Down's Syndrome

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (or part) instead of both. For this reason, it is also called trisomy 21. It is characterized by a variable degree of intellectual disability and physical features that give it a recognizable appearance. It owes its name to John Langdon Down, who was the first to describe this genetic alteration in 1866, although he never discovered the causes that produced it. In July 1958, a young researcher named Jérôme Lejeune discovered that the syndrome is an alteration in the mentioned pair of chromosomes.

The exact causes of the chromosome excess are not known. However, the risk factors are that the parents have conceived a child with Down syndrome, that either parent is a carrier of the gene translocation for Down syndrome, and the mother's advanced age. Although there is risk at any age, the risk of conceiving a person with Down syndrome gradually increases after age 35, as younger women tend to have more children. People with Down syndrome are more likely than population suffer from some diseases especially heart, digestive system and endocrine system due to excess protein synthesized by the extra chromosome. Current advances in deciphering the human genome are revealing some of the biochemical processes underlying intellectual disability, but currently there is no drug treatment that has been shown to improve the intellectual abilities of these people.

History

Portrait of Lady Cockburn with her three children of Sir Joshua Reynolds. The child behind the back of Lady Cockburn features some SD-compatible features.

The oldest known archaeological data on Down syndrome is the discovery of a skull in a Saxon village from the 7th century, in which structural anomalies compatible with a male with Down syndrome were described.

The tempera on wood The Virgin and Child by Andrea Mantegna (1430 - 1506) seems to represent a child with features reminiscent of trisomy, as well as the painting of Sir Joshua Reynolds (1773), Portrait of Lady Cockburn with her three children, showing one of the children with typical SD facial features.

The first documented report of a child with DS is attributed to Jean Étienne Dominique Esquirol in 1838 and was originally called "cretinism" or "furfuraceous idiocy". P. Martin Duncan in 1886 literally described "a girl with a small, round head, with slanted eyes, who hung her tongue and barely uttered a few words".

In that year, the English doctor John Langdon Down worked as director of the Earlswood Asylum for the Mentally Retarded in Surrey conducting an exhaustive study of many of his patients. With these data, he published in the London Hospital Reports an article entitled: «Observations in an ethnic group of mentally retarded», where he described in detail the physical characteristics of a group of patients who presented many similarities, their ability imitation and his sense of humor.

The first descriptions of the syndrome attributed its origin to various parental diseases and established its pathogenesis based on an involution or regression to a more "primitive" state of phylogeny.

John Langdon Down.

Some more curious theory indicated the potential of tuberculosis to "break the species barrier" so that Western parents could have "Oriental" children (or "Mongolians" in Doctor Down's expression due to the facial similarities of these individuals with nomadic groups in central Mongolia). After several scientific communications, finally in 1909 G. E. Shuttleworth mentioned for the first time advanced maternal age as a risk factor for the appearance of the syndrome. On the way to the name the syndrome was renamed "Kalmykian idiocy" or "unfinished children".

Regarding its etiology, in 1932 the Dutch ophthalmologist Petrus Johannes Waardenburg made reference for the first time to an abnormal distribution of chromosomal material as a possible cause of DS. In 1956 Tjio and Levan demonstrated 46 chromosomes in humans and shortly after, in 1959, Lejeune, Gautrier and Turpin showed that people with DS carry 47 chromosomes. The latter was demonstrated simultaneously by the English Pat Jacobs.

In 1961 a group of scientists (including a relative of Dr. Down) proposed the change from "Mongoloid idiocy" to the current name of "Down syndrome" since the terms "Mongol" or "Mongolism" " could be offensive. In 1965 the WHO (World Health Organization) made the nomenclature change effective after a formal request from the delegate of Mongolia. Lejeune proposed the alternative of "trisomy 21", shortly after the discovery of en which pair of chromosomes contained the excess genetic material.

Epidemiology

The Spanish Collaborative Study of Congenital Malformations (ECEMC) reported in 2004 a neonatal prevalence of 7.11 per 10,000 newborns with a trend to decrease in a statistically significant manner.

