Sickle Cell Disease (SCD): Practice Essentials, Background, Genetics
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.
Trisomy 21 Karyotype
Trisomy 21 karyotype
G-banded karyotype of a trisomy 21 female, showing three copies of human chromosome 21 (HSA21).
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Dandy-Walker Syndrome
By: C. J. Fields
What is Dandy-Walker Syndrome?Dandy-Walker is a brain developmental condition in which the cerebellum, the part of the brain responsible for the coordination of movement, is malformed. Typically, the central part of the cerebellum called the vermis is absent or has not developed fully.
Hydrocephaly is a related complication in individuals with Dandy-Walker due to cysts that form in the brain's fourth ventricle and block the flow of cerebrospinal fluid (CSF). This blockage allows excessive CSF to accumulate, swelling the ventricle and putting pressure on the brain. This swelling can increase the child's head size resulting in a condition known as macrocephaly ("macro" meaning big and "cephaly" meaning head).
Prevalence and SymptomsThe prevalence rate of Dandy Walker is 1 in every 25,000 newborns, and signs and symptoms of the syndrome typically occur within the first year of a child's life. While some children with Dandy-Walker have normal intelligence (rare), the associated brain abnormalities caused by Dandy-Walker usually result in intellectual impairments that can range from mild to profound depending on the abnormalities of the child's brain. Symptoms of Dandy-Walker vary with age and can include the following:
Symptoms in Infancy:Other symptoms and effects associated with Dandy-Walker may include hypertonia; leg paralysis; seizures; malformations of the face, arms, legs, fingers, and toes; and vision and hearing problems, including deafblindness. While rare, death can result in children with Dandy-Walker syndrome, but is usually due to complications related to hydrocephaly.
Causes of Dandy-WalkerThe etiology of Dandy-Walker is suspected to be genetic in nature. Dandy-Walker syndrome has been found to occur most often in children who have an extra copy of chromosome 18 (trisomy 18). However, Dandy-Walker is not exclusive to children with trisomy 18, nor does it occur in every child with trisomy 18. Dandy-Walker has also been associated with trisomy 13, 21, & 9. While children and brothers and sisters of people with Dandy-Walker have been shown to be at an increased risk of acquiring the syndrome, there is not an established pattern of inheritability of the syndrome, and Dandy-Walker can occur in children whose families have no history of the disorder.
TreatmentThere is no treatment for the physical brain development abnormalities that are present with Dandy-Walker syndrome, however, a Ventriculoperitoneal shunt can be surgically implanted to allow excessive cerebrospinal fluid to be drained away from the fourth ventricle of the brain, reducing complications from hydrocephalus.
For motor complications and neurological and cognitive disabilities that are present, a team approach that utilizes various therapies and educational adaptations designed to meet each child's specific mobility and learning needs will be necessary.
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