What is down syndrome?

Causes and Symptoms

Down syndrome is a genetic disorder—that is, a disorder arising from an abnormality in an individual’s genetic material. Down syndrome results from an incorrect transfer of genetic material in the formation of cells. Genetic information is contained in large “library” molecules of deoxyribonucleic acid (DNA). DNA molecules are formed by joining together units called nucleotides, which come in four different varieties: adenosine, thymine, cytosine, and guanine (identified by their initials A, T, C, and G). These nucleotides store hereditary information by forming “words” with this four-letter alphabet. In a gene, a section of DNA that contains the chemical message controlling an inherited trait, three consecutive nucleotides combine to specify a particular amino acid. This word order forms the “sentences” of a recipe telling cells how to construct proteins, such as those coloring the hair and eyes, from amino acids.

In living systems, tissue growth occurs through cell division processes in which an original cell divides to form two cells containing duplicate genetic material. Just before a cell divides, the DNA organizes itself into distinct, compact bundles called chromosomes. Normal human cells, diploid cells, contain twenty-three pairs (or a total of forty-six) of these chromosomes. Each pair is a set of homologues containing genes for the same traits. These chromosomes are composed of two DNA strands, chromatids, joined at a constricted region known as the centromere. The bundle is similar in shape to the letter X. The arms are the parts above and below the constriction, which may be centered or offset toward one end (giving arms of equal or different lengths, respectively). During mitosis, the division of nonsex cells, the chromatids separate at the centromere, forming two sets of single-stranded chromosomes, which migrate to opposite ends of the cell. The cell then splits into two genetically equivalent cells, each containing twenty-three single-stranded chromosomes that will duplicate to form the original number of forty-six chromosomes.

In sexual reproduction, haploid egg and sperm cells, each containing twenty-three single-stranded chromosomes, unite in fertilization to produce a zygote cell with forty-six chromosomes. Haploid cells are created through a different, two-step cell division process termed meiosis. Meiosis begins when the homologues in a diploid cell pair up at the equator of the cell. The attractions between the members of each pair then break, allowing the homologues to migrate to opposite ends of the cell, each twin to a different pole, without splitting at the centromere. The parent cell then divides once to form two cells containing twenty-three double-stranded chromosomes, and then divides again through the process of mitosis to form cells that contain only twenty-three single-stranded chromosomes. Thus, each cell contains half of the original chromosomes.

Although cell division is normally a precise process, occasionally an error called nondisjunction occurs when a chromosome either fails to separate or fails to migrate to the proper pole. In meiosis, the failure to move to the proper pole results in the formation of one gamete with twenty-four chromosomes and one with twenty-two chromosomes. Upon fertilization, zygotes of forty-seven or forty-five chromosomes are produced, and the developing embryo must function with either extra or missing genes. Since every chromosome contains a multitude of genes, problems result from the absence or excess of proteins produced. In fact, the embryos formed from most nondisjunctional fertilizations die at an early stage in development and are spontaneously aborted. Occasionally, nondisjunction occurs in mitosis, when a chromosome migrates before the chromatids separate, yielding one cell with an extra copy of the chromosome and no copy in the other cell.

Down syndrome is also termed trisomy 21, as it most commonly results from the presence of an extra copy of the smallest human chromosome, chromosome 21. Actually, it is not the entire extra chromosome 21 that is responsible but rather a small segment of the long arm of this chromosome. Only two other trisomies occur with any significant frequency: trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome). Both of these disorders are accompanied by multiple severe malformations, typically resulting in death within a few months of birth. Most incidences of Down syndrome are a consequence of a nondisjunction during meiosis. In about 75 percent of these cases, the extra chromosome is present in the egg. About 1 percent of Down syndrome cases occur after the fertilization of normal gametes from a mitosis nondisjunction, producing a mosaic in which some of the embryo’s cells are normal and some exhibit trisomy. The degree of mosaicism and its location will determine the physiological consequences of the nondisjunction.