According to the National Down Syndrome Society (NDSS). There are currently more than 400,000 people with Down syndrome in the United States.

There seems to be a statistical relationship (without knowing the mechanisms) between some maternal diseases such as Hepatitis, Mycoplasma hominis type 1, Herpes simplex type II and Diabetes and an increase in the incidence of DS onset; However, this statistical relationship is not as strong as in the case of maternal age. Some author has also related the low coital frequency as well as the use of anovulatories and spermicides with the appearance of the syndrome.

The probability of having a child with DS is higher than average for those parents who have had another previously. Typically the chance of having another child with DS in each subsequent pregnancy is one in every hundred live births. This must be weighed for each case with the mother's own risk according to her age. Family history also increases that risk.

Males with Down syndrome are considered sterile, but women frequently retain their reproductive capacity. In their case, the probability of fathering children with DS is also increased by up to 50%, although they can have children without trisomy.

Etiology

Each human cell has 23 pairs of chromosomes in its nucleus. Each parent provides half of the genetic information to its offspring, in the form of one chromosome from each pair. 22 of these pairs are called autosomes and the last one corresponds to the sex chromosomes (X or Y).

Traditionally, pairs of chromosomes are described and named based on their size, from pair 1 to 22 (from largest to smallest), plus the aforementioned pair of sex chromosomes. Chromosome 21 is actually the smallest, so it should be number 22, but an error in the 1960 Denver convention that assigned Down syndrome to pair 21 has survived to this day, and for reasons practices this nomenclature is maintained.

Chromosome 21 contains approximately 1% of an individual's genetic information in just over 400 genes, although the function of only a few is known precisely today.

Free trisomy

ICD-10 code: Q90.0

Down syndrome is caused by the appearance of an extra chromosome in the original 21st pair (three chromosomes: pair 21 “trisomy”) in the body's cells. The scientific nomenclature for this chromosome excess is 47, XX,+21 or 47, XY,+21; depending on whether it is a woman or a man, respectively. Most of the people with this syndrome (95%) owe the chromosome excess to an error during the second meiotic division (the one by which the gametes, eggs or spermatozoa lose half of their chromosomes). This variant is called "free" or regular trisomy, and the error is due in this case to an incomplete disjunction of the genetic material of one of the parents. (In the usual formation of gametes, the pair of chromosomes separates, so that each parent only transmits the information of one of the chromosomes of each pair. When disjunction does not occur, both chromosomes are transmitted).

The causes of the erroneous disjunction are not exactly known. As in other similar processes, multifactorial hypotheses have been proposed (environmental exposure, cellular aging...) without having been able to establish a direct relationship between any causative agent and the appearance of trisomy. The only factor that presents a stable statistical association with the syndrome is maternal age, which seems to support the theories that emphasize the deterioration of the genetic material over time.

In approximately 15% of cases the extra chromosome is transmitted by the spermatozoon and in the remaining 85% by the egg.

Translocation

Translocation of the long arm of chromosome 21 in one of the two chromosomes of pair 14.

ICD-10 code: Q90.2

After free trisomy, the most frequent cause of excess genetic material is translocation. In this variant, the extra chromosome 21 (or a fragment of it) is "stuck" to another chromosome (frequently to one of the two chromosomes of the 14 pair), so that the genetic count shows a figure of 46 chromosomes in each cell.. In this case there is no problem with chromosome disjunction, but one of them carries an "extra" fragment with the genes of the "translocated" chromosome. For the purposes of genetic information, it is still a trisomy 21 since the genetic endowment of that chromosome is doubled.

The frequency of this variant is approximately 3% of all DS and its importance lies in the need to carry out a genetic study on the parents to verify if one of them was a carrier without knowing it, or if this occurred for the first time in the embryo. (There are "healthy" carriers of translocations in which 45 chromosomes are counted, one of which is translocated, or attached, to another.)

