GENETIC SELECTION > INFORMATION > SHEET 2

Inherited genetic disorders

	Dr Fisher

DOCTOR FISHER: Annie, I’m sorry to tell you that you have a condition known as Friedreich’s ataxia.

Friedreich’s ataxia is an inherited disease of the central nervous system. It’s not an illness as such.

You can’t catch it, Friedreich’s ataxia is a genetic disorder.

In The Gift, Annie inherits a rare genetic disorder called Friedreich’s ataxia, caused by defects in a single gene. Friedreich’s ataxia is an inherited disease of the central nervous system in which there is a progressive deterioration of coordination and muscle control. It is caused by a single defective gene. This recessive disorder is very rare. Onset usually occurs between 5 and 20 years of age, the highest incidence being at puberty. Currently, there is no cure.

Friedreich’s ataxia is one of approximately 4000 known inherited genetic disorders in humans caused by defects in single genes. Most of them are rare. However, it has been estimated that we all carry some defective genes. In the play, Barbara Kaye, her husband and their son, Ryan, are all found to be healthy carriers of a defective copy of the gene. It is important to understand why, just like the characters in the play, we all potentially carry defective copies of genes. Usually we will remain unaffected throughout our lives. Unknowingly Barbara Kaye inherited a defective copy of the gene for Friedreich’s ataxia from one of her own parents. Therefore, Barbara was a carrier for Friedreich’s ataxia. However, as well as inheriting a defective copy of the gene for Friedreich’s ataxia from one parent, Barbara also inherited a normal copy of the gene from her other parent. The reason why Barbara was able to lead a healthy life, is because the normal copy is a dominant gene and ‘masks’ the defective copy of the Friedreich’s ataxia gene she carries.

DOCTOR FISHER: Both you and your husband Mrs Kaye, had this ‘rogue’ gene. But it didn’t show up in either of you, because you had each been born with a matching working gene which cancelled it out. It’s like - [ takes out two coins] say that the heads is the working gene, and the tails is the rogue gene for Friedreich’s ataxia. You and Annie’s father had, let’s say, one head and one tail each. You were carriers of the ‘tail’ or rogue gene. So, your children had a one in four chance of inheriting the disorder - two tails, and a two in four chance of being carriers - one tail - themselves. Annie, has two rogue genes....
Both Barbara and her husband (Annie’s and Ryan’s father)
were unknowingly carriers of a defective gene for Friedreich’s ataxia.

	Ryan Kaye

RYAN: OK…um…I know, Doctor, that Friedreich’s ataxia follows a classic Mendelian pattern of inheritance. That is to say, I have a one in four chance of inheriting this disorder, and a two in four chance that I will be carrying the defective gene and pass it on to my children.

According to Mendel’s laws of inheritance, given that both parents were healthy carriers, Annie and Ryan had, at conception, a one in four chance in the great lottery of inheritance of:

• inheriting two defective copies of the Friedreich’s ataxia gene;
• inheriting two normal genes;
• inheriting one normal and one defective gene;
• inheriting one defective and one normal gene.

Tragically the dice went against ANNIE and she inherited defective copies of the Friedreich’s ataxia gene from both her mother and her father. Her brother, RYAN, on the other hand inherited one defective and one normal gene, which means that he was a healthy carrier like his parents.

	THE KAYE FAMILY TREE
	Friedreich’s ataxia gene is denoted by a black ball.
	Barbara and her husband were healthy carriers of Friedreich’s ataxia.
	Annie inherited two copies of the Friedreich’s ataxia gene. She began to show symptoms at 16.
	Ryan inherited one normal and one defective gene. He is a healthy carrier of Friedreich’s ataxia.
	Jennifer is also a Friedreich’s ataxia carrier.
	Mark carries two normal copies of the gene and is not a carrier of Friedreich’s ataxia.

INHERITED SINGLE GENE DISEASES

Inherited single gene diseases may show three common types of inheritance pattern:

1. Recessive
2. Dominant
3. Sex-Linked

1. RECESSIVE DISORDERS

DOCTOR FISHER: Friedreich’s ataxia is an inherited disorder. It is a relatively rare recessive disorder as you need both parents to be carriers of the Friedreich’s ataxia gene.