In about 4 percent of all Down syndrome cases, the individual possesses not an entire third copy of chromosome 21 but rather extra chromosome 21 material, which has been incorporated via a translocation into a nonhomologous chromosome. In translocation, pieces of arms are swapped between two nonrelated chromosomes, forming hybrid chromosomes. The most common translocation associated with Down syndrome is that between the long arm (Down gene area) of chromosome 21 and an end of chromosome 14. The individual in whom the translocation has occurred shows no evidence of the aberration, since the normal complement of genetic material is still present, only at different chromosomal locations. The difficulty arises when this individual forms gametes. A mother who possesses the 21/14 translocation, for example, has one normal 21, one normal 14, and the hybrid chromosomes. She is a genetic carrier for the disorder, because she can pass it on to her offspring even though she is clinically normal. This mother could produce three types of viable gametes: one containing the normal 14 and 21; one containing both translocations, which would result in clinical normality; and one containing the normal 21 and the translocated 14 having the long arm of 21. If each gamete were fertilized by normal sperm, two apparently normal embryos and one partial trisomy 21 Down syndrome embryo would result. Down syndrome that results from the passing on of translocations is termed familial Down syndrome and is an inherited disorder.

The presence of an extra copy of the long arm of chromosome 21 causes defects in many tissues and organs. One major effect of Down syndrome is delayed mental development. The intelligence quotients (IQs) of affected individuals are typically in the range of 40–50. The IQ varies with age, being higher in childhood than in adolescence or adult life. The disorder is often accompanied by physical traits such as short stature, stubby fingers and toes, protruding tongue, and an unusual pattern of hand creases. Perhaps the most recognized physical feature is the distinctive slanting of the eyes, caused by a vertical fold (epicanthal fold) of skin near the nasal bridge that pulls and tilts the eyes slightly toward the nostrils. For Caucasians without Down syndrome, the eye runs parallel to the skin fold below the eyebrow; for Asians, this skin fold covers a major portion of the upper eyelid. In contrast, the epicanthal fold in trisomy 21 does not cover a major part of the upper eyelid.

It should be noted that not all defects associated with Down syndrome are found in every affected individual. About 40 percent of Down syndrome patients have congenital heart defects, while about 10 percent have intestinal blockages. Affected individuals are prone to respiratory infections and contract leukemia at a rate twenty times that of the general population. Although Down syndrome children develop the same types of leukemia in the same proportions as other children, the survival rates of the two groups are markedly different. While the survival rate for patients without Down syndrome after ten years is about 30 percent, survival beyond five years is negligible in those with Down syndrome. It appears that the extra copy of chromosome 21 not only increases the risk of contracting the cancer but also exerts a decisive influence on the disease’s outcome. Reproductively, males are sterile while some females are fertile. Although many Down syndrome infants die in the first year of life, the average life expectancy is about fifty years. This reduced life expectancy results from defects in the immune system, causing a high susceptibility to infectious disease. Many individuals with Down syndrome develop an Alzheimer’s-like condition later in life.

Treatment and Therapy

Trisomy 21 is one of the most common human chromosomal aberrations, occurring in about one out of every eight hundred live births. Even before the chromosomal basis for the disorder was determined, the frequency of Down syndrome births was correlated with increased maternal age. For mothers at age twenty, the incidence of Down syndrome is about 0.05 percent, but the incidence increases to 0.9 percent by age thirty-five and 3 percent at age forty-five. Studies comparing the chromosomes of the affected offspring with those of both parents have shown that the nondisjunction event is maternal about 75 percent of the time. This maternal age effect is thought to result from the different manner in which the male and female gametes are produced. Gamete production in the male is a continual, lifelong process, while it is a one-time event in females.

Formation of the female’s gametes begins early in embryonic life, somewhere between the eighth and twentieth weeks. During this time, cells in the developing ovary divide rapidly by mitosis, forming cells called primary oocytes. These cells then begin meiosis by pairing up the homologues. The process is interrupted at this point, and the cells are held in a state of suspended animation until needed in reproduction, when they are triggered to complete their division and form eggs. It appears that the frequency of nondisjunction events increases with the length of the storage period. Studies have demonstrated that cells in a state of meiosis are particularly sensitive to environmental influences such as viruses, x-rays, and cytotoxic chemicals. It is possible that environmental influences may play a role in nondisjunction events. Up to age thirty-two, males contribute an extra chromosome 21 as often as do females. Beyond this age, there is a rapid increase in nondisjunctional eggs, while the number of nondisjunctional sperm remains constant. Where the maternal age effect is minimal, mosaicism may be an important source of the trisomy. An apparently normal mother who possesses undetected mosaicism can produce trisomy offspring if gametes with an extra chromosome are produced. In some instances, characteristics such as abnormal fingerprint patterns have been observed in the mothers and their children with Down syndrome.