Mosaicism

ICD-10 code: Q90.1

The least frequent form of trisomy 21 is called "mosaic" (around 2% of cases). This mutation occurs after conception, so the trisomy is not present in all the cells of the individual with DS, but only in those that come from the first mutated cell. The percentage of cells affected can range from a few to almost all, depending on when the abnormal segregation of the homologous chromosomes occurred.

Expression of excess genetic material

The biochemical expression of the syndrome consists of the increase of different enzymes. One of the best known and most important is superoxide dismutase (encoded by the SOD-1 gene), which catalyzes the passage of superoxide anion into hydrogen peroxide. Under normal conditions this contributes to the body's antioxidant defense system, but its excess determines the accumulation of H2O2, which can cause lipid and protein peroxidation and damage DNA. Other genes involved in the appearance of disorders associated with DS are:

• COL6A1: its increased expression is related to heart defects
• ETS2: its increased expression can be caused by skeletal muscle alterations
• CAF1A: the increased presence of this gene may interfere with DNA synthesis
• Cystathione Beta Synthase (CBS): its excess can cause metabolic alterations and DNA repair processes
• DYRK: in excess proteins encoded by this gene appears to be the origin of cognitive disability
• CRYA1: its overexpression can cause cataracts (premature opacity of the crystalline)
• GART: the increased expression of this gene can alter the DNA synthesis and repair processes
• IFNAR: it is a gene related to interferon synthesis, so its excess can cause changes in the immune system.

Several microRNAs are also found on chromosome 21, the overexpression of which has been related to the deregulation of certain target genes located outside chromosome 21. One of the overexpressed microRNAs is miR–155, which has been implicated in the regulation of genes involved in cardiac involvement such as TFAM, in cognitive defects such as MeCP2, which is also altered by other mechanisms in Rett syndrome.

Differential gene expression expressed in domains

In 2014, a novel study was published using the fibroblasts of discordant monozygotic twins for Down syndrome. One of the twins had the syndrome and the other did not. This fact made it possible to study the genomic variability due to Down syndrome, eliminating the genetic variation between samples.

The study of the transcriptome of these fibroblasts showed differences in the expression of 182 genes. In addition, a lower expression of proteins involved in signaling pathways and inflammatory response was observed. One of the most outstanding facts is that well-defined chromosomal domains with different expression profiles were found, alternating regions of increased expression with other regions of decreased expression. Following these observations, it was concluded that differential gene expression in Down syndrome is not randomly organized, but rather follows a specific pattern along the chromosomes. These deregulated gene expression domains are known as GEDDs (Gene expression dysregulation domains). In parallel, the study of the fibroblast transcriptome of healthy monozygotic twins was carried out and these GEDDs domains were not observed. The domain organization in discordant twins could be attributed primarily to the extra copy of chromosome 21. In addition, gene expression in the trisomic cell context could be less fine-tuned and less dynamic.

Prior to these discoveries, the organization of mammalian chromosomes into domains had been described with the identification of LADs (Lamina associated domains), whose fundamental characteristic was the generalized inhibition of gene expression. These regions present low gene density and decreased gene expression among other characteristics. Genes in LADs are overexpressed in the Down syndrome twin, in contrast to genes located outside of LADs. From the comparison between these lamin-associated domains and the GEDDs, two fundamental conclusions were obtained: that the genome-nuclear lamin interaction could be modified in trisomic nuclei (derepression in trisomic cells) and that the topology of the LAD domains is not perturbed by the presence of an extra chromosome.

Regarding the chromatin environment in these domains of deregulated gene expression, no changes are observed in the genome topology of fibroblasts with Down syndrome, suggesting the existence of possible epigenetic modifications in the chromosomal domains of trisomic cells. Comparison of DNA methylation changes between the healthy twin and the Down syndrome twin, and subsequent comparison with the GEDDs shows that altered gene expression cannot be fully explained by methylation changes. Some previous studies have described that the cell cycle is longer in the trisomic nucleus without affecting the replication time. This would result in a longer open chromatin time and therefore an increase in transcription. Lastly, changes in transcriptional activity could be influenced by changes in chromatin marks such as H3K4me3. GEDDs coincide with methylated histone modifications in trisomic fibroblasts.

