Von Willebrand Disease: Types, Causes, and Symptoms

Trisomy 21 Causes Down Syndrome

One could argue that the presence of extra copies of chromosome 21 in DS patients is only a correlation between an abnormality and the disease. However, scientists have developed trisomic mouse models that display symptoms of human DS, providing strong evidence that extra copies of chromosome 21 are, indeed, responsible for DS. It is possible to construct mouse models of DS because mouse chromosomes contain several regions that are syntenic with regions on human chromosome 21. (Syntenic regions are chromosomal regions in two different species that contain the same linear order of genes.) With mapping of the human and mouse genomes now complete, researchers can identify syntenic regions in mouse and human chromosomes with great precision.

As shown in Figure 4, regions on the arms of mouse chromosomes 10 (MMU10), 16 (MMU16), and 17 (MMU17) are syntenic with regions on the long q arm of human chromosome 21. Using some genetic tricks, scientists have induced translocations involving these mouse chromosomes, producing mice that are trisomic for regions suspected to play a role in DS. (Note that these are not perfect models, because the trisomic regions contain many mouse genes in addition to those that are syntenic to human chromosome 21 genes.) These experiments have shown that genes from MMU16 are probably most important in DS, because mice carrying translocations from MMU16 display symptoms more like human DS than mice carrying translocations of MMU10 or MMU17.

Additional experiments have tried to identify particularly important genes within this region by transferring smaller segments of the interval on MMU16. For example, the three mouse models depicted on the right in Figure 4 carry different portions of MMU16, and all display some symptoms of DS. Of the three, the most faithful model of DS is the Ts65Dn mouse, which carries 132 genes that are syntenic with human chromosome 21. This particular mouse demonstrates many of the symptoms of human DS, including altered facial characteristics, memory and learning problems, and age-related changes in the forebrain.

These results are both daunting and promising. On one hand, they suggest that there will be no magic bullet for treating DS, because large numbers of genes are most likely involved in the condition. On the other hand, the results suggest that mouse models will be useful in developing treatments for the many DS patients around the world.

Figure 4: Regions of synteny between human chromosome 21 (HSA21) and mouse chromosomes (MMUs) 16, 17, and 10.

There are three partial trisomy mouse models of human trisomy 21, all trisomic for a portion of MMU 16. The gene content of these partial trisomies is shown on the right.

This Misunderstood Genetic Condition Has Afflicted Humans For Centuries, Fossil Evidence Reveals

Beneath the shadow of an ancient hilltop village of Alto de la Cruz situated in Spain's northern Navarre region, an infant was buried with all the pomp and finery not typically reserved for anyone in this region during the Iron Age. While the dead were usually cremated, this baby was placed beneath a dwelling surrounded by sheep and goat remains — likely offerings for the afterlife — bronze rings and a Mediterranean sea shell.

This infant, whose remains date back to nearly 800 to 500 B.C., wasn't the only one laid to eternal rest with such tender care. Since the 1940s, archaeologists have uncovered infants elsewhere in Spain, Greece, and Bulgaria buried in a similar reverent fashion. But only now, with the help of genetic sequencing, are scientists uncovering what exactly was so special about these children.

In a study published this week in the journal Nature Communications, a group of scientists found the baby of Alto de la Cruz and five other infant skeletons analyzed out of nearly 10,000 ancient remains had a condition familiar to us in the modern world: Down syndrome. Another skeleton of an infant girl also discovered in Alto de la Cruz had a different chromosomal condition known as Edwards syndrome.

"It will always continue to shock and surprise me how different yet similar we have been," Adam Rohrlach, the paper's first author and a statistician at the Max Planck Institute for Evolutionary Anthropology and the University of Adelaide in Australia, tells Inverse. "It's nice to know in our past, we absolutely loved everyone that we could have with respect to [Down Syndrome]. Babies were loved and in no case were they mistreated, in no case were they buried differently."

Down and Edwards syndromes belong to a class of chromosomal abnormalities called trisomies, where a pair of chromosomes — humans have 23 pairs for a total of 46 chromosomes — get an extra third. This tends to happen when, during cell division (either the mother's egg, father's sperm, or after fertilization), chromosomes are split unevenly such that a cell gets an extra copy instead of just a single chromosome. In the case of Down syndrome, there's one extra copy of chromosome 21; in Edwards syndrome, it's an extra copy of chromosome 18.

Remains of individual "CRU001" who was discovered in Alto de la Cruz. This baby boy had Down syndrome and was estimated to have been around 38 weeks gestation at his time of death.

Government of Navarre and J.L. Larrion.

For the most part, trisomies are lethal. Most babies born with Trisomy 18 die before they're born, and any who reach term won't make it past their first year of life. The odds are better for Trisomy 21 (aka Down syndrome) with advanced medical interventions that can significantly improve quality of life and life expectancy. However, thousands of years ago, anyone born with a trisomy wouldn't have survived.

While some studies suggest prehistoric societies like in northern Peru or modern-day Hungary cared for disabled individuals within the community, it's been challenging to peer into the archaeological record to say anything about trisomy, such as its prevalence in ancient times and potentially what life was like for such babies born, says Rohrlach.