Techniques such as amniocentesis, chorionic villus sampling, and alpha-fetoprotein screening are available for prenatal diagnosis of Down syndrome in fetuses. Amniocentesis, the most widely used technique for prenatal diagnosis, is generally performed between the fourteenth and sixteenth weeks of pregnancy. In this technique, about one ounce of fluid is removed from the amniotic cavity surrounding the fetus by a needle inserted through the mother’s abdomen. Although some testing can be done directly on the fluid (such as the assay for spina bifida), more information is obtained from the cells shed from the fetus that accompany the fluid. The mixture obtained in the amniocentesis is spun in a centrifuge to separate the fluid from the fetal cells. The chromosome analysis for Down syndrome cannot be conducted directly on the amount of cellular material obtained. Although the majority of the cells collected are nonviable, some will grow in culture. These cells are allowed to grow and multiply in culture for two to four weeks, and then the chromosomes undergo karyotyping, which will detect both trisomy 21 and translocational aberration.

In karyotyping, the chromosomes are spread on a microscope slide, stained, and photographed. Each type of chromosome gives a unique, observable banding pattern when stained, which allows it to be identified. The chromosomes are then cut out of the photograph and arranged in homologous pairs, in numerical order. Trisomy 21 is easily observed, since three copies of chromosome 21 are present, while the translocation shows up as an abnormal banding pattern. Termination of the pregnancy in the wake of an unfavorable amniocentesis diagnosis is complicated, because the fetus at this point is usually about eighteen to twenty weeks old, and elective abortions are normally performed between the sixth and twelfth weeks of pregnancy. Earlier sampling of the amniotic fluid is not possible because of the small amount of fluid present.

An alternate testing procedure called chorionic villus sampling became available in the mid-1980s. In this procedure, a chromosomal analysis is conducted on a piece of placental tissue that is obtained either vaginally or through the abdomen during the eighth to eleventh week of pregnancy. The advantages of this procedure are that it can be done much earlier in the pregnancy and that enough tissue can be collected to conduct the chromosome analysis immediately, without the cell culture step. Consequently, diagnosis can be completed during the first trimester of the pregnancy, making therapeutic abortion an option for the parents. Chorionic villus sampling does have some negative aspects. One disadvantage is the slightly higher incidence of test-induced miscarriage as compared to amniocentesis. Also, because tissue of both the mother and the fetus are obtained in the sampling process, they must be carefully separated, complicating the analysis. Occasionally, chromosomal abnormalities are observed in the tested tissue that are not present in the fetus itself.

Prenatal maternal alpha-fetoprotein testing has also been used to diagnose Down syndrome. Abnormal levels of a substance called maternal alpha-fetoprotein are often associated with chromosomal disorders. Several research studies have described a high correlation between low levels of maternal alpha-fetoprotein and the occurrence of trisomy 21 in the fetus. Through correlating alpha-fetoprotein levels, the age of the mother, and specific female hormone levels, between 70 and 80 percent of fetuses with Down syndrome can be detected. Although techniques allow Down syndrome to be detected readily in a fetus, there is no effective intrauterine therapy available to correct the chromosomal abnormality.

The care of a Down syndrome child presents many challenges for the family unit. Until the 1970s, most children with Down syndrome spent their lives in institutions. With the increased support services available, however, it is now common for children to remain in the family environment. Although many children with Down syndrome have happy dispositions, a significant number have behavioral problems that can consume the energies of the parents, to the detriment of other children. Rearing a child with Down syndrome often places a large financial burden on the family; for example, they are particularly susceptible to illness, possibly necessitating extensive medical care, and also have special educational needs. Since children with Down syndrome are often conceived late in the parents’ reproductive period, the parents may not be able to continue to care for these children throughout their offspring’s adult years. This is problematic because many individuals with Down syndrome do not possess sufficient mental skills to earn a living or to manage their affairs without supervision.

All women in their mid-thirties have an increased risk of giving birth to an infant with Down syndrome. Since the resultant trisomy 21 is not of a hereditary nature, the abnormality can be detected only by prenatal screening, which is recommended for all pregnancies of women older than age thirty-four.

