CUMHUR GÜNDÜZ, Özgür ÇOĞULU, Cihangir ÖZKINAY, Sarenur TÜTÜNCÜOĞLU, Gül SAPMAZ, Mehmet KÖSEM, Ferda ÖZKINAY

İdiyopatik mental retardasyonlarda frajil-X sendromu araştırılması

Frajil-X sendromu insanlarda kalıtsal zeka geriliğinin en sık nedenidir. Kalıtsal ve kalıtsal olmayan mental retardasyon nedenleri dikkate alındığında Down sendromundan sonra ikinci sırada gelmektedir. Frajil-X tanısı sitogenetik olarak folattan fakir besiyeri kullanılarak elde edilen lenfosit kültürlerindeki metafaz kromozomları inceleyerek konulmaktadır. Son yıllarda Frajil-X geni tanımlanmış ve DNA analizi ile moleküler tanı olanağı sağlanmıştır. Bu çalışmada Ege Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Genetik Laboratuvarına Frajil-X sitogenetik araştırması için yollanan mental retardasyonlu 66 olgu araştırıldı. Olguların hepsinde hem standart yöntemlerle hem de Frajil-X için folattan fakir besiyeri ile elde edilen metafazlarda kromozomlar değerlendirildi. Frajil-X için her olguda en az 100 metafaz değerlendirildi. Metodun frajil bölge göstermedeki uygunluğu kromozomlardaki yapısal frajil bölgeler saptanarak yapıldı. Çalışılan altmış altı olgudan 18' i Ege Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim dalı Genetik ve Nöroloji Bilim Dallarından klinik değerlendirmelerden geçmiş olgulardı. Diğerleri için çeşitli hastanelerden materyal yollanmıştı. Onsekiz olgunun klinik bulguları değerlendirildiğinde hepsinde olan bulgu mental retardasyondu. Geliş yakınmaları içinde ilk 3 sırayı gelişme geriliği, konvülsiyon ve konuşma güçlüğü alıyordu. Tüm olgular (66 olgu) içinde sitogenetik olarak 2 olguda (%3.03) Frajil-X tanısı konuldu. Bir olguda 49,XXXXY karyotipi saptandı. Çalışma sonucunda Frajil-X sıklığı mental retardasyonlu topluluklarda yapılan frajil tarama çalışmaları sonucu ile uygunluk gösterdi. Fakültemizde ilk kez uygulanan sitogenetik tanı yönteminin rutin çalışmalarda kullanılabileceği, olguların sitogenetik çalışmaya alınmadan önce iyi bir klinik seçimden geçmelerinin uygun olacağı kanısına varıldı.

Anahtar Kelimeler:

Zeka geriliği, Frajil X sendromu, Kromozomlar, Sitogenetik, Tanı, Genetik, biyokimyasal, Karyotipleme, Moleküler tanı teknikleri

Investigation of fragile X syndrome in idiopathic mental retardation

The fragile X syndrome is the most common cause of inherited mental deficiency and the second most frequent chromosomal cause of mental deficiency after Down syndrome. Cytogenetic diagnosis of the fragile X syndrome can be made by analyzing the metaphase chromosomes from lymphocytes culturing in folat-timidin deficient medium. Recently the gene causing fragile X syndrome has been cloned and molecular diagnosis has become available. In this study 66 mentally retarded patients who were referred to Ege University Medical Faculty Genetics Laboratories (both in Pediatrics Department and in Medical Biology Department) for cytogenetic analysis were investigated. For all cases we applied both standard and fragile X (using folat deficient medium) cytogenetic studies. In every patient 100 metaphases were analyzed to diagnose fragile X. Constitutional fragile sites which had been described before in normal individuals were evaluated to control whether the fragile X medium worked. 18 patients out of 66 patients were examined by pediatric neurologist and a clinical geneticist in Pediatrics department of Ege University Medical Faculty. Blood samples from the remaining patients were sent by the other hospital in Aegean region. The clinical findings of 18 patients were evaluated in detail. The common finding in all cases was mental retardation. On admission the first three complaints were developmental delay, convulsions and speech difficulties. Two cases of 66 (3.03%) were diagnosed as having fragile X cytogenetically. One case had the chromosome composition of 49,XXXXY. Our results were coincided to the results, which have been reported in similar studies on the same type of populations. It is widely known that molecular methods are more reliable in the diagnosis of fragile X syndrome. However this is, at present, not available in our hospital. Our study has shown that cytogenetic method can be effectively used for diagnosis of fragile X until the molecular methods are available.

