BIO 442 MENU
syllabus 
1 - genome
2 - mutate
3 -cell cycle
4 - karyotype
5 - chromoabn
6 -sex-determ
7 -prenatal
8 - mendelian
9 - complex
10 - non-trad
11 - clinical
12 - newborn
13 - teratog
14 - linkage
15 - DNA prof
16 - quanti
17 - links
18 - quizzes
(full title of lecture appears in status bar on the top or at the bottom of your window)
Biology 442 - Human Genetics
Newborn Screening
Newborn screening (sequential newborns in a population such as a state) is only done if the disease incidence is high enough in the population to warrant it if the testing is cost effective and if there is a treatment for the disease. In California, New Born screening includes one non-genetic disorder, hypothyroidism, and three genetic disorders, PKU, galactosemia, and sickle cell.
Children with hypothyroidism would be severely mentally retarded if they were not given thyroxin. Affected individuals used to be called "cretins." I once saw a 2 year old who was irreversibly MR because his parents took him home from the hospital and to another country prior to newborn screening. Sickle cell disease is treated with penicillin with some success. Babies with galactosemia cannot digest lactose, milk sugar, and must be places on a milk substitute. The defective enzyme is galactose-1-phosphate uridyltransferease and several variants are known including one which shows increased enzyme activity (LA) and other with less activity. The Duarte, D, allele makes 50% and the g allele makes less than 5%. Women with galactosemia experience premature ovarian failure and are advised to have their children early. The Duarte allele in the heterozygote (GD) has been associated with Müllerian agenesis, as was previously noted.
Children with PKU are placed on a restricted diet low in phenylalanine. It is essential that they stay on the diet until they are grown to prevent mental retardation. It is probably wise to keep them on the diet for all of their lives since there is some reason to believe that high phenylalanine levels can affect even the mature brain. Another, even more important reason, is that mothers with PKU who are not on the restricted diet will cause MR in their fetuses due to the high phenylalanine levels in their blood. The high levels of phenylalanine acts as a teratogen and interferes with normal differentiation and morphogenesis.
Other enzymes in the same pathway with PKU are known to cause other AR genetic disorders, namely, tyrosinosis, alkaptonuria (found in Egyptian mummies) and ,tyrosinase negative albinism (PKU children also have blond hair) Garrod was the first physician to understand that there were inborn errors of metabolism and he was aware of some of these disorders. Inborn errors of metabolism cause a build-up of the substrates and a deficiency of the product which can sometimes be helped by supplying the product and/or controlling the build up of substrates. There are several examples of which have already been discussed.
Other states have additional screening depending on the frequency of the disorder in their population (Maple Syrup Urine Disease, homocystinuria, biotinidase deficiency, CAH, CF, tyrosininemia).
Carrier Screening
Carrier (heterozygote) screening of adults in specific ethnic groups with a high incidence of a genetic disease has been done. The two most successful carrier screening programs are the TSD testing among Ashkenasi Jews where the carrier frequency is 1/30 and thalassemia in Greeks and Italians where the carrier frequency is 1/30. Sickle cell carrier frequency in African Americans is 1/12 and carrier screening is available but early attempts in mass screening were not handled well and were abandoned. However, newborn screening for sickle cell disease mandatory in California. Other disorders include thalassemia in SE Asians and Chinese where the carrier frequency is 1/25 and CF among northern Europeans where the carrier frequency is 1/23. Carrier testing by DNA analysis is limited if there is significant allelic heterogeneity as there is for CF. If the gene product is the source of the assay, then the detection is not dependent upon knowing the exact mutation in each affected family. Obviously, once a child is born with the disorder, there is a possibility of detecting the mutation and then monitoring future pregnancies by DNA analysis or protein/enzyme assay.
Treatment for Genetic Disorders
Three ways to work with genetic diseases are currently in use or being tested: 1. Indirect means: diet, medications, (or other means to supply missing products or eliminate excess substrates when the problem is a enzyme disorders) or medications, surgery, etc to correct problems; 2. Gene product replacement: direct enzyme replacement therapy or indirect enzyme replacement using bone marrow transplant (BMT) from a donor or tissue implants (myoblast transplants to supply dystrophin to the syncytial skeletal muscles). and 3. Gene therapy. Replacement of the defective gene with a functional gene. Initial attempts are being made using gene therapy with several disorders but there are many technical details which still need to be worked out. One technique involves inserting an RNA copy of the therapeutic gene in a "crippled" retrovirus vector which will adsorb to the target cells, enter and allow the therapeutic gene to be copied into the host cell DNA and stably integrated into its genome. The inserted vector DNA can then direct expression of the desired therapeutic gene in the target cells. This is called the in vivo gene therapy. Adenovirus vectors has been used to introduce CFTR into the lungs of CF patients with limited success. In ex vivo gene therapy, cells are removed from the patient and exposed to the vector in a tissue culture dish. Cells that take up the desired DNA are returned to the patient. ADA deficiency which causes severe immune deficiency, can be treated with BMT of an appropriately matched donor and improvement can be seen with blood transfusions, therefore, it was believed that very low levels of the enzyme could significantly improve the course of the disease. Therefore, T cells from 2 ADA-deficient children were treated in a tissue culture dish with a retroviral vector directing ADA gene expression. The number of T cells and several measures of immune function were significantly improved and ADA gene expression remained detectable for several years.
Current common treatment for genetic disorders include 1. Avoidance. Anti malarial drugs and fava beans for G6PD; barbiturates and alcohol for AIP; smoking for 1-antitrypsin (PI) deficiency. 2. Dietary restriction. Phenylalanine for PKU, galactose with galactosemia. 3. Replacement. Biotin for biotin deficiency; thyrozine for congenital hypothyroidism, Factor VIII in hemophilia; liver transplant for Wilson disease; insulin in diabetes; thalassemia uses transfusions with chelation therapy, folate to reduce risk for NTD. 4. Diversion. Sodium benzoate for urea cycle disorders; oral resins for FH, penicillamine for Cu chelation in Wilson disease. 5. Inhibition. Lovastatin for FH. 6. Depletion. Plasma exchange therapy for FH, phlebotomy for hemochromatosis.
Application of molecular prenatal diagnosis requires prior knowledge of the mutation(s) carried by the parent(s). These are usually determined from the study of a previously affected child. Genetic heterogeneity makes searching for unknown mutations a time-consuming and expensive process.