In conclusion, it could be said that the presence of a small extra DNA fragment in the genome (1%) can alter the entire transcriptome. This is interesting because perturbation of gene regulation may be common to other chromosomal abnormalities. The mechanisms behind this organization into GEDD domains can be explained in two ways. The first is that the overexpression of one or more HSA21 genes modifies the chromatin environment of the nuclear compartment in trisomic cells, which would alter the transcriptome and give rise to different phenotypes. The second explanation would be that GEDDs appear as a result of extra chromosome material in trisomy 21.

Clinical picture

People with Down Syndrome of varied ages

Once born with Down Syndrome, you can appreciate the characteristic facial features 7-month-old baby, you appreciate the bridge under the nose, scratched eyes and hand features chatter In this photograph of an 8-year-old you can see more notorious features such as cranial disproportionality Young with syndrome, you notice your unprotected jaw

DS is the most frequent cause of congenital psychic cognitive disability. It represents 25% of all cases of cognitive disability. It is a genetic syndrome rather than a disease, although it has symptoms of being a disease and is frequently associated with some. The final genotypic expression is very varied from one person to another. As common features, we can highlight their peculiar physiognomy, a generalized muscular hypotonia, a variable degree of cognitive disability and growth retardation.

Regarding the phenotype, more than 100 peculiar traits associated with DS have been described, which can present in an individual in a highly variable number. In fact, none is considered constant or pathognomonic, although the joint evaluation of those that appear is usually sufficient for diagnosis. The severity and variability of the different phenotypes in the population depend to a large extent on the genetic and epigenetic background of the individual.

Some of the most important features are a flat facial and occipital profile, brachycephaly (predominance of transverse head diameter), oblique palpebral fissures, diastasis recti (abdominal muscle laxity), depressed nasal root, epicanthal folds (skin fold at the inner corner of the eyes), short and wide neck with excessive nuchal epidermal fold, microdontia, high-arched palate, clinodactyly of the fifth finger (curved growth towards the ring finger), single palmar crease, and separation between the first and second toes. The most frequently associated diseases are congenital heart disease and diseases of the digestive tract (celiac disease, atresia/esophageal or duodenal stenosis, ulcerative colitis...). The only features present in all cases are generalized muscle atony (lack of adequate muscle tone, which makes motor learning difficult) and cognitive disability, although to highly variable degrees. They also present a higher risk than general population for the development of diseases such as leukemia (acute myeloid leukemia), diabetes, hypothyroidism, myopia, or atloaxial dislocation (instability of the joint between the first two vertebrae, atlas and axis, secondary to muscular hypotonia and ligamentous laxity). All this determines an average life expectancy between 50 and 60 years, although this average is obtained from a wide inter-individual range (serious heart malformations or leukaemia, when they appear, can cause premature death). The degree of intellectual disability is also highly variable, although mild or moderate disability is accepted as a constant finding. There is no relationship between the external features and the intellectual development of the person with DS.

Most frequent associated diseases

Heart Diseases

Between 40 and 50% of newborns with DS have congenital heart disease, that is, a pathology of the heart present at birth, and this is the main cause of mortality in children with DS. Some of these diseases only require surveillance to verify that their evolution is adequate, while others may require urgent surgical treatment. Almost half of them correspond to atrioventricular septal defects (absence of more or less complete closure of the wall that separates the atria and ventricles). A third part (around 30% according to the sources) are closure defects of the ventricular septum (wall that separates the ventricles from each other), and other diseases such as ostium secundum, patent ductus arteriosus or tetralogy of Fallot.

