Clinical Evaluation of Patients with Classical Rett Syndrome and MECP2 Gene Analysis

Öz

INTRODUCTION: This retrospective study aims to evaluate the clinical manifestations in genetically confirmed classical Rett syndrome (RTT) patients. METHODS: Sixteen patients clinically diagnosed with classical RTT between 2010 and 2020 were evaluated according to diagnostic criteria for this syndrome. The results of pyrosequencing, sanger sequencing, and multiplex ligation-dependent probe amplification of MECP2 gene were inspected. RESULTS: Besides the 4 main criteria of RTT which are necessery for the diagnosis of classical RTT, diurnal bruxism (16/16 patients), epilepsy (11/16; 68.7%) and microcephaly (11/16; 68.7%) were the most common features in the patients. Early onset epilepsy was detected in six patients (6/11; 54.5%). Four of them had drug-resistant epilepsy. Four out of 5 patients with late onset epilepsy had a good response to the anticonvulsant treatment. Scoliosis, breathing problems, peripheral vasomotor disturbances and sleep problems were detected in 37.5%, 18.7%, 25% and 12.5% of the patients, respectively. A total of 9 different MECP2 gene variants were identified in the 16 patients. Nonsense variant was the most common variant type (7/16; 43.7%). The detected variants were p.Arg168Ter (n =5); p.T158M (n = 2); p.R255X (n = 2); p.Arg106Trp (n = 1); p.Arg270GlufsTer19 (n = 1); p.Lys286ProfsTer2 (n = 1); p.Leu386_Thr400delinsPro (n = 1); Exon 4 del (n = 2) and Exon 3-4 del (n = 1). DISCUSSION AND CONCLUSION: The p.Arg168Ter variant is common in classical RTT patients in Turkey. diurnal bruxism, microcephaly and epilepsy are common features in this syndrome. Epilepsy develops in more than half of patients with classical RTT and especially early-onset epilepsy tends to be drug resistant in a substantial proportion of the patients.

Anahtar Kelimeler

• Rett Syndrome
• MECP2 gene
• epilepsy
• diurnal bruxism
• diurnal bruxism
• microcephaly
• drug resistant

Klasik Rett Sendromu Olan Hastaların Klinik Değerlendirmesi ve MECP2 gen Analizi

Öz

GİRİŞ ve AMAÇ: Bu retrospektif çalışma, genetik tanı almış klasik Rett Sendromu (RTT) hastalarında, klinik bulguları değerlendirmeyi amaçlamaktadır. YÖNTEM ve GEREÇLER: 2010-2020 yılları arasında, genetik polikliniğinde RTT tanısı almış 16 hasta, sendromun tanı kriterlerine göre değerlendirildi. Pyrosekans, sanger sekans ve multipleks ligasyona bağlı prob amplifikasyonu analiz sonuçları incelendi. BULGULAR: Klasik RTT tanısı için gerekli olan 4 ana kritere ek olarak, hastalarda en sık saptanan bulgular; diurnal bruksizm (16/16; %100), epilepsi (11/16; %68,7) ve mikrosefali (11/16; %68,7) idi. Erken başlangıçlı epilepsi, 6 hastada saptandı (6/11; %54,5). Bu hastaların dördünde, ilaca dirençli epilepsi vardı. Geç başlangıçlı epilepsisi olan 5 hastanın 4’ü antikonvülsan tedaviye iyi yanıt verdi. Skolyoz, nefes alma problemleri, periferik vazomotor bozukluk ve uyku problemleri sırasıyla %37,5; %18,7; %25 ve %12,5 sıklıkta saptandı. 16 hastada, toplam 9 farklı MECP2 gen varyantı tanımlandı. Nonsense varyant, ensık varyant tipiydi (7/16 hasta; %43,7). Çalışmada saptanan varyantlar; p.Arg168Ter (n =5); p.Thr158Met (n = 2); p.Arg255Ter (n = 2); p.Arg106Trp (n = 1); p.Arg270GlufsTer19 (n = 1); p.Lys286ProfsTer2 (n = 1); p.Leu386_Thr400delinsPro (n = 1); Exon 4 del (n = 2) ve Exon 3-4 del (n = 1) idi. TARTIŞMA ve SONUÇ: p.Arg168Ter, patojenik varyantı, Türk klasik RTT hastalarında yaygındır. Diurnal bruksizm, mikrosefali ve epilepsi, bu sendromun sık bulgularındandır. Klasik RTT'li hastaların yarısından fazlasında epilepsi gelişir ve özellikle erken başlangıçlı epilepsi, hastaların önemli bir kısmında ilaca dirençli olma eğilimindedir.

Anahtar Kelimeler

• Rett Sendromu
• MECP2 geni
• epilepsi
• Diurnal bruksizm
• mikrosefali
• ilaç direnci

Kaynakça

1. Zahorakova D, Lelkova P, Gregor V, Magner M, Zeman J, Martasek P. MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning. J Hum Genet. 2016;61:617-25.
2. Laurvick CL, de Klerk N, Bower C, Christodoulou J, Ravine D, Ellaway C, et al. Rett syndrome in Australia: a review of the epidemiology. J Pediatr. 2006;148:347–52.
3. Hagberg B. Rett syndrome: clinical peculiarities and biological mysteries. Acta Paediatr. 1995;84:971-6.
4. Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol. 2002;6:293–7.
5. Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Buisson NB, et al. RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68:944‐50.
6. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi H Y. Rett syndrome is caused by mutations in X‐linked MECP2, encoding methyl‐CpG‐binding protein 2. Nature Genetics. 1999;3:185–8.
7. Psoni S, Sofocleous C, Traeger-Synodinos J, Kitsiou-Tzeli S, Kanavakis E, Fryssira-Kanioura H. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res. 2010; 67:551-6.
8. Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, Macleod PJM, et al. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet. 2004;36:339–41.