Friedreich’s ataxia is a recessive disorder. Other recessive disorders include cystic fibrosis, sickle-cell disease and Tay-Sachs disease. If both parents of a child are like Barbara Kaye and her husband, who both carry one defective copy of the same gene, their children will have:

• a one in four chance of being affected by the disorder;
• a two in four chance of being a carrier for the disorder;
• a one in four chance of not even being a carrier.

Why is this?
As in The Gift, problems only arise when a man and a woman, who each carry one defective copy of a single gene, have children. The chances of both the man and the woman carrying the same recessive disease gene are relatively rare.

Cystic fibrosis is the most common single gene defect to affect northern Europeans. About 1 in 25 Caucasians carry one defective copy of the cystic fibrosis gene and one normal copy of the gene, as inherited either from their mother or from their father. The chances of two carriers being partners is (1 in 25) x (1 in 25) that is 1 in 625. As cystic fibrosis is a recessive genetic disease there is a one in four chance of each child born, to two carriers, of receiving the defective gene from both parents and suffering from the disease. The incidence of cystic fibrosis is roughly 1 in 2500 births - about what would be expected from a one in four chance out of every 625 couples who have children.

2. DOMINANT DISORDERS

	DOMINANT DISORDER
	In this family, the father is affected, even though he has just one copy of the 'rogue' gene.
	There is a 50/50 chance a child will be affected. In this case only one daughter is affected.

In dominant disorders the defective copy of the gene is dominant. One of the parents needs to carry a defective copy of the gene (and hence will be affected) for the disease to manifest itself in their children. Children, in cases where one parent is affected, have a 1 in 2 chance of inheriting a defective copy of the gene at conception. Such children will be affected by the disorder, even though they carry one defective and one normal copy of the gene. Unaffected (disease free) individuals cannot transmit such dominant disorders, since in order to pass the disease on to their children, they must carry a defective copy of the gene.

A particular problem with some dominant disorders is highlighted by Huntington’s disease. This serious brain disease is a dominant disorder affecting about 100 000 people worldwide. The symptoms of Huntington’s disease most commonly first appear in individuals of between 40 and 50 years of age. This is an age at which they are likely to have completed their own families, inadvertently passing on their disorder to their children while they are asymptomatic and apparently healthy.

The difference between a recessive and a dominant condition
It is worth emphasizing the exact difference between a recessive and a dominant condition. In the latter case, a defective copy of the gene is doing something that actively harms the body. One copy, on its own, is therefore sufficient to do serious damage, even when its partner gene is normal. Therefore, such a gene dominates. In the case of a recessive disease, the responsible gene is failing to make a crucial protein. In carriers, one copy of the gene makes enough of this protein for normal function, while the other does not produce a working protein. Such is the adaptability of the human body that carriers usually get by on half a dose of protein. Only when a person gets two faulty copies of a gene are they in a position in which no functional protein is being made. Then they suffer from symptoms due to the lack of that protein.

3. X-LINKED RECESSIVE DISORDERS

	X-LINKED
	Sperm and egg cells have just one sex chromosome and one set of autosomes.
	The sex of the baby depends on whether an X or Y bearing sperm fertilizes an egg.

In humans, there are 22 different autosomal chromosomes (simply numbered chromosome 1 through to chromosome 22) and two sex chromosomes (called the X and Y chromosomes). Sperm and egg cells, together with the cells that form them, are often referred to as germ-line cells. While other cells of the body (somatic cells) carry two sets of chromosomes (2 x 22 autosomal + 2 sex chromosomes), germ-line cells are unusual in that they carry just one set of autosomal chromosomes and one sex chromosome (22 + 1). When an egg is fertilized by a sperm at conception a single cell is formed with two sets of autosomes and two sex chromosomes. The sex of the embryo is dependent on whether the fertilizing sperm carried an X or Y chromosome. Genes that cause genetic disorders can be carried on the sex chromosomes as well as the autosomal chromosomes. Only one X chromosome is present in male cells and different patterns of inheritance are seen where a defective copy of a gene on this chromosome is present in a family. Most X-linked conditions occur in males who inherit an abnormal copy of the gene from their mothers. Since males only have one X chromosome, if it carries an abnormal copy of the gene, they will suffer from the disease. These mothers carry a copy of the altered gene but are usually unaffected if their other X chromosome has a normal working copy of the gene.

