What is Leukodystrophy?

The term Leukodystrophy  refers to a group of genetic disorders that are characterised by the imperfect growth, development or maintenance of the white matter which is known as myelin. Myelin is the insulation material that is  made from proteins and lipids ( fats etc) that is produced in the neuron to coat and protect the transmission arm of the neuron – the axon.This process is called Myelination.   Myelin is produced for the central nervous system in cells called an Oligodendrocytes and for the peripheral nervous system the same function is performed by the Schwann cells. The receiving arm of the  neuron is called a dendrite and is not myelinated.

Myelin is a spongy substance which is white in appearance and those axons which are myelinated are referred to as ” the white matter” of the brain.

The major purpose of the myelin is to increase the speed of transmission of an impulse ( message) to the next neuron and also to prevent the electrical current from escaping.  An impulse or message from one cell to another is an electro – chemical process.

When this process is disrupted or destroyed by a dysfunctional metabolic process, with a genetic cause and has a progressive clinical course it can be classified as a Leukodystrophy.

Leukodystrophies, as stated,  are characterised by the imperfect growth, development or maintenance of the white matter which is known as myelin. Terms often used with the various different Leukodystrophies include the following:

Demyelination:  The destruction, removal or loss of  the myelin sheath on a nerve or nerves.

Hypomyelination: The defective formation of myelin in the spinal cord, brain or peripheral nervous system.

Dysmyelination:  The improper laying down or breakdown of a myelin sheath of a nerve fibre caused by abnormal myelin metabolism.

The term Leukoencephalopathy refers to any of a group of diseases or disorder that affects the white matter of the brain.

INHERITANCE

DNA stands for (DeoxyriboNucleic Acid) which is made up of very long chains of   chemical ‘letters’: Adenine (A), Guanine (G), Thymine (T) and Cytosine (C). DNA contains the instructions for our genes. Genes are the instructions for making proteins. Proteins do the work within our cells and body. In humans, most genes are arranged on chromosomes that are found in the nucleus of cells.

Another place in the cell where DNA is found is in very small compartments called mitochondria (the energy centres of the cell) that are found scattered outside the nucleus The DNA in mitochondria is much smaller and has very little non-coding DNA. Some DNA variations can mean the gene instruction is incorrect so a faulty protein is made or the control switch is changed. A variation in a gene that creates a fault is called a pathogenic variant or mutation. When a DNA change causes a faulty protein in cells that needs that protein, it usually results in disease symptoms that cause a genetic condition.

There are 46 chromosomes contained in the nucleus of body cells:  Of these, 23 came from the mother’s egg and 23 came from the father’s sperm. When the egg and the sperm join together at the time of conception, the first cell of the baby is formed. This cell is copied to make all of the cells of the baby. The baby’s body cells now have 46 chromosomes, made up of 23 pairs, just like the parents.

Since the chromosomes come in pairs, there are also two copies of each of the genes. The exception to this rule applies to the genes carried on the sex chromosomes, X and Y. Since men have only one copy of the X chromosome, they have only one copy of all the genes carried on the X chromosome. Women have two copies of the X chromosome in their cells and so they have two copies of all the genes carried on the X chromosome.

When a gene variation is present in egg or sperm cells, it can be passed on to children (inherited).

If a DNA change occurs in only one of the pair of genes and this causes a health condition, it is called a dominant mutation. If a health condition only occurs when both copies of the gene are changed, this is called a recessive mutation. An autosomal gene is a gene located on a numbered chromosome and usually affects males and females in the same way. An X-linked gene is located on the X chromosome and affects males and female differently.

There are a number of ways that these mutations can be passed down. There are four possible combinations in every pregnancy of the genetic information that the child can receive from the parents.

