overload. Update on pathophysiology, diagnosis and treatment. American Journal of Hematology. 2006.
- ↑ Jin F, Qu LS, Shen XZ: Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. J Exp Clin Cancer Res. 2010 Mar 2;29:18.
- ↑ Machado MV, Ravasco P, Martins A, Almeida MR, Camilo ME, Cortez-Pinto H: Iron homeostasis and H63D mutations in alcoholics with and without liver disease. World J Gastroenterol. 2009 Jan 7;15(1):106-111.
- ↑ Steven M. LeVine, James R. Connor, Hyman M. Schipper: Redoxactive Metals in Neurological Disorders. New York Academy of Sciences, 2004.
- ↑ James F. Collins: Molecular, Genetic, Nutritional Aspects of Major and Trace Minerals. Academic Press, London 2017.
- ↑ Sareen S. Gropper, Jack L. Smith, Timothy P. Carr: Advanced Nutrition and Human Metabolism. Cengage Learning, 7th edition, Boston 2016.
- ↑ L. C. Pilling, J. Tamosauskaite, G. Jones et al: Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. British Medical Journal|BMJ. 2019 Jan 16;364:k5222.
