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The 50Th Anniversary of the Discovery of Trisomy 21: the Past, Present, and Future of Research and Treatment of Down Syndrome

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The 50Th Anniversary of the Discovery of Trisomy 21: the Past, Present, and Future of Research and Treatment of Down Syndrome REVIEW The 50th anniversary of the discovery of trisomy 21: The past, present, and future of research and treatment of Down syndrome Andre´Me´garbane´, MD, PhD1,2, Aime´ Ravel, MD1, Clotilde Mircher, MD1, Franck Sturtz, MD, PhD1,3, Yann Grattau, MD1, Marie-Odile Rethore´, MD1, Jean-Maurice Delabar, PhD4, and William C. Mobley, MD, PhD5 Abstract: Trisomy 21 or Down syndrome is a chromosomal disorder HISTORICAL REVIEW resulting from the presence of all or part of an extra Chromosome 21. Clinical description It is a common birth defect, the most frequent and most recognizable By examining artifacts from the Tumaco-La Tolita culture, form of mental retardation, appearing in about 1 of every 700 newborns. which existed on the border between current Colombia and Although the syndrome had been described thousands of years before, Ecuador approximately 2500 years ago, Bernal and Briceno2 it was named after John Langdon Down who reported its clinical suspected that certain figurines depicted individuals with Tri- description in 1866. The suspected association of Down syndrome with somy 21, making these potteries the earliest evidence for the a chromosomal abnormality was confirmed by Lejeune et al. in 1959. existence of the syndrome. Martinez-Frias3 identified the syn- Fifty years after the discovery of the origin of Down syndrome, the term drome in a terra-cotta head from the Tolteca culture of Mexico “mongolism” is still inappropriately used; persons with Down syn- in 500 patients with AD in which the facial features of Trisomy drome are still institutionalized. Health problems associated with that 21 are clearly displayed. Examining more recent artifacts, dif- syndrome often receive no or little medical care, and many patients still ferent authors reported apparent depictions of the syndrome in die prematurely in infancy or early adulthood. Nevertheless, working 15th and 16th century paintings.4,5 On the basis of this evidence, against this negative reality, community-based associations have lob- it is likely that people with Trisomy 21 have been a part of bied for medical care and research to support persons with Down human culture for thousands of years. syndrome. Different Trisomy 21 research groups have already identified Esquirol, a psychiatrist from the school of Pinel, was inter- candidate genes that are potentially involved in the formation of specific ested in the phenotypic differences between mental retardation Down syndrome features. These advances in turn may help to develop and psychosis: he was the first to write a phenotypic description targeted medical treatments for persons with Trisomy 21. A review on of Trisomy 21 in 1838 (Table 1). At the same time, Seguin those achievements is discussed. Genet Med 2009:11(9):611–616. established the first training program for mentally retarded Key Words: Down syndrome, trisomy 21, mouse, treatment, genes children and published in 1846 a treaty on “the education of idiots” in which he gives an extended description of Trisomy 21 named “idiotie furfurace´e.” Twenty years later, an English ifty years ago, Lejeune et al.1 discovered that Down syn- physician, John Langdon Down published an essay describing Fdrome (DS) results from the presence of an additional Chro- the phenotype of children with common features distinct from mosome 21. A common defect present in about 1 in 700 other children with mental retardation. He was the first to make liveborn children, it is the most frequent cause of mental retar- the distinction between children who were “cretins” (later found dation and a recognized genetic etiology of Alzheimer disease to have hypothyroidism) and what he referred to as “Mongol- (AD). Recent progress in studies of mouse models of Trisomy oids.” Down based the name on his feeling that these children 21 suggests a link between characteristic phenotypic changes in looked like people from Mongolia, who were erroneously DS and increased dosage of specific genes, which may allow an thought to have an arrested development.6 By the turn of the understanding of the molecular basis of these abnormalities. If century, mongolism had unfortunately become a widely used so, it may soon be possible to understand and to effectively treat descriptive term for DS. the most distressing symptoms and signs of this disorder. Chromosomal basis 1 2 From the Institut Je´roˆme Lejeune, Paris, France; Unite´deGe´ne´tique Until the middle of the 20th century, the cause of Trisomy 21 Me´dicale, Laboratoire de Biologie Mole´culaire et Cytoge´ne´tique, Faculte´de Me´decine, Universite´ Saint-Joseph, Beirut, Lebanon; 3CHU Dupuytren, Li- remained unknown. However, its presence in all races, the moges, France; 4Functional and Adaptive Biology, Universite´ Paris-Diderot, association of its incidence with increasing maternal age, and its Paris, France; and 5Department of Neurology and Neurological Sciences, exceptional occurrence in siblings had already been noted. The Neuroscience Institute, Stanford University School of Medicine, Stanford, possibility that Trisomy 21 might be due to a chromosomal California. abnormality was suggested in 1932 by Waardenburg (a Dutch Andre´Me´garbane´, MD, PhD, Unite´deGe´ne´tique Me´dicale, Faculte´de ophthalmologist)7 and Davenport8 (an American geneticist). In Me´decine, Universite´ Saint-Joseph, 42, rue de Grenelle, Paris 75007, France. 