In the new study, Rohrlach and his colleagues examined an archaeological library consisting of over 9,800 human skeletal remains collected from the last several decades. These human remains come from all over the world, but a majority of them hail from Europe. Some skeletons date as far back as the Paleolithic Period, or Stone Age, as old as 45,000 years ago; other remains are more contemporary within the last century.

To find which skeletons had a chromosomal abnormality, the researchers did shotgun sequencing, a method of sequencing DNA that doesn't focus on a specific part of the genome but quickly scans random bits from bones, teeth, or other organic remains. This is particularly useful for ancient DNA, which is often highly degraded and fragmented. Trisomy also tends to be easy to spot because you have that whole extra chromosome.

Rohrlach and his colleagues found seven cases of trisomy associated with infant skeletons ranging in age from as young as 26 weeks (meaning it died before birth) to six months of age. Six of the babies had Down Syndrome: three infants from Iron Age Spain, a girl from Greece dating back to the Bronze Age, a 16th-century infant from Finland, another infant from Stone Age Ireland, and a six-month-old girl from Bulgaria. An infant with Edwards syndrome who likely died at term was also found in Alto de la Cruz.

Artistic rendition of Las Eretas, an archaeological site that was once a proto-urban center in Early Iron Age Navarra, Spain. One infant skeleton with Down syndrome was uncovered at this site.

Iñaki Diéguez/Javier Armendáriz.

Considering most of the babies were buried within dwellings — especially in Iron Age Spain, where cremations were likely the norm — and with grave goods like fine jewelry (the infant from Greece was found adorned with a beautifully colored necklace made of glass, faience, and carnelian beads), the researchers believe their burials reflected the love their parents or immediate community had for them.

Another component of the study was to see if it was possible to see whether genetic conditions like Down syndrome could be identified just by looking at the bones themselves. For example, with Down syndrome, vitamin deficiencies can impact bone density and shape, the latter especially visible to the naked eye.

The skeletons did exhibit abnormalities consistent with Down and Edwards syndrome, such as poor bone density; one skeleton had a bit of bone protruding from his skull, which the researchers don't believe was the result of any violence inflicted on the child. But Rohrlach cautions it's hard to say for sure what's associated with the condition or with the mother's health impacting fetal development.

While the study did find the prevalence of Down and Edwards syndrome in ancient times was as rare as it is today, the biased sampling makes it difficult to definitively conclude how rare such pregnancies were.

Rohrlach hopes future research will unlock more insight into the lives of those whose stories aren't often told.

"These are people that either had a lived experience, or their experience was short but certainly influenced the people around them," he says. "Parents know what it's like to lose a child and that can't be a modern phenomenon. So to not report on that part of it, to not look into how they were buried and how they were loved — and maybe even the negative side, maybe how they were mistreated, which we, fortunately, didn't observe — that's just as important as the genetic results."

Learn Something New Every Day

Down Syndrome, Edwards Syndrome Found In Ancient Individuals

Researchers have reported chromosomal disorders discovered from prehistoric skeletal remains, dating up to approximately 5,500 years old — including six cases of Down syndrome and one case of Edwards syndrome. According to the authors of a paper published in the journal Nature Communications, the findings may represent the first time Edwards syndrome has been identified from historic or prehistoric remains.

Individuals with chromosomal trisomy carry three copies of a chromosome in their cells, instead of two. Trisomy of chromosomes number 21 or 18 result in Down syndrome and Edwards syndrome, respectively. There have only been a few documented cases of Down syndrome in ancient individuals, largely owing to difficulties in identifying genetic disorders without modern techniques for analysing ancient DNA samples. How certain ancient societies were affected by and responded to genetic disorders remains elusive.

Dr.Adam Rohrlach from the Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany and others screened almost 10,000 genomes from ancient human skeletal remains from either Ireland, Bulgaria, Greece, Spain or Finland for chromosomal trisomies and identified six cases of Down syndrome and one case of Edwards syndrome. These individuals, who mostly died either before or shortly after birth. Some of the cases were particularly ancient; two were from as far back as the Bronze Age (about 2,700 BCE) and one from the Neolithic period (about 3,500 BCE).

"When skeletal preservation and completeness was sufficient, we record all observed pathological lesions, and match these to osteological markers which are consistent with a diagnosis of the trisomy," they write.

"Three cases of trisomy 21 [Down syndrome], and the case of trisomy 18 [Edwards syndrome] were detected in two contemporaneous sites in early Iron Age Spain (800-400 BCE), potentially suggesting a higher frequency of burials of trisomy carriers in those societies," they write.

The authors note that all individuals appear to have been cared for after death through various rituals indicating recognition of them as part of their communities, and in a few cases were given exceptional burials or elaborate grave goods. For example, the individual buried in Early Iron Age Navarra, Spain, was buried with bronze rings, a Mediterranean seashell, and surrounded by the remains of three sheep and/or goats. The findings offer some perspective into the way that these conditions were recognised among past communities.

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