9. Kriaucionis S, Bird A. The major form of MeCP2 has a novel N-terminus generated by alternative splicing. Nucleic Acids Res. 2004;32:1818–23.
10. Yntema HG, Kleefstra T, Oudakker AR, Romein T, de Vries BBA, Nillesen W, et al. Low frequency of MECP2 mutations in mentally retarded males. Eur J Hum Genet. 2002;10:487–90.
11. Grozeva D, Carss K, Spasic-Boskovic O, Tejada MI, Gecz J, Shaw M, et al. Targeted next generation sequencing analysis of 1000 individuals with intellectual disability. Hum Mutat. 2015;36:1197–204.
12. Ehrhart F, Sangani NB, Curfs LMG. Current developments in the genetics of Rett and Rett‐like syndrome. Curr Opin Psychiatry. 2018;31:103–8.
13. Christodoulou J, Grimm A, Maher T, Bennetts B. RettBASE: the IRSA MECP2 variation database—a new mutation database in evolution. Hum Mutat. 2003;21:466–72.
14. Percy AK, Lane JB, Childers J, Skinner S, Annese F, Barrish J, et al. Rett syndrome: North American database. J Child Neurol. 2007;22:1338–41.
15. Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett Syndrome: A Genetic Update and Clinical Review Focusing on Comorbidities. ACS Chem Neurosci. 018;9:167-76.
16. Lima FT, Brunoni D, Schwartzman JS, Pozzi MC, Kok F, Juliano Y, et al. Genotype–phenotype correlation in Brazillian Rett syndrome patients. Arq Neuropsiquiatr. 2009; 67(3A):577–84.
17. Pan H, Li MR, Nelson P, Bao XH, Wu XR, Yu S. Large deletions of the MECP2 gene in Chinese patients with classical Rett syndrome. Clin Genet. 2006;70:418-9.
18. Hardwick SA, Reuter K, Williamson SL, Vasudevan V, Donald J, Slater K, et al. Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband. Eur J Hum Genet. 2007;15:1218-29.
19. Archer H, Whatley S, Evans J, Ravine D, Huppke P, Kerr A, et al. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. J Med Genet. 2006;43:451-6.
20. Zengin-Akkuş P, Taşkıran EZ, Kabaçam S, Şimşek-Kiper PO, Haliloğlu G, Boduroğlu K, et al. Clinical and molecular evaluation of 16 patients with Rett syndrome. Turk J Pediatr. 2018;60:1-9.
21. Williamson SL, Christodoulou J. Rett syndrome: new clinical and molecular insights. Eur J Hum Genet. 2006;14:896-903.
22. Amir RE, Van den Veyver IB, Schultz R, Malicki DM, Tran CQ, Dahle EJ, et al. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol. 2000;47:670-9.
23. Magalhães MH, Kawamura JY, Araújo LC. General and oral characteristics in Rett syndrome. Spec Care Dentist. 2002;22:147-50.
24. Fuertes-González MC, Silvestre FJ. Oral health in a group of patients with Rett syndrome in the regions of Valencia and Murcia (Spain): a case-control study. Med Oral Patol Oral Cir Bucal. 2014;19:e598-604.
25. Bebbington A, Anderson A, Ravine D, Fyfe S, Pineda M, de Klerk N, et al. Investigating genotype-phenotype relationships in Rett syndrome using an international data set. Neurology. 2008;70:868-75.
26. Halbach NS, Smeets EE, van den Braak N, van Roozendaal KEP, Blok RMJ, Schrander-Stumpel CTRM, et al. Genotype-phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice. Am J Med Genet A. 2012;158A:340-50.
27. Gold WA, Krishnarajy R, Ellaway C, Christodoulou J. Rett syndrome: a genetic update and clinical review focusing on comorbidities. ACS chemical neuroscience. 2017;9:167-76.
28. Jian L, Nagarajan L, de Klerk N, Ravine D, Bower C, Anderson A, et al. Predictors of Seizure Onset in Rett Syndrome. J Pediatr. 2006;149:542-7.
29. Jian L, Nagarajan L, de Klerk N, Ravine D, Christodoulou J, Leonard H. Seizures in Rett syndrome: an overview from a one-year calendar study. Eur J Ped Neurol. 2007;11:310–7.
30. Pintaudi M, Calevo MG, Vignoli A, Parodi E, Aiello F, Baglietto MG, et al. Epilepsy in Rett syndrome: clinical and genetic features. Epilepsy Behav. 2010;19:296-300.
31. Glaze DG, Percy AK, Skinner S, Motil KJ, Neul JL, Barrish JO, et al. Epilepsy and the Natural History of Rett Syndrome. Neurology. 2010;74:909-12.
32. Nissenkorn A, Gak E, Vecsler M, Reznik H, Menascu S, Zeev BB. Epilepsy in Rett syndrome‐The experience of a National Rett Center. Epilepsia. 2010;51:1252–8.