Huntington hastalığı tanısı almış hastalarda ve ailelerinde CAG trinükleotid tekrar sayılarının fragman analizi ile tespiti

Yıl 2019, Cilt: 44 Sayı: 2, 517 - 523, 30.06.2019

Davut Alptekin Perçin Pazarcı Mehmet Ali Bereketoğlu Mehmet Ali Erkoç Nermin Seda Ilgaz Ümit Lüleyap

https://doi.org/10.17826/cumj.461390

Öz

Amaç: Huntington Hastalığı (HD), sinir sistemini etkileyen otozomal dominant bir hastalıktır. Huntingtin genindeki CAG trinükleotit tekrarı (TNR) artışı hastalığa neden olur. Normal bireylerde 10-35 TNR bulunurken HD'de bu sayı 36-37'yi aşmaktadır. Bu çalışmada, HD tanılı ailede TNR sayılarının araştırılması ve anormal alleli olan bireyler için genetik danışmanlık yapılması amaçlanmıştır.

Gereç ve Yöntem: Örnekler, HD nedeniyle 60 yaşında ölen bir erkeğin aile üyelerinden oluşmaktadır. Rastgele seçilen 57 sağlıklı birey de kontrol için analiz edilmiştir. TNR sayıları fragman analizi ile belirlenmiştir.

Bulgular: Aile bireylerinin TNR sayıları 17, 21, 23, 25, 33, 36 ve 39 olarak belirlendi. Rastgele seçilmiş sağlıklı kişilerin TNR sayıları 26'nın altında bulundu. 33 ve 36 TNR'li bireyler risk grubu olarak kabul edildi. 39 TNR'li bireyler HD’ye sahip olarak kabul edildi.

Sonuç: Bazı deneklerin 39 TNR'si olduğundan, bu kişilerin hekim kontrolünde olması gerektiği vurgulanmıştır. Çocuk sahibi olmayı planlayanlara prenatal tanı önerilmektedir. Ek olarak, 33 ve 36 CAG trinükleotid tekrarı olan deneklerin, HD ile ilgili yeni nesilleri bilgilendirmeleri ve gelecekte kendilerinin de etkilenebilecekleri bildirilmektedir.

Anahtar Kelimeler

Huntington hastalığı, Huntingtin geni, Nörodejeneratif hastalıklar, Trinükleotid tekrarları

Detection of CAG trinucleotide repeat numbers with fragment analysis in patients diagnosed with Huntington’s disease and in their families

Öz

Purpose: Huntington's Disease (HD) is an autosomal dominant disorder affecting nervous system. CAG trinucleotide repeat (TNR) increase in Huntingtin gene causes the disease. In normal individuals, 10-35 TNRs are found whereas in HD this number exceeds 36-37. This study aimed to investigate TNR numbers in individuals with HD diagnosed family and to provide genetic counselling for individuals with abnormal alleles.

Materials and Methods: Subjects consist of family members of a male who died at age of 60 due to HD. Randomly selected 57 healthy individuals are also analysed for control. TNR numbers were determined by fragment analysis.

Results: TNR numbers of family members were determined as 17, 21, 23, 25, 33, 36 and 39. TNR numbers of randomly selected healthy people were found below 26. Individuals with 33 and 36 TNRs were considered as risk groups. Individuals with 39 TNRs were considered as HD patients.

Conclusion: Since some subjects had 39 TNRs, it was emphasized that these people should be under physician control. Prenatal diagnosis is recommended to those who plan to have children. In addition, subjects with 33 and 36 CAG trinucleotide repeats are advised to inform new generations about HD and that they may be affected in future.

Anahtar Kelimeler

Huntington's disease, Huntingtin gene, Neurodegenerative diseases, Trinucleotide Repeats

