Early-Onset Hereditary Alzheimer’s Disease Caused by p.M139V Mutation in the PSEN1 Gene – a Case ReportAlzheimerova demence je nejčastější demence u pacientů ve starším věku. V některých rodinách může být geneticky podmíněna. Naše kazuistika ukazuje případ 43letého muže, v jehož rodině se vyskytlo dalších šest členů rodiny s manifestací demence ve věku 40–50 let. Genetickým vyšetřením byla u pacienta prokázána patogenní mutace c.415A>G (p.M139V) v exonu 5 genu PSEN1 v heterozygotním stavu. Stejná mutace byla zjištěna u demencí postiženého bratrance. V rodině tak byla potvrzena hereditární predispozice k časné formě Alzheimerovy demence s autozomálně dominantní dědičností na molekulární úrovni. Vývoj onemocnění byl u pacienta sledován po dobu osmi let. Postupně dochází k deterioraci kognitivních funkcí a vývoji atrofických změn mozku dle magnetické rezonance. Obdobné změny jsou pozorovány u jeho bratrance. Genetické vyšetřování v rodinách zasažených demencí může být do budoucna důležité především pro možnost včasné léčby pacientů v riziku.

Czech version

Authors: P. Bártová ¹; S. Walczysková ²; P. Plevová ²; L. Ratajová ³; J. Havelka ⁴; E. Šilhánová ²; P. Ressner ¹; D. Školoudík ^1,5
Authors‘ workplace: Neurologická klinika OU a FN Ostrava ¹; Oddělení lékařské genetiky, OU a FN Ostrava ²; Neurologická ambulance, Mladá Boleslav ³; Radiodiagnostické oddělení, OU a FN Ostrava ⁴; Neurologická klinika LF UP a FN Olomouc ⁵
Published in: Cesk Slov Neurol N 2011; 74/107(5): 569-574
Category: Case Report

Overview

Alzheimer’s disease is the most frequently diagnosed form of dementia in older patients. In some families, a tendency to this disorder may be inherited. This case report describes a 43-year-old man in the family of whom are six other members suffering from dementia, between the ages of 40 and 50 years. Molecular genetic analysis revealed a pathogenic c.415A>G (p.M139V) mutation in exon 5 of the PSEN1 gene in the heterozygous state. The same mutation was found in a cousin who has also suffered from dementia since the age of 45. Thus a hereditary predisposition to the early-onset form of Alzheimer’s disease was confirmed in this family at a molecular level. The patient was followed up for eight years. Gradual deterioration of cognitive functions and progression of brain atrophy was observed on MRI. Similar changes were observed in the cousin. Genetic testing in families suffering from dementia may be important in the future, together with the development of drugs capable of preventing the disease.

Key words:
Alzheimer’s dementia – hereditary disease – the PSEN1 gene – gene mutation

Sources

1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366(9503): 2112–2117.

2. Jirák R, Koukolík F. Demence. Praha: Galén 2002: 106–144.

3. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron 2010; 68(2): 270–281.

4. Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 2010; 23(4): 213–227.

5. Kowalska A. Genetics of dementias. Part 4: a spectrum of mutations responsible for the familial autosomal dominant form of Alzheimer’s disease. Postepy Hig Med Dosw 2009; 63: 583–591.

6. Vetrivel KS, Zhang YW, Xu H, Thinakaran G. Pathological and physiological functions of presenilins. Mol Neurodegener 2006; 1: 4.

7. Vetrivel KS, Thinakaran G. Membrane rafts in Alzheimer’s disease beta-amyloid production. Biochim Biophys Acta 2010; 1801(8): 860–867.

8. Jozwiak K, Zekanowski C, Filipek S. Linear patterns of Alzheimer’s disease mutations along α-helices of presenilins as a tool for PS-1 model construction. J Neurochem 2006; 98(5): 1560–1572.

9. Das HK. Transcriptional regulation of the presenilin-1 gene: implication in Alzheimer’s disease. Front Biosci 2008; 13: 822–832.

10. Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3): 189–198.

11. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6(8): 734–746.

12. Ressner P, Hort J, Rektorová I, Bartoš A, Rusina R, Línek V et al. Doporučené postupy pro diagnostiku Alzheimerovy nemoci a dalších nemocí spojených s demencí. Cesk Slov Neurol N 2008; 71/104(4): 494–501.

13. Finckh U, Müller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W et al. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 2000; 66(1): 110–117.

14. Mazura I, Koukolík F, Jirák R. Molecular genetic analysis of Alzheimer’s dementia in the Czech population. The APP-717 mutation in the gene for amyloid protein precursor. Cas Lek Cesk 1999; 138(3): 75–77.

15. Hüll M, Fiebich BL, Dykierek P, Schmidtke K, Nitzsche E, Orszagh M et al. Early-onset Alzheimer’s disease due to mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up of a patient with a mutation at codon 139. Eur Arch Psychiatry Clin Neurosci 1998; 248(3): 123–129.

16. Zekanowski C, Styczyńska M, Pepłońska B, Gabryelewicz T, Religa D, Ilkowski J et al. Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer’s disease in Poland. Exp Neurol 2003; 184(2): 991–996.

17. Fox NC, Kennedy AM, Harvey RJ, Lantos PL, Roques PK, Collinge J et al. Clinicopathological features of familial Alzheimer’s disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain 1997; 120(Pt 3): 491–501.

18. Rektorová I. Frontotemporální lobární degenerace – diagnosa z neuro-psychiatrického pomezí. Neurol pro praxi 2006; 4: 199–202.

19. Golan MP, Styczyńska M, Jóźwiak K, Walecki J, Maruszak A, Pniewski J et al. Early-onset Alzheimer’s disease with a de novo mutation in the presenilin 1 gene. Exp Neurol 2007; 208(2): 264–268.

20. Koukolík F, Jirák R. Alzheierova nemoc a další demence. Praha: Grada 1998: 89–90.

21. Hort J, O’Brien JT, Gainotti G, Pirttila T, Popescu BO, Rektorová I et al. EFNS Scientist Panel on Dementia. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. Eur J Neurol 2010; 17(10): 1236–1248.

22. Styczyńska M, Strosznajder JB, Religa D, Chodakowska-Zebrowska M, Pfeffer A, Gabryelewicz T et al. Association between genetic and environmental factors and the risk of Alzheimer’s disease. Folia Neuropathol 2008; 46(4): 249–254.

23. Hsiung GY, Sadovnick AD, Feldman H. Apolipoprotein E ε4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging. CMAJ 2004; 171(8): 863–867.

24. Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson: Genetics in Medicine. 6th ed. Philadelphia: WB Sounders Company 2001: 203–247.

25. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics. Oxford: Oxford University Press 2005: 296–297.

26. International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group of Huntington’s Chorea. Guidelines for the molecular genetics predictive test in Huntington’s disease. Neurology 1994; 44(8): 1533–1536.

27. Coustasse A, Pekar A, Sikula A, Lurie S. Ethical considerations of genetic presymptomatic testing for Huntington’s disease. J Hosp Mark Public Relations 2009; 19(2): 129–141.

28. Hort J, Rusina J. Paměť a její poruchy. Praha: Maxdorf 2007: 158–177.