D1. WHAT IS THE GENETIC CAUSE OF CNS?
In 1952 Drs. Crigler and Najjar first reported the condition that bears their name after studying a group of patients in Maryland USA. These people lived in a relatively closed community and had close family links. Since then research into the genetic basis of CNS has provided a solid level of understanding of the causes of the condition. For our purpose here it is necessary to start by explaining some basic concepts of genetics.
Simply stated, every person has a series of genes that provide the codes that largely control the vast number of attributes that makes her or him an individual human being. We all have two copies of every gene. We receive one copy from our mother and one from our father. Eye colour and height are some of the more obvious characteristics, but there are many much more complex processes in the human make up. Some people like to think of a person's genes as being similar to the software in a computer.
Genes themselves are made up of chains of DNA that form codes to control all aspects of our functioning. Although the codes are complex and are being progressively better documented and understood, the basic building blocks of DNA are very simple. It is made up of only four compounds joined together in long chains. The names of the four compounds (adenine, cytosine, guanine and thymine) are normally abbreviated to A, C, G and T.
A particular gene may be made up of many thousands of these four compounds arranged in a very specific order, like coloured beads on a string. It is the precise order in which they appear that determines what they do. For example, a part of a gene that has the compounds in the order A T G C will not perform the same task as A G T C. Even very minor errors in the genetic code can have major impacts.
One gene is designed to produce the glucuronyl transferase enzyme that, in the liver, adds one or two sugar molecules to bilirubin and allows the bilirubin to be removed from the body. Part of the gene code determines how much of the enzyme is produced and another part determines the chemical make up of the actual enzyme.
Unfortunately, in some people the gene code is faulty. This is because the genes picked up from both parents contain errors.
If a code error is on the part of the gene that determines the amount of enzyme produced, the result may be inadequate or even zero production of the enzyme. If the code error is elsewhere, there may be enough enzyme produced, but the enzyme may be faulty and either not perform its task or do so imperfectly.
D2. WHY CAN APPARENTLY NORMAL PARENTS HAVE A CNS CHILD?
For some genetic conditions there is not a problem providing an individual has at least one copy of the gene that is error free. This is referred to as a recessive condition.
If either the father or the mother has two good copies of the gene, their offspring will not have CNS because the child will have at least one good gene received from the unaffected parent.
If both parents have one good copy and one faulty copy, neither will have Crigler Najjar Syndrome because, for them, their good gene will create the required enzyme to remove bilirubin. However, they will each be carriers of the condition, often unknowingly. Their children will receive one copy of the gene from each parent. Which copy they receive from each is determined absolutely by chance. There are four possibilities:
For parents who are both “carriers”, there are three chances out of four that a particular child will not have CNS, but one chance in four that it will.
Fortunately, in the wider community, errors in this particular gene are rare. A marriage between two completely unrelated people who each have a faulty gene is even more rare. Nevertheless such situations do happen. Where the mother and father have some family relationship or are in a relatively small community where marriage within the community is common, the risk of both parents having a defective gene is significantly greater.
In theory it is possible for a child to have CNS by a chance genetic occurrence between conception and birth. This is referred to as a spontaneous mutation. No such CNS cases have been reported in the literature.
D3. IF PARENTS HAVE A CNS CHILD, WILL ALL THEIR CHILDREN HAVE THE CONDITION?
Not necessarily. For parents who do not have CNS themselves, each subsequent child has three chances out of four of not having CNS. The fact that a first child has CNS means that each subsequent child will still have a 75% chance of not having CNS and a 25% chance that it will. There are families where twins have been born with one having CNS and one not. Families with three CNS children do exist.
D4. IF MY FIRST CHILD DOES NOT HAVE CNS DOES THAT MEAN ALL MY CHILDREN WILL BE FREE OF CNS?
CNS is very rare in the wider community and for the vast majority of children there will be no CNS problems. Where there has been CNS in the family history of one parent, the possibility of a CNS child will be greater, even if the first child does not have the condition. In these circumstances parents should seek genetic counselling prior to having children.
If both parents are carriers of faulty genes, the fact that the first and /or second child does not have CNS provides no assurance that subsequent children will be free of CNS. There has been reported at least one case where the parents only became aware that they were CNS carriers when their third child had the condition.
D5. ARE BOYS MORE LIKELY THAN GIRLS TO GET CNS?
No. In the wider community the chance of a newborn having CNS is very low, but is equal for boys and girls.
D6. CAN A CRIGLER NAJJAR SUFFERER HAVE NORMAL CHILDREN?
Yes. If the partner of a person with CNS has two non-defective copies of the relevant gene, any offspring of the couple will not have CNS. Since the vast majority of people have two error-free genes this is by far the most likely situation in the wider community.
For people with CNS, genetic counselling prior to marriage should be considered. Genetic counselling is strongly recommended prior to pregnancy. This is particularly important if the couple have some family relationship or are in a relatively isolated social community where intermarriage is common.
In recent years there have been several women with CNS who have had successful pregnancies. During pregnancy and at birth, well-informed, specialised medical supervision is essential.