Large family genetic analysis: effects of variegated porphyria and hemophilia b on reproductive traits
Introduction. The relevance of the study of genetic pathologies is due to the growing prevalence in most countries, disability and mortality of persons, high costs of support and treatment. The modern classifications include various forms of porphyria and hemophilia. The study of pathologies in historical persons, when it is possible to collect information from different sources regarding members of a large family over a long period of time, is of interest for understanding the mechanisms of the development of the disease at the present time. Aim is to analyze the genetic characteristics of variegated porphyria and hemophilia B in a large family. Materials and methods. Data from current guidelines and clinical protocols, scientific literature and genetic databases (OMIM) on various forms of porphyria and hemophilia are analyzed. Information about 1362 people from the British royal family in 18–20th centuries was collected from open sources and scientific literature. A pedigree of 10 generations, 27 nuclear families with persons with variegated porphyria and hemophilia B has been compiled. Genealogical, segregation, linkage, statistical analysis was performed. The results were used to study reproductive traits. Results. Genealogical analysis showed a family accumulation of porphyria – its prevalence among relatives in a large family was 1,8 %, which is three orders of magnitude higher than among the population of different countries. It was established that there is no statistically significant difference in the sex ratio among patients with the specified pathologies. Data from genealogical and segregation analysis and a penetration rate of 92 % suggest an autosomal dominant type inheritance with incomplete penetrance of disease which is consistent with the literature. The independent nature of inheritance of variegated porphyria and hemophilia B was established. It was found that in persons with porphyria reproductive traits are 3,3–4,1 times differ than the reproductive traits of persons with porphyria and hemophilia at the same time. A statistically significant difference was established between the analyzed traits of patients with porphyria, who at the same time are carriers of the mutation that causes hemophilia, and the indicators of healthy individuals.
Nakaz MOZ Ukrainy №641/84 vid 31.12.2003 Pro udoskonalennia medyko-henetychnoi dopomohy v Ukraini. 2003. Available from: https://zakon.rada.gov.ua/rada/show/va641282-03#Text
Budreviciute A, Damiati S, Sabir DK, Onder K, Schuller-Goetzburg P, Plakys G, et al. Management and Prevention Strategies for Non-communicable Diseases (NCDs) and Their Risk Factors. Front Public Health. 2020 Nov 26; 8: 574111. DOI: https://doi.org/10.3389/fpubh.2020.574111
Jackson M, Marks L, May GHW, Wilson JB. The genetic basis of disease. Essays Biochem. 2018 Dec 2; 62 (5): 643–723. DOI: https://doi.org/10.1042/EBC20170053. Erratum in: Essays Biochem. 2020 Oct 8; 64 (4): 681.
Nakaz MOZ Ukrainy № 778 vid 27.10.2014 Pro zatverdzhennia pereliku ridkisnykh (orfannykh) zakhvoriuvan. 2014. Available from: https://zakon.rada.gov.ua/laws/show/z1439–14#Text
Zakon Ukrainy vid 02.12.2021 Pro Derzhavnyi biudzhet Ukrainy na 2022 rik. 2022. Available from: https://zakon.rada.gov.ua/laws/show/1928–20#Text
Kirschner J, Cathomen T. Gene Therapy for Monogenic Inherited Disorders. Dtsch Arztebl Int. 2020 Dec 21; 117 (51–52): 878–885. DOI: https://doi.org/10.3238/arztebl.2020.0878.
Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, et al. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med. 2020 Jan 2; 382 (1): 29–40. DOI: https://doi.org/10.1056/NEJMoa1908490
Kothadia JP, LaFreniere K, Shah JM. Acute Hepatic Porphyria. 2022 May 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537178/
Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2019 Nov; 128 (3): 320–331. DOI: https://doi.org/10.1016/j.ymgme.2018.11.012
Gonzalez-Mosquera LF, Sonthalia S. Acute Intermittent Porphyria. StatPearls [Internet]. 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547665/
Macalpine I, Hunter R, Rimington C. Porphyria in the royal houses of Stuart, Hanover, and Prussia. A follow-up study of George 3d's illness. Br Med J. 1968 Jan 6; 1(5583):7-18. DOI: https://doi.org/10.1136/bmj.1.5583.7
Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov; 128 (3): 164–177. DOI: https://doi.org/10.1016/j.ymgme.2019.04.008
Usta Atmaca H, Akbas F. Porphyria cutanea tarda: a case report. J Med Case Rep. 2019 Jan 21; 13 (1): 17. DOI: https://doi.org/10.1186/s13256-018-1956-9
Bonkovsky, Herbert L et al. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Molecular genetics and metabolism. 2019 Nov; 128 (3): 213–218. DOI: https://doi.org/10.1016/j.ymgme.2019.03.002
Cuny JF. Porphyries cutanées [The cutaneous porphyrias]. Ann Dermatol Venereol. 2019 Feb; 146 (2): 143–159. French. DOI: https://doi.org/10.1016/j.annder.2018.12.005