In general, almost all of these defects cause inappropriate blood flow from the left to the right chambers of the heart, which increases pulmonary circulation. Tetralogy of Fallot, on the other hand, causes a reverse shunt, which decreases pulmonary blood flow and cyanosis appears (bluish color due to deficient oxygenation of the blood), especially in crises of crying or exertion. This is a serious pathology that requires surgery, usually in the first year of life, to repair the defects. Clinical examination of the newborn often does not offer suspicious data, so up to 50% of newborns with congenital heart disease may remain undiagnosed in the neonatal stage. For this reason, performing an ultrasound of the heart is recommended for all newborns with DS. Heart valve defects (most commonly mitral valve prolapse) may develop in adolescence or young adulthood. Adults with DS present, on the other hand, a lower risk of arteriosclerosis and lower blood pressure figures than those of the general population, which is why they are considered a population group protected against coronary disease (angina pectoris, myocardial infarction...).

Diagram of defects present in Fallot's tetralogy: A. Pulmonary stenosis, B. Finished aorta, C. Defect of ventricular sept, D. Right ventricle hypertrophy.

Eco-Doppler showing mitral insufficiency (inability of the valve to close completely, causing blood regurgitation to the left atrium, in blue. This degenerative valvular pathology may appear early in people with SD.

Congenital and degenerative cardiopathies in Down syndrome

Gastrointestinal disturbances

The frequency of occurrence of digestive anomalies or malformations associated with DS is much higher than expected in the general population: around 10% of people with DS present one of these disorders. The list of anomalies and their clinical expression (severity with which they occur) is very broad and variable, but those with the highest incidence are esophageal atresia, duodenal atresia or stenosis, anorectal malformations, aganglionic megacolon (disease of Hirschsprung) and celiac disease. Esophageal atresia consists of the interruption of the lumen of the esophagus (it is "obstructed" by incomplete development).

The risk of occurrence in children with DS is almost 30 times higher than in the general population, and requires early surgical treatment to prevent aspiration of saliva and food into the airways and allow adequate transit of food to the stomach. A similar picture occurs in duodenal atresia or stenosis (atresia: total obstruction, stenosis: partial obstruction), but in this case in the portion of intestine located immediately behind the stomach. It may be due to mechanical compression of the pancreas by an abnormality in its development called “annular pancreas”. This malformation (duodenal atresia) appears in up to 8% of newborn children with DS.

The imperforate anus is the most frequent anorectal malformation in children with DS: an incidence of 2-3% has been described (that is, two or three days out of every hundred newborn children with DS present it), while its Appearance in the general population is estimated at around one in 5,000. Its diagnosis is clinical and its treatment is surgical. Other relatively frequent disorders are megacolon, or excessive dilation of the distal portion of the digestive tract due to a relaxation defect, and celiac disease (digestive intolerance to gluten), which also appear more frequently than in newborns. without the syndrome.

Endocrine disorders

People with DS of any age are at higher than average risk of developing thyroid disorders. Almost half present some type of thyroid pathology during their lives. It is usually mild acquired or autoimmune hypothyroidism that in many cases does not require treatment, although when its severity requires it, it should be established as early as possible so as not to compromise the potential for intellectual development.

Vision disorders

More than half (60%) of people with DS present with a vision disorder amenable to treatment or intervention during their lifetime. Astigmatism, congenital cataracts or myopia are the most frequent diseases. Given the enormous importance that the visual sphere represents for the learning of these children, periodic check-ups are recommended to correct any deficit at this level early.

Hearing disorders

The particular anatomical arrangement of the face of people with DS determines the frequent appearance of transmission hearing loss (hearing deficits due to poor transmission of sound waves to brain receptors). This is due to the presence of trivial but very frequent diseases such as earwax impactions, serous otitis, cholesteatomas or ear canal stenosis, which causes decreased hearing acuity in up to 80% of these individuals.