X-LINKED RECESSIVE

  1. This means that in every pregnancy there is 1 chance in 4, (25% chance) that a son will inherit the Y chromosome from his father and X-linked recessive gene mutation from his mother. In this case, no working gene or the right amount of the gene product will be able to be made by his cells. He will therefore be affected by the condition.
  1. 1 chance in 4, (25% chance) that a son will inherit the Y chromosome from his father and the working copy of the X-linked gene from his mother. He will not be affected by the condition.
  1. 1 chance in 4, (25% chance) that a daughter will inherit both working copies of the X-linked genes: one copy from her father and one from her mother. In this case she will not only be unaffected by the condition but she will also NOT be a carrier of the X-linked recessive gene mutation.
  1. 1 chance in 4, (25% chance) that a daughter will inherit from her father the working copy of the X-linked gene and the X-linked recessive gene mutation from her mother. She will be a genetic carrier of the condition like her mother.

In summary, if pregnant with a son, there is a 50% chance they will be affected by the condition and if pregnant with a daughter, a 50% chance they will be a genetic carrier of the condition.

If the father is affected by an X-linked recessive genetic condition

If the father is affected by an X-linked recessive genetic condition, the chance of passing on the recessive gene mutation is different for his sons and daughters.

This means that in every pregnancy

  1. All sons will inherit the working X-linked gene copy from their mother and the Y chromosome from their father and will therefore not have the condition.
  1. All daughters will inherit a working copy of the X-linked gene from their mother and Xlinked recessive gene mutation from their father. They will be carriers of the X-linked recessive gene mutation and can pass the faulty gene on to their children.

X-LINKED DOMINANT

If the mother is affected by a condition caused by an X-linked dominant gene mutation

When the mother is affected by a condition caused by an X-linked dominant gene mutation there are four possible combinations of the genetic information the child can receive from the parents.

This means that in every pregnancy there is a:

  1. 1 chance in 2 (2 chances in 4 or 50% chance) that both her sons and daughters will inherit the X-linked dominant gene mutation from her and be affected by the condition. No working gene product or the right amount of the gene product will be able to be made by the cells.
  1. 1 chance in 2 (2 chances in 4 or 50% chance) that her children (both sons and daughters) will inherit the working copy of the gene from her and will not be affected by the condition.

If the father is affected by a condition caused by an X-linked dominant gene mutation

When the father is affected by a condition caused by an X-linked dominant gene he will pass on the X-linked dominant gene mutation (on the X chromosome) to all his daughters and his Y chromosome to all his sons. The unaffected mother will only give working copies of the gene to her children. There are four possible combinations of the genetic information the child can receive from the parents.

  1. This means that in every pregnancy: None of his sons can inherit the X-linked dominant gene mutation since the son only inherits the Y chromosome from the father. They will inherit the working gene copy from their mother. None of their sons will have the condition.
  1. All of their daughters will inherit the working gene copy from their mother and the X-linked dominant gene mutation from their father. All of their daughters will have the condition.

AUTOSOMAL RECESSIVE

Autosomes are numbered chromosomes 1 to 22

If both parents are genetic carriers for the same autosomal recessive gene mutation

  1. This means that in every pregnancy there is: 1 chance in 4 (25% chance) that they will have a child who inherits both copies of the recessive gene mutation from his/her parents. In this case, no working gene product will be produced and their child will be affected by the condition caused by this gene.
  1. 1 chance in 4 (25% chance) that their child will inherit both copies of the working gene and will be unaffected by the condition and not a genetic carrier.
  1. 1 chance in 2 (2 chances in 4 or 50% chance) that their child will inherit the recessive gene mutation and the working copy of the gene from the parents and he/she will be an unaffected genetic carrier of the condition, just like the parents.

If one parent is a genetic carrier for the autosomal recessive gene mutation

This means that in every pregnancy there is:

  1. No chance that the couple will have a baby affected with the genetic condition caused by this particular gene.
  2. 1 chance in 2 (2 chances in 4 or 50% chance) that they will have a child who inherits both copies of the working gene from his/her parents. In this case, the child will be unaffected by the condition.
  1. 1 chance in 2 (2 chances in 4 or 50% chance) that their child will inherit the recessive gene mutation and the working copy of the gene from the parents and he/she will be an unaffected genetic carrier of the condition.