	X-LINKED
	In this family, the mother is a healthy carrier of an X-linked disorder.
	One son inherits the ‘rogue’ gene. As he has no normal copy he will be affected. One daughter also inherits a copy of the rogue gene. However as she also has a normal copy she will be healthy – but a carrier.

Females may occasionally show some features of the disease, depending on the condition. An affected male never transmits the disease to his sons since the X chromosome is always passed on from mother to son. When the mother carries a copy of a gene for an X-linked disease, the chance of inheriting the altered gene is 1 in 2 in each pregnancy for both boys and girls, but only the male offspring will be affected. Abnormal copies of genes on the X chromosome may thus give rise to disease in males in several different generations, connected through the female line. Duchenne muscular dystrophy is a wasting disease of the muscles. Because the gene is sex linked, the disorder is much more common among boys. Parents who have seen one of their sons die of muscular dystrophy are in the agonizing position of knowing that their other sons have a one in two chance of having inherited it.

	X-LINKED
	In this family, the father is affected by an X-linked disorder.
	The sons inherit the Y chromosome from their father. All daughters inherit a ‘rogue’ gene, i.e., are healthy carriers.

MULTIFACTORIAL DISORDERS

While inherited diseases - as a result of a single defective copy of a gene - are comparatively rare, there is a genetic component in many common diseases, such as coronary heart disease and some cancers. One out of four people in Britain will die of cancer, whereas cystic fibrosis afflicts 1 out of 2500 of the population. The genetic inheritance pattern of these multifactorial diseases is far harder to define than those of single gene disorders because:

• they are caused by a combination of more than one defective copy of a gene and do not follow the classic Mendelian patterns of inheritance previously described. Researchers not only have to identify the important genes, but also how they interact with one another;
• environmental factors influence many of these diseases. These are often difficult to identify, but diet and exercise clearly play a role in heart disease for instance. Progress has recently been made in unravelling multifactorial conditions, such as breast cancer or Alzheimer’s disease, to which some people appear to have a genetic predisposition. It is becoming possible, through genetic screening programs, to identify individuals who have inherited a particular combination of defective genes and are more likely to develop a disease. It may be possible to advise these individuals on how to minimise the risk from avoidable environmental factors.

WHAT CAUSES DEFECTIVE GENES?

Mutational changes in DNA are at the heart of evolution. Mutations are not simply accidents. Species have evolved so that they have a definite but low rate of DNA copying errors, in order to generate genetic variation, which allows evolution. With highly-evolved species, many mutations are harmful. But mutations are still necessary and genetic disease is a by-product of this process.

Mutational changes in our DNA occur for the following reasons:

Copying errors
To build a human being from a fertilized egg involves making hundreds of millions of cells, each with its own copy of the original genetic message. Throughout our adult life, millions of our cells divide each second and every minute we produce thousands of miles of newly copied DNA. As the copying process is imperfect - just like making a series of photocopies one from the other - there are plenty of opportunities for mistakes or mutations. As a result every one of us accumulates a large number of new mutations in our body cells during our lives, and the number increases as we get older.

Environmental causes
For example smoking, diet, radiation. If you habitually smoke cigarettes you expose the cells lining your lungs to a cocktail of potent chemicals that can damage the DNA; similarly if you spend a lot of time sunbathing, your skin cells receive high doses of ultraviolet light, which also damages the DNA in these cells. When your damaged cells reproduce, the new cells inherit these mutations. These somatic mutations may lead to cancer. Usually mutations occur outside genes and have no functional consequences, but some mutations occur within genes. The majority of these happen in our somatic (body) cells. Most are harmless. However, some mutations involve growth-controlling genes that can lead to cancer. The risk of cancer rises as we get older because the number of mutations we accumulate in our somatic cells increases with age.

A minority of mutations happen to genes in our germ (sex) cells and these mutations are potentially serious as they can lead to the inheritance of a genetic disease.