When 2 rights make a wrong: Combating childhood heart disease
When the body can’t distinguish its right side from its left during development, a child can develop a condition called heterotaxy in which the heart is severely malformed, leading to congenital heart disease. To improve survival in these children, researchers at Yale School of Medicine sought to identify the genes that cause heterotaxy. They have shown in a new study that patients with heterotaxy have considerably more copy number variations (CNVs) on their genomes than do control patients.
The findings are published January 31 in Proceedings of the National Academy of Sciences (PNAS) Early Edition. Mustafa Khokha, M.D., assistant professor of pediatrics and genetics at Yale, and co-authors studied over 200 patients with heterotaxy as well as a large number of control subjects. They identified and analyzed genome-wide CNVs in humans and then tested these genes in a frog model called Xenopus tropicalis. Copy number variations are insertions or deletions of regions of the genome, so parts of the genome might be deleted or a region might be duplicated.
Khohka said that the frog is a good model for testing genes identified from patients with heterotaxy because the developmental program to establish the left-right axis is nearly identical in frogs compared to humans.
“Five of the seven genes we identified in heterotaxy patients also cause left-right axis abnormalities in frogs when CNV genes were reduced,” said Khohka. “Therefore, we have shown that children with heterotaxy have a higher burden of CNVs that also cause abnormalities in frogs.”
Khokha explained that while humans may appear symmetric across our right and left sides externally, internally our organs are not symmetric. For example, our heart sits on the left side of our body along with the stomach and spleen. Our liver sits on the right. Also, the left and right side of the heart perform very different functions; the right side pumps blood to lungs while the left pumps blood to the body. In children with heterotaxy, because the body cannot properly place the organs on the left or right sides, the heart in particular is severely malformed and can lead to severe disease. In fact, about 90 percent of these children have complex congenital heart disease, which requires surgery to reconstruct their hearts for the child to survive.
Heterotaxy syndrome is a rare birth defect that involves the heart and other organs. The beginning of the word (hetero-) means “different” and the end (–taxy) means “arrangement.”
In heterotaxy syndrome, paired organs, such as the lungs or kidneys, are often mirror images of one another instead of having the unique characteristics of right and left that are normally present.
There are different forms of heterotaxy. All usually involve heart defects, of varying type and severity. In addition, organs such as the stomach, intestines, liver and lungs may be in abnormal places in the chest and abdomen. The intestines may have malrotation, which is when the loops of bowel are lined up incorrectly. With this problem the bowel can twist on itself (volvulus), so many children with malrotation need abdominal surgery to correct it. Some children with heterotaxy can have a very serious condition of the liver called Biliary atresia. This also may require surgical intervention. There may also be irregularities with the skeleton, central nervous system and urinary tract.
The spleen may not work correctly or may be missing entirely. This can cause many problems, because the spleen helps the body fight infections. When the spleen is missing or doesn’t work correctly, patients have a more difficult time recovering from surgeries or infections. (Patients with heterotaxy may require multiple surgeries.) In some cases, there may be a functioning spleen, but it may be divided into several smaller spleens (polysplenia).
Sometimes children with heterotaxy have dextrocardia. This means the heart is in the right chest instead of the left chest.
Here are general descriptions of two types of heterotaxy. The morphology (structure) of the heart varies from child to child. The Cardiac Center team will explain your child’s heart structure to you in detail. Types of heterotaxy include:
* Asplenia or right atrial isomerism: Children with this condition have multiple heart defects. They may have septal defects (holes between the tissue dividing the two sides of the heart) and problems with heart valves, particularly the pulmonary valve. They may also have abnormalities of the blood returning from the lungs to the heart (anomalous pulmonary venous connection). The spleen may be absent (asplenia), and the liver and other organs may be on the wrong side of the body.
* Polysplenia or left atrial isomerism: Children with this condition may have septal defects (holes between the tissue dividing the two sides of the heart) as well as problems with heart valves and the heart’s electrical system. Some children with this problem have complete heart block, which is when the upper-chamber electrical system does not communicate with the lower-chamber electrical system. Most children require pacemakers for this problem. The spleen may be absent, or there may be several small spleens (polysplenia), instead of one spleen.
What do the terms “right atrial isomerism” and “left atrial isomerism” mean? The heart has tiny pouches, one on each of the two upper chambers, called atrial appendages. In a normal heart, the left atrial appendage looks different than the right. In heterotaxy, the two appendages look similar. “Isomerism” means mirror images. Hence the terms “right atrial isomerism” and “left atrial isomerism.”
“This study is a big step toward understanding what causes congenital heart disease and hopefully will give us some idea of which genes lead to better or worse outcomes,” said Khohka. “We also hope to improve our understanding of the genes that affect left-right development and the mechanisms involved in determining your left side from your right side. We also believe our results show that combining human genetics with rapid model systems such as the frog will allow us to rapidly identify genes that affect embryonic development and better understand the causes of these childhood diseases.”
Martin Brueckner, a senior author on this study has been awarded a U01 grant from the NHLBI of the NIH. In this “bench to bassinet” program, they plan to identify many more patients with congenital heart disease and identify the mutations that have caused their disease. A better understanding of the mutations that cause congenital heart disease might allow physicians to tailor surgery and long-term care to improve patient outcomes, he said, adding that congenital heart disease is clearly a broad spectrum of diseases and identifying the causative genes will allow physicians to better define the specific disease for any one patient.
Signs and Symptoms
Babies with Heterotaxy can have symptoms that start shortly after birth from any of the organs listed above. The heart is involved about 80%
of the time and the first thing that may be seen is a blue color to the skin (cyanosis) that most commonly is found on the lips and under the
fingernails. Over time, your baby may develop poor feeding, fast breathing, increased sweating when they eat, or poor weight gain. All of these
findings are signs that the heart is not able to pump enough blood to the body to meet its needs and is called “heart failure.” Sometimes your
doctor might hear an unusual heart beat or an extra sound when they listen to the heart (heart murmur). Heterotaxy can also affect the liver and
intestine. Biliary atresia is due to a failure of the bile ducts in the liver to form correctly and can cause jaundice (a yellow color of the skin). If
the intestines are abnormally positioned inside the body, then it is more likely for the intestine to get blocked and your baby may have vomiting
or swelling of their stomach when they eat. When the spleen is involved your child can have either no spleen (asplenia) or many little spleens
(polysplenia). Even if there are many little spleens, sometimes they don’t work well enough to help fight off certain types of infections.
Possible Causes
The exact cause of Heterotaxy is not known, but the symptoms result from the way that the internal organs turn into position during
fetal development. This rotation can be affected by many different factors including: infection, genetics, or exposures to certain chemicals.
There are a few reports of families having several members with Heterotaxy, but the exact cause has not been identified yet.
Diagnosis
Making the diagnosis of Heterotaxy syndrome involves an ultrasound of the heart (echocardiogram) that will allow a pediatric
cardiologist to best see the structures of your child’s heart. An electrocardiogram (EKG) is usually done to ensure there are no heart rhythm
problems. An x-ray can help to evaluate the heart size and look for what side the abdominal organs and heart are on. The intestines can also be
twisted incorrectly and an upper gastrointestinal series should be done to look for this. A liver-spleen scan should also be done to check for a
functioning spleen. Finally, a cardiac catheterization procedure may be needed for a more detailed view of the child’s heart structures in
preparation for corrective surgery.
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In addition to Khokha and Brueckner, other Yale authors on the study include Richard P. Lifton, Khalid Fakhro, Murim Choi, Stephanie M. Ware, John Belmont, and Jeffrey Towbin.
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Contact: Karen N. Peart
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203-432-1326
Yale University