If one parent is affected by the autosomal recessive condition

There are two possible scenarios:

  1. One parent would have the genetic make-up of the person (non-carrier) and the other would have the genetic make-up of the affected person.
  1. One parent would have the genetic make-up of the person (unaffected genetic carrier) and the other would have the genetic make-up of the affected person.

For scenario 1) the outcomes for each pregnancy are the same whether it is the mother who is affected or the father.

This means that in every pregnancy there is:

  1. 4 chances in 4 (100% chance) that their child will inherit the recessive gene mutation and the working copy of the gene from the parents and he/she will be an unaffected genetic carrier of the condition.

For scenario 2) the outcomes for each pregnancy are the same whether it is the mother who is affected or the father.

This means that in every pregnancy there is:

  1. 1 chance in 2 (2 chances in 4 or 50% chance) that they will have a child who inherits both copies of the recessive gene mutation from his/her parents. In this case, the child will be affected or predisposed to develop the condition.
  1. 1 chance in 2 (2 chances in 4 or 50% chance) that their child will inherit the recessive gene mutation and the working copy of the gene from the parents and he/she will be an unaffected genetic carrier of the condition.

If both parents are affected by the autosomal recessive condition

This means that in every pregnancy there is:

  1. 4 chance in 4 (100% chance) that they will have a child who inherits both copies of the recessive gene mutation from his/her parents.

AUTOSOMAL DOMINANT

Autosomes are numbered chromosomes 1 to 22

If one parent has an autosomal dominant gene mutation

One parent would have the affected genetic make-up and the other would not. The outcomes for each pregnancy are the same whether it is the father who has the dominant gene mutation or the mother.

This means that in every pregnancy there is:

  1. 1 chance in 2 (chances in 4 or 50% chance) that they will have a child who inherits both copies of the working gene from his/her parents. In this case, the child will be unaffected by the condition
  1. 1 chance in 2 (2 chances in 4 or 50% chance) that their child will inherit the dominant gene mutation and the working copy of the gene from the parents and he/she will be affected or predisposed to developing the condition caused by the gene mutation.

If both parents have the autosomal dominant gene mutation

This means that in every pregnancy there is:

  1. 1 chance in 4 (25% chance) that they will have a child who inherits both copies of the working gene from his/her parents. In this case, the child will be unaffected by the condition

 

  1. 1 chance in 2 (2 chances in 4 or 50% chance) that their child will inherit the dominant gene mutation and the working copy of the gene from the parents and he/she will be affected or predisposed to developing the condition caused by the gene mutation, like their parents.
  1. 1 chance in 4 (25% chance) that they will have a child who inherits both copies of the dominant gene mutation from his/her parents. Depending on the condition, the child may be more severely affected than their parents, or may not even survive, and/ or have a younger age of onset for conditions that develop later in life.

MOSAICISM

Mosaicism means that a person has a mixture of cells with different genetic information. Mosaicism can occur in the cells in one part of the body (such as in the egg or sperm) or in a generalised way throughout all of a person’s cells

GERMLINE MOSAICISM (MOSAICISM IN SPERM CELLS AND EGG CELLS)

A DNA mutation may not be present in the body cells, but is in the germ cells (egg or sperm cells). An indication that this is possible is when a healthy couple have more than one child with a condition that is usually passed down by an affected parent (autosomal dominant inheritance).

When parents have one child with a condition that is caused by an autosomal dominant gene mutation, but neither parent has the gene mutation on a blood test, it is usually assumed that the condition in the child occurred due to a new or spontaneous mutation in the egg or sperm, or shortly after conception. (De Novo)

If they have a second child with the same condition, the chance of the condition occurring again because of another spontaneous mutation in the same gene is highly unlikely.

The explanation may be that one of the parents is mosaic for the mutation in their germ cells that produce the egg or sperm, but have a working copy of the gene in their body cells.

 

DE NOVO

In other cases, a new gene variation can arise in an egg or sperm cell. This is called a de novo change.  The person arising from that egg or sperm cell will be the first in the family to have the DNA change which may then be passed down to his or her children and future generations.