Fedotov VP, Diudiun AD. Porfirii (klinichna lektsiia). Dermatovenerolohiia. Kosmetolohiia. Seksopatolohiia. HZ Dnipropetrovska medychna akademiia MOZ Ukrainy. 2011;1-4:132-150. Available from: https://repo.dma.dp.ua/2527/1/25_Fedot_33.pdf
Stölzel U, Doss MO, Schuppan D. Clinical Guide and Update on Porphyrias. Gastroenterology. 2019 Aug; 157 (2): 365–381.e4. DOI: https://doi.org/10.1053/j.gastro.2019.04.050
Nehrych TI, Yur MI, Khoma A I. ta in. Problemy diahnostyky ta likuvannia hostroi porfiriinoi polineiropatii Mizhnar. nevrol. zhurn. 2015: 8 (78): 73–76. Available from: http://www.mif-ua.com/archive/article/42067
Bonnin A, Picornell A, Orfila J, Castro JA, Ramon MM. Clinic and genetic evaluation of variegate porphyria (VP) in a large family from the Balearic Islands. J Inherit Metab Dis. 2009 Dec; 32 Suppl 1. DOI: https://doi.org/10.1007/s10545-009-1059-2
Ahmed jan N, Masood S. Erythropoietic Protoporphyria. StatPearls [Internet]. 2022 Oct. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563141
Shah A, Bhatt H. Cutanea Tarda Porphyria. StatPearls [Internet]. 2021 Sep. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563209/
Di Pierro E, De Canio M, Mercadante R. Laboratory Diagnosis of Porphyria. Diagnostics (Basel). 2021 Oct; 11(8):1343. Available from: https://www.frontiersin.org/articles/10.3389/fgene.2022.993453/full
Ramanujam VS, Anderson KE. Porphyria Diagnostics-Part 1: A Brief Overview of the Porphyrias. Curr Protoc Hum Genet. 2015 Jul 1; 86: 17.20.1–17.20.26. DOI: https://doi.org/10.1002/0471142905.hg1720s86
Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015 Sep 1; 8: 201–14. DOI: https://doi.org/10.2147/TACG.S48605
Hrechanina OI, Hrechanina YuB, Beletska SV, ta insh. Porfiriia: metod. nastan. z dystsypliny «Medychna henetyka» dlia pidhotovky likariv-interniv, studentiv 5 kursu, y likariv-kursantiv tsykliv pisliadyplomnoi osvity; Kharkiv, KhNMU; 2018. 28 p.
Singal AK, Anderson KE. Variegate Porphyria. GeneReviews. 2013 Feb. Available from: https://www.ncbi.nlm.nih.gov/books/NBK121283/
Doherty TM, Kelley A. Bleeding Disorders. StatPearls [Internet]. 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541050/
Castaman G, Matino D. Hemophilia A and B: molecular and clinical similarities and differences. Haematologica. 2019 Sep;104(9):1702-1709. DOI: https://doi.org/10.3324/haematol.2019.221093
Hemophilia. Situational analysis of problems in Ukraine. Quantitative research of the international research of the international research Agency IFAK Institute of Gmnh&Co; 2018. 20 p.
Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, et al. WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 Aug;26 Suppl 6: 1–158. DOI: https://doi.org/10.1111/hae.14046
Vydyborets, SV, Derpak YuYu, Popovych YuYu. Hemophilia. Family Medicine. 2018 Dec;6:61–66. DOI: https://doi.org/10.30841/2307-5112.6.2018.169142
OMIM #176200. [Internet]. [cited 2022 Оct 26]. Available from: https://www.omim.org/entry/176200
OMIM #306900. [Internet]. [cited 2022 Оct 26]. Available from: https://www.omim.org/entry/306900?search=306900&highlight=306900
Stein P, Badminton M, Barth J, Rees D, Stewart MF; British and Irish Porphyria Network. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013 May; 50 (3): 217-223. DOI: https://doi.org/10.1177/0004563212474555
Vogel and Motulsky's. Human Genetics: Problems and Approaches 4th ed. Springer; 2010. 1034 p.
Macalpine I, Hunter R. The 'insanity' of King George III: a classic case of porphyria. Brit. Med. J. 1966 Jan;1(5479):65–71. DOI: https://doi.org/10.1136/bmj.1.5479.65
Warren MJ, Jay M, Hunt DM, Elder GH, Rohl JCG. The maddening business of King George III and porphyria. Trends Biochem. 1996 Jun;21(6):229-234. DOI: https://doi.org/10.1016/S0968-0004(96)80022-3
Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler ELW, Moliaka YK. Genotype analysis identifies the cause of the 'Royal disease'. Science. 2009 Oct; 326 (5954): 817. DOI: https://doi.org/10.1126/science.1180660
Mager, Hugo. Elizabeth: Grand Duchess of Russia. Carroll and Graf Publishers; 1998. 45 p.
Elder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis. 2013 Sep;36(5):849-57. DOI: https://doi.org/10.1007/s10545-012-9544-4
OMIM #600923. [Internet]. [cited 2022 Оct 26]. Available from: https://www.omim.org/entry/600923?search=600923&highlight=600923
ОМІМ 613609. [Internet]. [cited 2022 Оct 26]. Available from: omim.org/entry/613609?search=613609&highlight=613609
Barton, James C et al. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene. 2015 Dec; 574(2): 179–192. DOI: https://doi.org/10.1016/j.gene.2015.10.009
Andersson C, Innala E, Bäckström T. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med. 2003 Aug;254(2):176–83. DOI: https://doi.org/10.1046/j.1365-2796.2003.01172.x
Vassiliou D, Sardh E. Acute hepatic porphyria and maternal health: Clinical and biochemical follow-up of 44 pregnancies. J Intern Med. 2022 Jan;291(1):81-94. DOI: https://doi.org/10.1111/joim.13376
Baumann K, Kauppinen R. Penetrance and predictive value of genetic screening in acute porphyria. Mol Genet Metab. 2020 May;130 (1): 87–99. DOI: https://doi.org/10.1016/j.ymgme.2020.02.003
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