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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282XOn-line version ISSN 1678-4227

Arq. Neuro-Psiquiatr. vol.77 no.12 São Paulo Dec. 2019  Epub Jan 10, 2020 

Historical Note

Rett syndrome: the Brazilian contribution to the gene discovery

Síndrome de Rett: a contribuição brasileira para a descoberta do gene

José Luiz Pinto Pereira1  2  3 

José Luiz Pedroso4

Orlando G. P. Barsottini4

Alex Tiburtino Meira5

Hélio A. G. Teive5

1Prefeitura Municipal de Curitiba, Serviço de Atendimento Móvel de Urgência (SAMU), Curitiba PR, Brasil

2Hospital John Hopkins, Investigações Genéticas (1999-2000), EUA

3Instituto Kennedy Krieger, Investigações Genéticas (1999-2000), EUA

4Universidade Federal de São Paulo, Departamento de Neurologia, São Paulo SP, Brasil

5Universidade Federal do Paraná, Departamento de Medicina Interna, Serviço de Neurologia, Curitiba PR, Brasil


A brief history of the syndrome discovered by Andreas Rett is reported in this paper. Although having been described in 1966, the syndrome was only recognized by the international community after a report by Hagberg et al. in 1983. Soon, its importance was evident as a relatively frequent cause of severe encephalopathy among girls. From the beginning it was difficult to explain the absence of male patients and the almost total predominance of sporadic cases (99%), with very few familial cases. For these reasons, it was particularly difficult to investigate this condition until 1997, when a particular Brazilian family greatly helped in the final discovery of the gene, and in the clarification of its genetic mechanism. Brief references are made to the importance of the MECP2 gene, 18 years later, as well as to its role in synaptogenesis and future prospects.

Keywords: Rett syndrome; brain diseases; genes


Uma breve história de uma síndrome neurológica descoberta por Andreas Rett é relatada neste artigo. Embora tenha ocorrido em 1966, a síndrome só foi reconhecida pela comunidade internacional após um relato de Hagberget al, em 1983. Logo, sua importância ficou evidente como causa relativamente frequente de encefalopatia grave entre as crianças do sexo feminino. Desde o início, foi difícil explicar a ausência de envolvimento de pacientes do sexo masculino e a quase absoluta preponderância de casos esporádicos (99%), com muitos poucos casos familiares. Por essas razões, foi difícil investigar essa condição até 1997, quando uma família brasileira em particular ajudou muito na descoberta final do gene e no esclarecimento de seu mecanismo genético. São feitas referências sucintas à importância do gene MECP2, dezoito anos depois, bem como ao seu papel na sinaptogênese e nas perspectivas futuras.

Palavras-chave: Síndrome de Rett; encefalopatias; genes

Rett syndrome, which was described 52 years ago in Vienna, Austria, by Andreas Rett, a pediatrician, is caused by a heterozygous mutation of the MECP2 gene located in the distal region of the X chromosome, which encodes a MECP2 protein, or methyl-CpG 2 binding repressor protein, which binds to methylated DNA1,2. This is a protein with two isoforms, preferentially expressed in the brain, regulating the synaptogenesis process. Approximately 80% of the time this mutation is found with the classic phenotypes, but mutation of the gene can also occur in 50% of the cases of atypical phenotypes or mild forms of the syndrome; X-linked non-random inactivation might explain most of this clinical variability. The MECP2 is a small gene, with only four exons, two of them being coding exons (3 and 4).1,2 Hundreds of mutations have been identified, 54% of them are related to causing Rett syndrome. This gene has the function of silencing others, regulating the synaptogenesis process in the infant brain, which peaks in the first two years of life – when the classic syndrome is expressed clinically as stagnation and even regression of neurological or psychomotor development. Rett syndrome is a sexually-dominant disease, much more common in females and extremely rare in males1,2. In this historical review we discuss the Brazilian contribution to the discovery of the gene of Rett syndrome.