Kaynakça

• 1. Rosenberg NK, Sorensen SA, Christensen AL. Neuropsychological characteristics of Huntington's disease carriers: a double blind study. J Med Genet. 1995; 32:600-4.
• 2. Lanska DJ. George Huntington (1850-1916) and hereditary chorea. J Hist Neurosci. 2000; 9:76-89.
• 3. Walker FO. Huntington's disease. Lancet. 2007; 369:218-28.
• 4. Dayalu P, Albin RL. Huntington Disease. Neurol Clin. 2015; 33:101-14.
• 5. Wallace DC, Hall AC. Evidence of genetic heterogeneity in Huntington's chorea. J Neurol Neurosurg Psychiatry. 1972; 35:789-800.
• 6. Nance MA, Myers RH. Juvenile onset Huntington's disease?clinical and research perspectives. Mental Retardation and Developmental Disabilities Research Reviews. 2001; 7:153-7.
• 7. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983; 306:234-8.
• 8. Macdonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Srinidhi L et al. A Novel Gene Containing a Trinucleotide Repeat That Is Expanded and Unstable on Huntingtons-Disease Chromosomes. Cell. 1993; 72:971-83.
• 9. Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993; 4:387-92.
• 10. Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993; 4:393-7.
• 11. Legius E, Cuppens H, Dierick H, Van Zandt K, Dom R, Fryns J-P et al. Limited Expansion of the (CAG)n Repeat of the Huntington Gene: A Premutation (?). Europ J Hum Genet. 1994; 2:44-50.
• 12. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996; 59:16-22.
• 13. McNeil SM, Novelletto A, Srinidhi J, Barnes G, Kornbluth I, Altherr MR et al. Reduced Penetrance of the Huntington's Disease Mutation. Hum Mol Genet. 1997; 6:775-9.
• 14. Milunsky JM, Maher TA, Loose BA, Darras BT, Ito M. XL PCR for the detection of large trinucleotide expansions in juvenile Huntington's disease. Clin Genet. 2003; 64:70-3.
• 15. Nahhas FA, Garbern J, Krajewski KM, Roa BB, Feldman GL. Juvenile onset Huntington disease resulting from a very large maternal expansion. Am J Med Genet A. 2005; 137A:328-31.
• 16. Yoon G, Kramer J, Zanko A, Guzijan M, Lin S, Foster-Barber A et al. Speech and language delay are early manifestations of juvenile-onset Huntington disease. Neurology. 2006; 67:1265-7.
• 17. Nance MA, Seltzer W, Ashizawa T, Bennett R, McIntosh N, Myers RH et al. Laboratory Guidelines for Huntington Disease Genetic Testing. The American Journal of Human Genetics. 1998; 62:1243-7.
• 18. Potter NT, Spector EB, Prior TW. Technical Standards and Guidelines for Huntington Disease Testing. Genet Med. 2004; 6:61-5.
• 19. Semaka A, Creighton S, Warby S, Hayden MR. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clin Genet. 2006; 70:283-94.
• 20. Quarrell OW, Tyler A, Cole G, Harper PS. The problem of isolated cases of Huntington's disease in South Wales 1974-1984. Clin Genet. 1986; 30:433-9.
• 21. Shiwach R. Psychopathology in Huntington's disease patients. Acta Psychiatr Scand. 1994; 90:241-6.
• 22. Sakazume S, Yoshinari S, Oguma E, Utsuno E, Ishii T, Narumi Y et al. A patient with early onset Huntington disease and severe cerebellar atrophy. Am J Med Genet A. 2009; 149A:598-601.
• 23. Barbeau A. PARENTAL ASCENT IN THE JUVENILE FORM OF HUNTINGTON'S CHOREA. The Lancet. 1970; 296:937.
• 24. van Dijk JG, van der Velde EA, Roos RAC, Bruyn GW. Juvenile Huntington disease. Hum Genet. 1986; 73:235-9.
• 25. Ridley RM, Frith CD, Crow TJ, Conneally PM. Anticipation in Huntington's disease is inherited through the male line but may originate in the female. J Med Genet. 1988; 25:589-95.
• 26. Went LN, Vegter-van der Vlis M, Bruyn GW. PARENTAL TRANSMISSION IN HUNTINGTON'S DISEASE. The Lancet. 1984; 323:1100-2.
• 27. Akbas F, Erginel-Unaltuna N. DNA testing for Huntington disease in the Turkish population. Eur Neurol. 2003; 50:20-4.
• 28. Atac FB, Elibol B, Schaefer F. The genetic analysis of Turkish patients with Huntington's disease. Acta Neurol Scand. 1999; 100:195-8.
• 29. Georgiou N, Bradshaw JL, Chiu E, Tudor A, O'Gorman L, Phillips JG. Differential clinical and motor control function in a pair of monozygotic twins with Huntington's disease. Mov Disord. 1999; 14:320-5.
• 30. Friedman JH, Trieschmann ME, Myers RH, Fernandez HH. Monozygotic Twins Discordant for Huntington Disease After 7 Years. Arch Neurol. 2005; 62.
• 31. Panas M, Karadima G, Markianos M, Kalfakis N, Vassilopoulos D. Phenotypic discordance in a pair of monozygotic twins with Huntington’s disease. Clin Genet. 2008; 74:291-2.
• 32. Bouchghoul H, Clément S-F, Vauthier D, Cazeneuve C, Noel S, Dommergues M et al. Prenatal testing in Huntington disease: after the test, choices recommence. Europ J Hum Genet. 2016; 24:1535-40.
• 33. Blancato JK, Wolfe E, Sacks PC. Preimplantation genetics and other reproductive options in Huntington disease. Huntington Disease: Elsevier; 2017. p. 107-11.
• 34. Gacy AM, Goellner G, Juranic N, Macura S, McMurray CT. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell. 1995; 81:533-40.
• 35. Khan N, Kolimi N, Rathinavelan T. Twisting Right to Left: A…A Mismatch in a CAG Trinucleotide Repeat Overexpansion Provokes Left-Handed Z-DNA Conformation. PLoS Comp Biol. 2015; 11:e1004162.
• 36. Lee JK, Conrad A, Epping E, Mathews K, Magnotta V, Dawson JD et al. Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence. EBioMedicine. 2018.