Odontostomatological disorders

People with DS have a lower incidence of caries, but they frequently present morphological disorders due to dental malpositions, agenesis (absence of formation of any dental piece), or delayed dental eruption. Periodic check-ups are necessary for early correction of the most important disorders or those that compromise the masticatory or phonatory function.

Immunodeficiency and susceptibility to infection

People with DS present certain immunological anomalies of variable characteristics and intensity that are not easily assimilated to the cataloged immunodeficiencies. They are the main cause of the increased susceptibility of these people to certain infectious diseases. Other factors inherent to DS contribute to this: their frequent contacts with other people with neurological functional disabilities in education or special care centers, the intense affectivity of these people and the frequent coexistence of other anomalies, such as heart disease, which also entail a greater risk or vulnerability to infection.

Respiratory tract infections currently represent the second cause of death (after congenital heart disease) and the leading cause of hospitalizations and complications in children with DS.

Diagnosis

Measurement of the nucal fold by conventional ultrasound.

Since 1979, a blood test has been available in laboratories that makes it possible to establish a diagnostic suspicion for various congenital defects (spina bifida and other neural tube defects). This test is the determination of AFP (alpha-fetoprotein) values, which are increased in embryos with these developmental disorders. Several years later, a statistical relationship was established between low levels of this protein and the appearance of chromosomal disorders, especially DS. In later years some similar associations with other substances in maternal blood were discovered. Nowadays, the determination of AFP, estriol and hCG (human chorionic gonadotropin) is common to determine the risk of appearance of DS. This is called a "triple test." Some laboratories include the determination of inhibin (quadruple test). The values of these substances in the blood, as well as data about maternal age and personal and family history allow calculating a risk of DS onset, but do not imply a certain diagnosis. Certain measurements that are made during ultrasounds (length of the femur, thickness of the nuchal fold, and others) also provide information for calculating this risk, but they do not allow a definitive diagnosis to be established either.

In order to unequivocally detect the chromosomal abnormality during the prenatal period, chromosome counting techniques are used, so it is necessary to have a fetal cell. Access to embryonic cellular material can pose a certain risk, both for the mother and the fetus, so its indication is limited to those pregnancies in which a higher risk of the appearance of trisomy has been detected than in the general population. (positive triple test, maternal age over 35 or paternal age over 50, family or personal history of DS, or parents with a balanced translocation or other chromosomal abnormalities).

The most frequently used technique to obtain fetal genetic material is amniocentesis. This technique became widespread in the 1960s, and consists of ultrasound-guided puncture of the amniotic cavity through the abdomen. Thus, a sample of amniotic fluid is obtained, from which it is possible to obtain fetal cells for study. It should preferably be performed between weeks 14 to 17 of pregnancy. It is a relatively harmless technique with little discomfort, but carries a 1-2% risk of miscarriage, fetal injury, or maternal infection.

In the mid-1980s another technique began to be used, called chorionic villus sampling: a piece of placental material is obtained vaginally or through the abdomen, usually between 8 and 11 weeks of pregnancy. This technique can be performed before there is a sufficient amount of amniotic fluid necessary for amniocentesis to be carried out, and the chromosome study is faster since cell culture is not needed to obtain a sufficiently large sample. It presents a risk to the mother and fetus similar to that of amniocentesis.

Since 2012, there has been a test for the determination of fetal DNA in maternal blood that allows obtaining results with a sensitivity close to 100% (although positive results require confirmation by amniocentesis).

Treatment

The improvement in the treatment of diseases associated with DS has increased the life expectancy of these people, from 14 years a few decades ago, to almost normal (60 years, in developed countries) today. Throughout the last 150 years, different empirical treatments have been postulated (thyroid hormone, growth hormone, glutamic acid, dimethyl sulfoxide, vitamin and mineral complexes, 5-Hydroxytryptophan or piracetam) without any of them having been shown in double-blind longitudinal studies that its administration causes no significant positive effect on the motor, social, intellectual or verbal expression development of people with DS. To date, there is no effective pharmacological treatment for DS, although the studies carried out with the sequencing of the human genome allow us to predict a possible course of action (enzymatic or genetic), although in the still somewhat distant future.

