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New Treatments for Genetic Disorders

This lecture will discuss modes of inheritance, dominant, recessive, chromosomes and how to look at chromosomes, dysmorphology in terms of looking at a kid with unusual features and kind of what you think about when you are trying to decide when to go further in a workup genetic disorders, gene disorders. Some syndromes with mental retardation genetic disorders, gene disorders. Syndromes with congenital heart disease, sort of making an association between the congenital heart defect and the known birth defects syndrome.

Mitochondrial inheritance: this is a pedigree from a large family in the Midwest that was affected with a mitochondrial disorder, and you may notice that there are a lot of people who aren’t alive in this pedigree. The patients who were determined to be affected with a mitochondrial mutation were the patients in black and ultimately after we did the molecular testing we found many others were also affected. However, the big issue here is you see many people who are affected. The other big issues that you may notice in this family tree is that all the people who are affected are only through the female line. That’s because your mitochondria are only given to you by your mother.

One of the mitochondrial disorders that we see is mitochondrial myopathy and cardiomyopathy, and that was the pedigree from the family you saw in the beginning of this section. These individuals have a mutation and a gene that encodes for a transfer RNA that transfers leucine. These individuals generally have symptoms if 80% of their mitochondria.

Another mitochondrial disorder is called MELAS. It stands for mitochondrial encephalopathy lactic acidosis and stroke. This is a mutation in the transfer RNA from leucine and lysine. These individuals present early in life with stroke-like episodes. They develop a myopathy and they have lactic acidosis.

Multifactorial inheritance. This is probably the most common form of inheritance, accounting for things like diabetes, coronary artery disease. Basically in multifactorial inheritance there is no clear pattern of inheritance and it seems to be a combination of sort of a genetic liability and environment interaction. Some common birth defect syndromes appear to be inherited in a multifactorial pattern and these include cleft lip and palate, and neural tube defects.

Let’s quickly look at some common aneuploidy’s now. We’ll talk about them again in detail but just to kind of get everybody’s feet a little wet. Aneuploidy’s are syndromes that are too many chromosomes that are not a multiple of 23, which is half of 46. The common ones we see are Down syndrome, trisomy 13 and trisomy 18. This is a nice young man with Down syndrome who is a model for the Lands End catalog. If you saw this child in your office or in the shopping mall or in the park, you would recognize him as a child with Down syndrome.

This is an individual who, at the time of this picture, was about five-years-old, and she has trisomy 18. Every once in awhile these kids do survive and one of the key things that we see in newborns with trisomy 18 is they have this kind of unusual overlapping finger pattern where they have their second digit and their fifth digit overlapped over their third and fourth digit.

The third common aneuploidy that we see is trisomy 13 and this is a child with trisomy 13. She has a cleft lip and palate, she is small for gestational age. You’ll notice when you count her fingers there are six, and that’s very common. She has a prominent calcaneus that’s sometimes called "rocker-bottom" feet and this would be the most common karyotype in an individual with trisomy 13, so three copies of 13.

Another aneuploidy that we see commonly is Turner’s syndrome. This is a young woman with Turner’s syndrome. She would have short stature for her age, she’s got some neck webbing, she’s got wide spaced nipples. She’s got what they call an "increased carrying angle" and I do too. When you put your arms down to your side you can’t bring them all the way down to your side. This is an infant with Turner’s syndrome and she’s got some neck webbing.

Deletion disorders. These are disorders that are caused by pieces of chromosomes that are missing. So loss of chromosome segments. Two of the common syndromes that we see are 4P- (minus) and 5P- (minus) and these individuals generally have dysmorphic features and developmental delays. This is a child with 4P- or Wolf-Hirschhorn syndrome. He’s got wide-spaced eyes, he has this sort of flat nasal bridge and high arched eyebrows that you may see. When you look in Smith they call it a Roman Shield-type face. These children have midline defects so they frequently have congenital heart disease, and they can have cleft lip and palate. So Wolf-Hirschhorn syndrome has a deletion of 4P.

This is another deletion disorder and this is a child with Cri de Chat, or 5P-. This child has facial asymmetry, she has a wide space between her eyes, she has marked epicanthal folds. This is her karyotype. She is missing a little piece on top of chromosome 5.

Wolf-Hirschhorn syndrome and Cri de Chat fall into disorders that are called contiguous gene syndromes, but frequently the deletions on those chromosomes are big enough to see with conventional metaphase studies.

This is another disorder caused by a micro-deletion disorder and this is velocardiofacial syndrome. These two young women are affected, this is their unaffected sister. You can see that they have different facies from their sister. They have this sort of long nose with narrow alae nasi - you know the sides of your nose is called the alae nasi - there’s a name for everything. They have narrow palpebral fissures and the current terminology that we are using now for velocardiofacial syndrome and DiGeorge syndrome is 22Q deletion syndrome.

Other things that could go wrong with chromosomes. Translocations. A translocation is essentially an exchange of genetic material between two homologous chromosomes. One in 500 people carry a balanced translocation. It’s a common cause of infertility. If you have a history of someone who has had multiple miscarriages, it’s one of the things that should be considered - is doing chromosomes on the parents. If an individual is balanced they are generally phenotypically normal. There are some exceptions. An individual who has an unbalanced translocation will generally have a number of birth defects. A special kind of translocation is a robertsonian translocation and this is when two of the acrocentric chromosomes are attaching together at the centromeres, so 13, 14, 15 and 20, 21 and 22, and those are the chromosomes that have that sticky satellite DNA on top. Frequently a carrier of a robertsonian translocation will have 45 chromosomes.

Reciprocal translocations. These are translocations that are exchanging material between two non-homologous chromosome segments. That involves the non-acrocentric chromosomes. Just a caveat; this can also involve the long arms of the acrocentrics. The risks to the offspring vary with the size of the segment involved. So you generally give people numbers if they are carriers, but you can say that they have a risk of having abnormal offspring or miscarriage, and you would be able to offer amniocentesis for prenatal diagnosis.

Approach to a child with dysmorphic features. General considerations when you see a child who appears dysmorphic, growth parameters are really important. So height, weight, head circumference. Many syndromes have abnormal growth patterns and these are important clues. Asymmetric growth patterns; what if a child has a really big head but an average size body? Neurofibromatosis is an example of kids who have really large head circumferences but fairly normal size bodies. Then there are some syndromes that have prenatal or postnatal onset of growth deficiency.

Common birth defect syndromes; this syndrome has been on exams for a very long time. This was on my Board exam, it was on my pediatrics Board exam, it was on my genetics Board exam. Does everybody know what this is? Okay good. So you’ll all get that question right. So Cornelia de Lange’s syndrome. These children are quite mentally retarded, although there have been some children who have the phenotype and are mildly affected. So there is sort of spectrum. These children generally are microcephalic, they tend to be hairy.