For parents of a child with Down syndrome, genetic counseling can be beneficial in determining their risk factor for future pregnancies. The genetic counselor determines the specific chromosomal aberration that occurred, using chromosome studies of the parents and affected child as well as additional information provided by the family history. If the cause was nondisjunction and the mother is young, the recurrence risk is much less than 1 percent; for mothers over the age of thirty-four, it is about 5 percent. If the cause was translocational, the Down syndrome is hereditary and risk is greater—statistically, there is a one-in-three chance that the next child will have Down syndrome. In addition, there is a one-in-three chance that offspring without Down syndrome will be carriers of the syndrome, producing it in the next generation. It is suggested that couples who come from families having a history of spontaneous miscarriages, which often result from lethal chromosomal aberrations, or incidence of Down syndrome, undergo chromosomal screening to detect the presence of a Down syndrome translocation.

Perspective and Prospects

English physician John L. H. Down is credited with recording the first clinical description of Down syndrome in 1886. Since the distinctive epicanthic fold gave children with the syndrome an appearance that Down associated with Asians, he called the condition mongolism—an unfortunate term implying that those affected with the condition are throwbacks to a more “primitive” racial group. Today, the inappropriate term has been replaced with the name Down syndrome.

A French physician, Jérôme Lejeune, suspected that Down syndrome had a genetic basis and began to study the condition in 1953. A comparison of the fingerprints and palm prints of affected individuals with those of unaffected individuals showed a high frequency of abnormalities in the prints of those with Down syndrome. These prints appear very early in development and serve as a record of events that take place early in embryogenesis. The extent of the changes in print patterns led Lejeune to the conclusion that the condition was the result of the action not of one or two genes but of many genes or even an entire chromosome. Upon microscopic examination, he observed that Down syndrome children possess forty-seven chromosomes instead of the forty-six chromosomes found in normal children. In 1959, Lejeune published his findings, showing that Down syndrome is caused by the presence of the extra chromosome that was later identified as a copy of chromosome 21. This first observation of a human chromosomal abnormality marked a turning point in the study of human genetics. It demonstrated that genetic defects not only were caused by mutations of single genes but also could be associated with changes in chromosome number. Although the presence of an extra chromosome allows varying degrees of development to occur, most of these abnormalities result in fetal death, with only a few resulting in live birth. Down syndrome is unusual in that the affected individual often survives into adulthood.

Bibliography

A.D.A.M. Medical Encyclopedia. "Down Syndrome." MedlinePlus. National Center for Biotechnology Information, 10 May 2013. Web. 21 Aug. 2014.

Cohen, William, Lynn Nadel, and Myra E. Madnick, eds. Down Syndrome: Visions for the Twenty-First Century. New York: Wiley, 2002. Print.

Faragher, Rhonda, and Barbara Clarke. Educating Learners with Down Syndrome: Research, Theory, and Practice with Children and Adolescents. New York: Routledge, 2014. Digital file.

Hassold, Terry J., and David Patterson, eds. Down Syndrome: A Promising Future, Together. New York: Wiley, 1999. Print.

Miller, Jon F., Mark Leddy, and Lewis A. Leavitt, eds. Improving the Communication of People with Down Syndrome. 2nd ed. Baltimore: Brookes, 2003. Print.

Moore, Keith L., and T. V. N. Persaud. The Developing Human. 9th ed. Philadelphia: Saunders/Elsevier, 2013. Print.

Morales, Guadalupe Elizabeth. Ernesto Octavio López Ramírez. Down Syndrome: Beyond the Intellectual Disability—Persons with Their Own Emotional World. New York: Nova Biomedical, 2013. Print.

National Center on Birth Defects and Developmental Disabilities. "Facts about Down Syndrome." Centers for Disease Control and Prevention 7 Aug. 2014. Web. 21 Aug. 2014.

National Down Syndrome Society. http://www.ndss.org.

Pueschel, Siegfried M. A Parent’s Guide to Down Syndrome. Updated ed. Baltimore: Paul H. Brookes, 2008. Print.

Pueschel, Siegfried M., ed. Adults with Down Syndrome. Baltimore: Brookes, 2006. Print.

Rondal, Jean A., et al., eds. Down’s Syndrome: Psychological, Psychobiological, and Socioeducational Perspectives. San Diego: Singular, 1996. Print.

Selikowitz, Mark. Down Syndrome: The Facts. 3rd ed. New York: Oxford UP, 2008. Digital file.

Wood, Debra. "Down Syndrome." HealthLibrary. EBSCO, 7 May 2014. Web. 21 Aug. 2014.