The only treatments that have shown a significant influence on the development of children with DS are Early Care programs, aimed at early stimulation of the central nervous system during the first six years of life. Especially during the first two years, the CNS presents a very high degree of plasticity, which is useful for enhancing learning mechanisms and adaptive behavior. Individuals with severe learning difficulties have often been institutionalized, but it has been found that they must live at home, where they develop their full potential more fully. The curricular adaptation allows in many cases a normalized integration in regular schools, although their special educational needs must be taken into account. The mental age that they can reach is yet to be discovered, and depends directly on the educational and social environment in which they develop. When this is too protective, boys and girls tend (as would happen in a person without DS) to let themselves go, hardly discovering their potential. Stimulating contexts help to generate self-improvement behaviors that promote the development of intelligence. As a consequence, it is impossible to determine the jobs and performances that they can achieve during adult life. Strengthening their initiatives and breaking with the static approaches that have historically persecuted them are unavoidable social commitments that current societies must attend to.

Recently, a clinical trial has been published describing a moderate improvement with a treatment that combines cognitive stimulation with the administration of a compound present in green tea, epigallocatechin gallate. A multidisciplinary team led by doctors Mara Dierssen and Rafael de la Torre has shown that epigallocatechin gallate causes a significant improvement in the intellectual capacity and physical health of those affected. Said compound affects the DYRK1A gene, related to the formation of the brain and overactivated by the extra chromosome of Down syndrome; this gene produces an excess of proteins associated with cognitive alterations that this compound returns to normal levels.

Early attention

All children need stimuli for the proper development of their motor, cognitive, emotional and adaptive abilities. Children with DS are no exception, although their processes of perception and acquisition of knowledge are somewhat different from those of the rest of the population: The visual capacities of children with DS are, for example, superior to their hearing, and their ability Comprehensive understanding is superior to expression, so their language is scarce and appears with a certain delay, although they compensate for their verbal deficiencies with more developed skills in non-verbal language, such as eye contact, social smiles or the use of signs to communicate. understand. Muscular atony also determines differences in the development of the ability to walk, or in fine motor skills. All these aspects must be contemplated in specific early care programs (during the first six years of life) to maximize the most appropriate adaptive and learning mechanisms. Trying to teach a child with DS to read using conventional methods, for example, can become a very difficult task, if their superior visual ability is not taken into account. Today there are graphic methods (based on cards, or tokens, that associate image and word) that are achieving far superior results to the classic chain of letters in these children. In addition, the objective of these programs is not only the acquisition of skills, but that these are achieved much sooner, allowing to continue with educational programs that fully integrate the person with DS in normalized environments.

Vaccinations

Recommended vaccines, dose number and ages are listed in children with Down Sd. (footnotes: http://www.pap.es)

A good number of the infections that these children frequently suffer are preventable by vaccination, so that vaccines become an important tool in improving the health levels of these people. Experts recommend the following as systematic vaccinations for children with DS:

• Hepatitis B.
• Diphtheria, tetanus and cough.
• Measles, rubella and parotiditis.
• Polio.
• Gripe.
• Pneumococcal disease.
• Hepatitis A.
• Haemophilus disease influenzae type b.
• Varicela.
• Rotavirus.

Vaccination guidelines vary depending on the age and vaccination history of each individual, and will be determined by pediatricians or family doctors in each case.

Forecast

The mechanisms that cause disability in people with DS are still unknown, although the sequencing of the human genome and various studies carried out in subjects with partial translocations are beginning to serve to discover the genes responsible for the condition. These phenotypic maps have also been compared with some cases of monosomy 21 (absence of one of the two chromosomes of pair 21, the opposite situation to DS), thus obtaining maps of traits associated with excess or deficiency of chromosome dose. In the coming decades, all this knowledge about the functioning and expression of genes will surely make it possible to establish new therapeutic strategies capable of reversing the cognitive disorders associated with Down syndrome, and many of its associated problems.