A medical aphorism teaches students and professionals that in the act of diagnosing and treating, more than the examination or technological resources, the clinic diagnosis is paramount. Andreas Rett (Figure 1), working at the Boltzman Institute in Vienna, based on isolated clinical patients, described what appeared to be a disease seen exclusively in females. His reasoning was initially based on only 22 young women3,4. We now know that Rett syndrome has also been described in male patients, but they are very rare and present with a more severe phenotype. Andreas Rett was born in Furth, Bavaria, on January 2, 1924 and studied medicine at the University of Innsbruck (Austria) and Bonn (Germany). After receiving his medical degree, he specialized in developmental pediatrics and began to practice in Vienna, where he worked until the end of his life3,4. In the clinic, he mostly focused on examining and treating children who had developmental delay or special educational needs. He was a great clinician, whose considerable capacity for observation allowed him to identify a new neurological entity, later coined Rett syndrome. Nowadays, this has been recognized as a cause of physical and mental impairment in girls (1/10,000 female births). The syndrome was named Rett syndrome by Bengt Hagberg (Figure 2) in a seminal article, in 19835.

Figure 1 Andreas Rett (1924–1997). 

Figure 2 Bengt Hagberg (1923–2015). 


In this syndrome, girls, as described by Rett, had a very typical condition and progression: a normally-born child with no history of gestational or obstetric events, families with no histories of other cases, or even those with other genetic disorders, who presented with developmental delay between six months and two years of age; this occurs mainly because de novo pathogenic variants occur much more frequently in male gametogenesis1,2,3,4. In the original description, patients also presented with peculiar and typical involuntary movements with their hands: the Rett-type manual stereotypic movement disorders. Nowadays, it is known that this phenotype occurs in other disorders, such as FOXG1- and CDKL5-associated encephalopathy, and many others6,7. In 1966, Rett described this clinical condition in German3, in a periodical of limited circulation, presenting an English version only in 19774. However, it took a long time for this content to circulate among peers in the community of child neurologists and neurologists in Europe1,3,4. In 1983, Hagberg et al.5 published a report on 35 patients. From then on the neurological community of Europe and the USA gradually recognized the syndrome. Although Rett syndrome typically occurs in females, pathogenic mutation in MECP2 in males usually does not have the Rett syndrome-like phenotype but instead presents with a severe epileptic encephalopathy, with hypotonia and apnea. The exception to the previous statement is males with Klinefelter syndrome (47, XXY), which also has a Brazilian contribution8,9.

Rett syndrome, genetic studies, and the Brazilian contribution

SakkuBai Naidu (Figure 3) and Hugo Moser, from the Kennedy Institute, promoted the first American conference on Rett syndrome in 1986, where they reported on the natural history of 70 patients10,11. In Brazil, in 1987, Sergio Rosemberg et al. reported on the analysis of the first five Brazilian patients12. In 1991, linked to the International Rett Syndrome Association, the Paraná region of the Brazilian Rett Syndrome Association was founded in Curitiba, when the diagnoses of some patients were recognized. Subsequently, a monograph on 12 Brazilian patients was written13. One family had three affected siblings (Figure 4). It was known that, in international literature, no more than a dozen familial cases (full-sisters or half-sisters) had been reported, among more than 3,000 sporadic cases1,2,5. The case histories of the three patients were presented at a medical conference on the syndrome in Gothenburg, Sweden, in 199614. On this occasion, DNA samples of the three Brazilian girls and their parents were also forwarded by Dr. José Luiz Pinto Pereira (Figure 3) to other groups of geneticists in London and Stockholm. SakkuBai Naidu, a neurogeneticist at the Kennedy Institute, had been studying the syndrome at Johns Hopkins Hospital for more than a decade and was interested in this family with three affected sisters, a unique case now known worldwide. In order to make further research possible, in October 1997 the patients were moved to Baltimore. Initially, Naidu et al. published the chromosome mapping of Rett syndrome and a candidate region on the telomere of Xq10 in collaboration with geneticists from Stockholm and London. Soon after, the confirmation of the genetic locus in Xq2.815 was also published by Sirianni et al.16, including Dr. Pereira (a neuropediatrician) and Professor Pilotto (a geneticist and professor at the Federal University of Paraná). In this manner, not only could the gene locus be confirmed, but it was also possible to demonstrate that the DNA sequences were inherited by the affected children from the mother and were not shared in the same chromosomal subregion by their normal sisters16. Finally, in the same year, another group of geneticists led by Dr. Hudha Zoghbi, with Dr. Uta Francke as a collaborator, both from the Howard Hughes Medical Institute, Baylor College of Medicine, made the final discovery of the gene, leading to further publications17,18. In these publications, the participation of the Brazilian family, with three affected sisters, was highly relevant to the discovery of the Rett syndrome gene. In conclusion, these three Brazilian sisters made an enormous contribution to the genetic description of the MECP2 as the cause of Rett syndrome.