Keywords:

Mental Retardation, Fragile X Syndrome, Chromosomes, Cytogenetics, Diagnosis, Genetics, Biochemical, Karyotyping, Molecular Diagnostic Techniques,

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2. Harvey J, Judge C, VVİener S. Familiar X linked retardation with an X Chromosome Abnormality. J Med Genet 1977; 14: 46-50.
3. Sherman S. Epidemiology. Hagerman RJ, Silverman AC ed. Fragile-X Syndrome. Baltimore and London: The Johns Hopkins University Press, 1991: 72-3.
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6. Pieretti M, Zhang F, Fu YH et al. Absence of expression of FMR-I gene in fragile x syndrome. Celi, 1991; 66: 817-22.
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9. Heitz D, Deuys D, Imbert G, Kretz C, Mandel JL, "Inheritance of the Fragile X Syndrome: Size of the Fragile X Premutation is a Majör Determinant of the Transition to full mutation", J Med Genet 1992; 29: 794-801.
10. Simpson NE, Nevvman BJ, Partington MW. Fragile-X syndrome: III. Dermatoglyphic studies in male. Am J Med Genet 1984; 17: 195-207.
11. Musumeci SA, Ferri R, Colognole RM, Neri G, Sanfilippo S Bergonzi P. Prevalance of a novel epileptogenic EEG pattern in the Martin-Bell syndrome. Am J Med Genet 1988; 30: 207-12.
12. Harvey J, Judge C, VVeiner S. Familial X-linked mental retardation with an X-chrosome abnormality. J Med Genet 1977; 14: 46-50.
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14. Fryns JP: X-linked mental retardasyon. Alan R, Lisa ed. Medical Genetics: Past, Present and Future. Newyork: 1985: 309-19.
15. Winiewski KE, Segan SM, Miezejeski CM, Sersen EA, Rudelli RD. The Fragile X syndrome. Neurologicai electrophysiological and neuropathological abnormalities. Am J Med Genet 1991: 38; 47-80.
16. Reiss AL, Patel S, Kumar AJ, Freund L. Preliminary communication: Neuroanatomical variations of he posterior fossa in man with Fragile X (Martin-Bell) Syndrome. Am J Med Genet 1988; 31: 407-14.
17. Fryns JP, Vanden Berge H. The concurrence of Klinefelter syndrome and Fragile X syndrome. Am J Med Genet 1988; 30: 109-13.
18. Fuster C, Templado C, Miro R, Barrios L, Egozcuc J. Concurence of the triple-X syndrome and expression of the fragile site Xq27,3. Hum Genet 1988; 78:293.
19. VVatson MR, Breg Wri Pouls D, Brown WT, Caroll A, Hovvard Peebles PN, Meryash D, Shapio LR. Aneuploidy and the Fragile X syndrome. Am J Med Genet 1988; 30: 115-21.
20. Mazurczak T, Bocian E, Milevski Michel Obersiytyn E, Stanczak H, Bal J, Szamotulska K, Kavvarch, MW. Frequency of Fragile X syndrome among institionalized mentally retarded males in Poland. Am J Med Genet 1996; 64: 134-6.
21. Perroni, L, Grasso M, Amusti A, Lo Nigro C, Croci GF, Zelante L, Garani GP, Bricarelli DF. Molecular and cytogenetics analysis of the fragile X syndrome in a series of 453 mentally retarded subjects: A study of 87 families. Am J Med Genet, 1996; 64: 176-80.
22. Jack P. Cytogenetics. Hageman RJ, Silverman AC ed. Fragile-X Syndrome: Diagnosis, treatment and Research. Baltimore: Johns Hopkins University Press, 1991: 98-145.
23. Kremer EJ, Pritchard Mi Lynch M, Yu S, Holman Ki Baker E, VVarnen ST, Schlessinger D, Sutherland Gr, Richard Rl, Mapping of DNA instability at the Fragile X to a trinucleotide repeat sequence p(CCG)n. Science 1991; 252: 1711-14.
24. Oberle I, Rousseau F, Heitz D, Kretz C, Devys S, Hanauer A, Boue J, Bertheas MF, Mandel JL. İnstability of a 5500-base Pair DNA segment. Science 1991; 252: 1097-1102.
1. Girand F, Aymes S, Maltei MG. Constitutional chromosome breakage. Hum Genet 1976; 34: 125-36.
2. Harvey J, Judge C, VVİener S. Familiar X linked retardation with an X Chromosome Abnormality. J Med Genet 1977; 14: 46-50.