In 1981 the first specific Health Program for people with DS was designed, but the most widely accepted and disseminated in the scientific community is the one designed by the Down Syndrome Medical Interest group (DSMIG). In these health programs, they contemplate the minimum preventive actions for an adequate early diagnosis and follow-up of diseases or complications that may occur, significantly improving the prognosis of these people. On the other hand, the increasingly widespread programs of early stimulation, and the progressive change of mentality that society is experiencing with respect to intellectual disability are the main reasons for the great transformation that is taking place around people with SD. Just a few decades ago, these people were removed from society in institutions, or hidden by their parents, based on a false guilt complex. Despite the enormous effort that is still pending, it has been verified how an environment based on acceptance, on the adaptation of learning methods and on the virtue of diversity is giving people with DS sufficient autonomy to work, living with a partner or developing artistic skills that were unthinkable a very short time ago.

Health program summary table for people with Down syndrome

Legislation

In Mexico

In April 2020, the Supreme Court of Justice of the Nation invalidated the new Law for the Comprehensive Care of People with Down Syndrome in Mexico City, since the proper consultation with the community directly involved was not carried out, that is, with people who have the syndrome. The legislature of that city received a period of ninety days to comply with this requirement and, meanwhile, the text of the law in force (the Law for the Comprehensive Care of People with Down Syndrome in CDMX) will continue to be applied.

In England

The British abortion law allows aborting children with Down syndrome until the day of delivery, although any other abortion is prohibited after 24 weeks of gestation.

Culture and Down syndrome

Cinema

• Charly (1967), led by Cliff Robertson.
• Johnny Stecchino (1991) by Roberto Benigni.
• The eighth day (Le huitième jourof Jaco van Dormael (1996).
• All for her. (Jewel), by Paul Shapiro (2001).
• Red ink (Peruvian film) (Nelson) by Francisco Lombardi (2000).
• I'm Sam. (2001), led by Jessie Nelson and interpreted by Sean Penn (2001).
• I love you, Eugene.directed by Francisco José Fernández (2002).
• The Dream Hunter (Dreamcatcherbased on Stephen King's homonymous novel, directed by Lawrence Kasdan (2003).
• León and OlvidoXavier Bermúdez (2004).
• Life and colorof Santiago Tabernero (2005).
• The words of Veroof Octavi Masiá (2005).
• Breakfast in Pluto (2005), led by Neil Jordan.
• Diary of a scandal (2006), led by Richard Eyre.
• Me, too. (2009), directed by Alvaro Pastor and Antonio Navarro and interpreted by Lola Dueñas and Pablo Pineda.
• Anita (2009), directed by Marcos Carnevale and interpreted by Alejandra Manzo.
• Jan's story (2016), directed by Bernardo Moll Otto.
• Champions (2018), directed by Javier Fesser.
• The Peanut Butter Falcon (2019), directed by Tyler Nilson and Michael Schwartz and starring Zack Gottsagen, Shia LaBeouf, Dakota Johnson and Bruce Dern.

Literature

• The girl who never grew up (The Child Who Never Grew) of Pearl S. Buck (1950).
• The Bolves of GodMorris West.
• « Broken Eyes» (Related Eyes) Women ' s models) of Almudena Grandes (1996).
• Maria Caracolitofrom Pipo Pescador (1997).
• The message of birdsby Joan Manuel Gisbert (2001).
• The Dream HunterStephen King.
• The meu germà PolIsabel-Clara Simó.
• The river of EdenJosé María Merino.
• To anger two meeks (The wrath of the meekManuel Esteban.
• My brother chases dinosaursGiacomo Mazzariol. Edit. Tinta Cloud (March 2017).

Sports

• Trisome Games, the I Olympiad for People with Down Syndrome, held in Florence in 2016.
• Sara Marín, five gold medals winner gymnast.