1950, a study of chromosomes on a testicular sample taken from E-mail: [email protected]. patients with Trisomy 21 was undertaken by Penrose. The Disclosure: The authors declare no conflict of interest. conclusion was that neither triploidy nor aneuploidy was the 9 Submitted for publication May 21, 2009. cause. With the discovery of karyotyping techniques, and the as- Accepted for publication June 14, 2009. signment, in 1956, of the exact chromosome number in humans Published online ahead of print July 24, 2009. Lejeune et al.1,10 were able to show, in 1959, that Trisomy 21 DOI: 10.1097/GIM.0b013e3181b2e34c resulted from an additional chromosome. The extra chromo- Genetics IN Medicine • Volume 11, Number 9, September 2009 611 Me´garbane´ et al. Genetics IN Medicine • Volume 11, Number 9, September 2009 changes in biopterin metabolism; and (3) the peculiar sensitivity Table 1 Principle dates in Trisomy 21 syndrome of trisomic 21 lymphocytes to methotrexate.15 To counter the 500 BC: First representation of Trisomy 21 presumed effects of abnormal gene dose, some authors sug- gested vitamin supplements. In the 1960s, Dr Henry Turkel 1838: First phenotypic description of trisomy 21 by Esquirol claimed that a mixture of 48 ingredients could improve the 1846: Treaty on “the education of idiots” and extended intelligence of children with DS, which he administered to his description of Trisomy 21 by Séguin patients for more than 40 years. No double-blind study was ever performed. No evidence emerged that this was beneficial. Few 1866: John Langdon Down describes the phenotype of children years later, Harrell et al.16 reported that supplementary vitamins with Trisomy 21 and minerals and thyroid hormone improved intelligence quo- 1932: A possible chromosomal origin suspected by Waardenburg tient scores and normalized physical appearance in children and Davenport with mental deficiency. Reportedly, three children with DS showed the best results. The study was not performed scientif- 1959: Lejeune et al. and Jacobs et al. find an extra Chromosome 21 ically, and seven studies performed in the next decade using this 1961: Geneticists complained about the term “mongolism”; mixture showed no benefit.17 Antioxidants and folinic acid were replaced by “Down Syndrome or Anomaly,” or “Trisomy also suggested as treatments.18,19 Although on the surface this 21 Anomaly” suggestion is reasonable, no proof has been provided for a 1989: Individualization of the DCR beneficial effect on psychomotor development. Nowadays, cardiac surgery, vaccinations, antibiotics, thyroid 1990s: First trisomic mouse lines hormones, leukemia therapies, and anticonvulsive drugs (e.g., 1997: Cold Spring Harbor meeting defining DCR-1 as a region vigabatrin) have considerably improved the quality of life and with the largest number of associated DS features life expectancy of individuals with DS. Indeed, life expectancy that was barely 30 years in the 1960s is now reaching more than 2000: Sequencing of Chromosome 21 by Hattori et al. 50 years of age. Simultaneously, early rehabilitation allowed DCR, Down syndrome critical region. better socialization. Nevertheless, physicians managing patients on a daily basis still have to face practical questions such as pain detection, sleep apnea, depression, and prevention of premature ageing. The clinical trials meant to improve cognitive functions some was subsequently labeled Number 21, and the clinical have been so far deceiving.20–26 Most of them have relied on condition was thus called Trisomy 21. After the report by vitamins or trace elements supplementation. Despite the physi- Lejeune et al., rapid confirmation was provided by Jacobs et cians’ involvement, the way these trials have been conducted is al.11 and Fraccaro et al.12 A year later, Harnden et al.13 reported somehow questionable because of clinical variability and a the first case of double aneuploidy (a boy with Trisomy 21 and limited number of patients and “bottom effect” of the psycho- Klinefelter syndrome); this was followed rapidly by the discov- metric tests. ery that some familial cases of Trisomy 21 were caused by translocations and the fact that the phenotype of Trisomy 21 Phenotype–genotype
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