3. Sherman S. Epidemiology. Hagerman RJ, Silverman AC ed. Fragile-X Syndrome. Baltimore and London: The Johns Hopkins University Press, 1991: 72-3.
4. Lubs AH. A marker X chromosome. Am J Hum Genet 1969; 21: 231 -4.
5. Verkerk AJ, Pieretti M Sutcliffe JS et al. Identification of a gen (FMR-I) containing a cgg repeat coincident with a breakpoint cluster region exhibiting length variation infragile x syndrome. Celi 1991; 65: 905-14.
6. Pieretti M, Zhang F, Fu YH et al. Absence of expression of FMR-I gene in fragile x syndrome. Celi, 1991; 66: 817-22.
7. Jones KL: Simith's recognizable pattems of human malformations. Philadelphia, London: WB Saunder Co, 1988: 126-7.
8. Lubs HA: X-Linked mental retardation and the Fragil-X. Emery A EH ed. Principles and Practice of Medical Genetics. Edinburg, London: Churchill Livingstone Co, 1990: 301-9.
9. Heitz D, Deuys D, Imbert G, Kretz C, Mandel JL, "Inheritance of the Fragile X Syndrome: Size of the Fragile X Premutation is a Majör Determinant of the Transition to full mutation", J Med Genet 1992; 29: 794-801.
10. Simpson NE, Nevvman BJ, Partington MW. Fragile-X syndrome: III. Dermatoglyphic studies in male. Am J Med Genet 1984; 17: 195-207.
11. Musumeci SA, Ferri R, Colognole RM, Neri G, Sanfilippo S Bergonzi P. Prevalance of a novel epileptogenic EEG pattern in the Martin-Bell syndrome. Am J Med Genet 1988; 30: 207-12.
12. Harvey J, Judge C, VVeiner S. Familial X-linked mental retardation with an X-chrosome abnormality. J Med Genet 1977; 14: 46-50.
13. Largo Rh, Schinzel A, "A: Developmental and Behavioral Disturbances in 13 Boys with Fragile X Syndrome", Eur J Pediatrics 1985; 143:269-75.
14. Fryns JP: X-linked mental retardasyon. Alan R, Lisa ed. Medical Genetics: Past, Present and Future. Newyork: 1985: 309-19.
15. Winiewski KE, Segan SM, Miezejeski CM, Sersen EA, Rudelli RD. The Fragile X syndrome. Neurologicai electrophysiological and neuropathological abnormalities. Am J Med Genet 1991: 38; 47-80.
16. Reiss AL, Patel S, Kumar AJ, Freund L. Preliminary communication: Neuroanatomical variations of he posterior fossa in man with Fragile X (Martin-Bell) Syndrome. Am J Med Genet 1988; 31: 407-14.
17. Fryns JP, Vanden Berge H. The concurrence of Klinefelter syndrome and Fragile X syndrome. Am J Med Genet 1988; 30: 109-13.
18. Fuster C, Templado C, Miro R, Barrios L, Egozcuc J. Concurence of the triple-X syndrome and expression of the fragile site Xq27,3. Hum Genet 1988; 78:293.
19. VVatson MR, Breg Wri Pouls D, Brown WT, Caroll A, Hovvard Peebles PN, Meryash D, Shapio LR. Aneuploidy and the Fragile X syndrome. Am J Med Genet 1988; 30: 115-21.
20. Mazurczak T, Bocian E, Milevski Michel Obersiytyn E, Stanczak H, Bal J, Szamotulska K, Kavvarch, MW. Frequency of Fragile X syndrome among institionalized mentally retarded males in Poland. Am J Med Genet 1996; 64: 134-6.
21. Perroni, L, Grasso M, Amusti A, Lo Nigro C, Croci GF, Zelante L, Garani GP, Bricarelli DF. Molecular and cytogenetics analysis of the fragile X syndrome in a series of 453 mentally retarded subjects: A study of 87 families. Am J Med Genet, 1996; 64: 176-80.
22. Jack P. Cytogenetics. Hageman RJ, Silverman AC ed. Fragile-X Syndrome: Diagnosis, treatment and Research. Baltimore: Johns Hopkins University Press, 1991: 98-145.
23. Kremer EJ, Pritchard Mi Lynch M, Yu S, Holman Ki Baker E, VVarnen ST, Schlessinger D, Sutherland Gr, Richard Rl, Mapping of DNA instability at the Fragile X to a trinucleotide repeat sequence p(CCG)n. Science 1991; 252: 1711-14.
24. Oberle I, Rousseau F, Heitz D, Kretz C, Devys S, Hanauer A, Boue J, Bertheas MF, Mandel JL. İnstability of a 5500-base Pair DNA segment. Science 1991; 252: 1097-1102.