Figure 3 Dr. SakkuBai Naidu and Dr. Pereira (JLPP, personal archive, with permission). 

Figure 4 Three Brazilian sisters with classical Rett syndrome, who participated in the study that enabled the description of the MECP2 gene as the genetic cause of the disease (1997, JLPP, personal archive, with permission of the author and the patient's family). 


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3. Rett A. [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien Med Wochenschr. 1966 Sep;116(37):723-6. German. [ Links ]

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6. Ma M, Adams HR, Seltzer LE, Dobyns WB, Paciorkowski AR. Phenotype differentiation of FOXG1 and MECP2 Disorders: a new method for characterization of developmental encephalopathies. J Pediatr. 2016 Nov;178:233-240.e10. ]

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8. Schwartzman JS, Souza AM, Faiwichow G, Hercowitz LH. [Rett phenotype in patient with XXY karyotype: case report]. Arq Neuropsiquiatr. 1998 Dec;56(4):824-8. Portuguese. ]

9. Schwartzman JS, Bernardino A, Nishimura A, Gomes RR, Zatz M. Rett syndrome ina boy with a 47,XXY karyotype confirmed by a rare mutation in the MECP2 gene. Neuropediatrics 200;32(3):162-4. ]

10. Naidu S, Murphy M, Moser HW, Rett A, Opitz JM, Reynolds JF. Rett syndrome: natural history in 70 cases. Am J Med Genet Suppl. 1986;1 S1:61-72. ]

11. Murphy M, Naidu S, Moser HW, Opitz JM, Reynolds JF. Rett syndrome: bservational study of 33 families. Am J Med Genet Suppl. 1986;1 S1:73-6. ]

12. Rosemberg S, Arita F, Campos C, Coimbra R, Posadas R, Ellovitch S, et al. [Rett syndrome: analysis of the first five cases diagnosed in Brazil]. Arq Neuropsiquiatr. 1987 Jun;45(2):143-52. Portuguese. ]

13. Pereira JS. Síndrome de Rett: uma introdução ao seu diagnóstico clínico e diferencial, e ao planejamento de ações de reabilitação. Curitiba: Secretaria de Estado da Educação; 1992. [ Links ]

14. Three sisters with Classic Rett Syndrome. In: Annals from World Congress on Rett Syndrome; 1996 Aug 30th-Sep 1st; Sweden. Gothenburg: Springer. Eur Child Adolesc Psychiatry. 1997 6 Suppl 1: 1-108. [ Links ]

15. Xiang F, Zhang Z, Clarke A, Joseluiz P, Sakkubai N, Sarojini B, et al. Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq. J Med Genet. 1998 Apr;35(4):297-300. ]

16. Sirianni N, Naidu S, Pereira J, Pillotto RF, Hoffman EP. Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am J Hum Genet. 1998 Nov;63(5):1552-8. ]

17. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185-8. ]

18. Wan M, Stephen L, Xianyu Z, Houwink-Manville I, Song H, Amir R, et al. Recurrent spontaneous and familial MECP2 mutation at CpG hotspots. Am J Human Genet. 1999;65(6):1520-9. [ Links ]

Received: November 07, 2018; Revised: March 04, 2019; Accepted: March 20, 2019

Correspondence: Hélio A. G. Teive; Universidade Federal do Paraná, Departamento de Medicina Interna, Serviço de Neurologia, Curitiba PR, Brasil; R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900; E-mail:

Conflict of interest: There is no conflict of interest to declare.

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