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Chromosomal anomalies These are genetic diseases that are due to an abnormal number or structure of the chromosomes. A frequent chromosome anomaly is Down syndrome. Monogenic diseases These are genetic diseases that are due to a mutation(s) in only 1 gen. They can be inherited in different ways: autosomal dominant, autosomal recessive, X-linked or Y-linked. Frequent monogenic diseases are cystic fibrosis, thalassemia and fragile X syndrome. Metabolic diseases These are monogenic that are due to the deficiency of a protein which is important in the metabolism. Examples of metabolic diseases are Phenylketonuria (PKU) and Gaucher disease. Multifactorial diseases These are diseases with a small genetic component. They are due to an interaction between environmental factors and several hereditary factors. Examples of multifactorial diseases are spina bifida, and diabetes. Specific diseases Specific information on genetic diseases can be found on these websites. Chromosomal anomalies A. Deviations of the number of chromosomes (aneuploidy) Each individual has 46 chromosomes in every cell of the body. Individuals with too many or too few chromosomes have a chromosome anomaly referred to as a numerical chromosome anomaly or aneuploidy. Since there are 46 chromosomes there exist chromosome anomalies. In most of the cases the patients suffer from serious physical and mental handicaps. The most well-known example of a chromosome anomaly is down syndrome. In 1866 Doctor Langdon Down described this chromosome anomaly for the first time in the medical literature. In genetics, and in medicine in general, it is quite common to call diseases after the doctor that described them for the first time. A syndrome is a disease with anomalies of several organs, such as the eyes, brain and the heart. Many syndromes are due to a genetic anomaly.
Down syndrome is caused by an extra (third) chromosome 21. These individuals have therefore not 46, but 47 chromosomes. Whereas everyone has two chromosomes 21, they have 3. Therefore, Down syndrome is also called trisomy 21. The trisomy is usually due to an abnormality of the egg of the mother: normally all reproductive cells (eggs and sperms) carry only 23 chromosomes (one of each). At fertilisation the 23 chromosomes from the female egg than join the 23 chromosomes from the male sperm to form a fertilised egg or zygote with the normal 46 chromosomes. When one of the reproductive cells has an extra chromosome 21, the fertilised egg has 47 chromosomes with 3 chromosomes 21, resulting in Down syndrome.
With the age of the mother, particularly from 36 year on, increases the risk that the egg contains 2 instead of 1 chromosome 21. Therefore, also the risk on a child with Down syndrome steadily increases with maternal age. For this reason pregnant woman with a certain age (frequently from the age of 36 years) have prenatal tests to exclude Down syndrome. An average couple has risk of approximately 1 on 200 on a child with a chromosome anomaly, and 1 on 600 for trisomy 21.
Other numerical chromosome anomalies are trisomy 13 (Patau syndrome), and trisomy 18 (Edwards syndrome). Trisomy 13 is a very severe chromosome anomaly with early death. The trisomy 13 babies frequently have cleft lip and palate, and congenital heart malformations.
Also trisomy 18 or Edwards syndrome is a serious syndrome where the babies generally die in the first life year. The babies have malformations of many organs.
The numerical chromosome anomalies of the sex chromosomes, the X and Y chromosome, are less severe. Girls with Turner syndrome have 1 instead of 2 X chromosomes (monosomy X): they are small, have no menstruation and are sterile. Frequently also there exists a broad neck (webbed neck). The intellectual development is normal or slightly behind.
When the mother of a child with a numerical chromosome anomaly is pregnant again, there is a slightly increased risk on a second child with a chromosome anomaly (1-2% on top of the risk defined by the maternal age). The risk in other family members is not increased. The numerical chromosome anomalies are therefore in fact not hereditary in the sense of transmission to the progeny, but still they are anomalies of our hereditary material.
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A. Autosomal dominant diseases Autosomal dominant diseases are hereditary diseases where a mutation in one copy of an autosomal gene causes the disease. A person with such a disease therefore has 1 mutated and 1 normal copy of the disease gene. On the other hand the mutation can also arise in the patient as a new mutation (referred to as de novo mutation). Each patient with an autosomal dominant disease has a risk of 1 on 2 on a child with the same syndrome, although the severity of the syndrome can change from person to person, even within the same family.
Autosomal dominant diseases are frequently inherited from generation to generation. When a generation is skipped, one says that the disease has incomplete penetrance.
B. Autosomal recessive diseases Autosomal recessive diseases are hereditary diseases with a mutation in both copies of the gene. The patients have therefore 2 mutant genes and no normal gene. A family member with a recessive mutation in 1 copy and a normal second copy is a carrier or heterozygote. Both parents of a patient with an autosomal recessive disease are always carriers. Usually the parents do not know they are carriers until the birth of the first affected. The risk on future children with the disease (recurrence risk) is 1 on 4 for each child. The children of an affected patient are all carriers, but there exists only a small risk that the children of a patient also show the disease. Healthy brothers and sisters of a patient have a chance of being a carrier of 2 on 3. Related (consanguineous) parents have an increased risk on autosomal recessive diseases because the risk that they are both carrier of the same recessive mutation is increased as compared to unrelated couples.
C. X-linked diseases X-linked diseases are hereditary diseases with a single mutation in an X-linked gene. Most of the X-linked diseases are more serious in men than in women because men have only 1 X chromosome, whereas women have 2. Frequently female members are carriers of the mutation, but have no symptoms of the disease. Exclusion of carriership in these female family members of affected men is very important because they a risk to transmit the disease to affected sons. The risk that a carrier female has an affected son is 1 on 4. The mutation also arise in the patient as a new mutation (de novo mutation). The risk that an affected man transmits an X-linked disease to his sons is not increased as he transmits his Y and not his X chromosome to his sons. However, each of his daughters will be a carrier with possibly mild symptoms of the disorder.
E. Characteristics of monogenic diseases The most important characteristics of monogenic diseases are summarised in the table below.
* = Risks apply to the patient which has the genetic disease. Metabolic diseases Metabolic diseases are hereditary diseases of the metabolism, also referred to as inborn errors or metabolism. They arise by gene mutations, which lead to a deficiency of a particular enzyme. Enzymes are proteins that convert certain substances into our body into other substances. A person with a metabolic disease has therefore a deficiency of a particular enzyme leading to an abnormal metabolism of specific metabolites (an excess of some metabolites, and a shortage of other metabolites). Metabolic diseases have a recessive inheritance (autosomal recessive or X-linked recessive). There exist more than 100 metabolic diseases. These can be detected by assay of the activity of the deficient enzyme in blood or skin cells. Also determination of metabolites in blood or urine is possible to detect these diseases. Molecular testing of the gene which is mutated in the disease, can confirm the diagnosis. Some well-known inborn errors or metabolism are phenylketonuria (PKU) and Tay-Sachs disease.
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