Introduction to Chromosome Diseases

Chromosome diseases are genetic diseases where a large part of the genetic code has been disrupted. Chromosomes are long sequences of DNA that contain hundreds or thousands of genes. Every person has 2 copies of each of the 23 chromosomes, called chromosomes 1..22 and the 23rd is the sex chromosome, which is either X and Y. Men are XY and women are XX in the 23rd chromosome pair.

Causes of chromosome diseases: Chromosomal diseases arise from huge errors in the DNA that result from having extra chromosomes, large missing sequences, or other major errors. These are usually caused by a random physical error during reproduction and are not inherited diseases (i.e. both parents are usually free of the condition).

Spontaneous chromosome errors: Most chromosomal diseases arise spontaneously from parents where neither has the disease. A large genetic mistake typically occurs in the woman's egg, which may partially explain why older women are more likely to have babies with Down syndrome.

Many chromosome errors cause the fetus to be aborted before birth, but some syndromes can be born and survive, though all typically suffer severe mental and physical defects. Down syndrome is the most common and well-known chromosome defect, but there are many.

Types of chromosome diseases: There are several common types of chromosome errors that cause disease. The effects of errors in the sex chromosomes (X and Y) differ greatly from errors in the autosomes (chromosomes 1..22). The following major classes of chromosome diseases can occur:

• Trisomy conditions: Most people have 2 copies of each chromosome, but some people are born with 3 copies, which is called trisomy. Trisomy can occur in chromosomes 1..22 (autosomal trisomy) and also in the sex chromosome (see below). Down syndrome is a trisomy affecting the autosome chromosome 21.
• Monosomy conditions: When a person has only one of a given chromosome, rather than a pair, this is called monosomy. These conditions are very rare for autosomes (chromosomes 1..22) because body cells without pairs do not seem to survive, but can occur in the sex chromosome (monosomy X is Turner syndrome).
• Sex chromosome conditions: Typically men are XY and women are XX in the pair for the 23rd chromosome. However, sometimes people are born with only one sex chromosome (monosomy of the sex chromosome), or with three sex chromosomes (trisomy of the sex chromosome).

Rarer types of chromosome diseases: There are also some other rarer types of chromosome conditions that may lead to diseases:

• Translocation disorders: Partial errors in chromosomes can occur, where a person still only has a pair, but accidentally has entire sequences misplaced. These can lead to diseases similar to trisomy. For example, Translocation Down Syndrome is a subtype of Down Syndrome caused by translocation of a large sequence of a chromosome.
• Subtraction disorders: The process of translocation can also cause large sequences of DNA to be lost from chromosomes. This creates diseases similar to monosomy conditions.
• Mosaicisim: This refers to the bizarre situation where people have two types of cells in the body. Some cells have normal chromosomes, and some cells have a disorder such as a trisomy.
• One-sided chromosome disorders: For these unusual diseases it matters whether the chromosomes were inherited from the father or mother.

Non-contagiousness of chromosome diseases: All types of genetic diseases occur at birth including chromosome diseases. You cannot catch the disease from someone else who has the disease. You are either born with the error in your chromosomes or not Genetic tests can determine whether or not a person has a chromosome disease, even as early as in the fetus by antenatal testing for genetic diseases.

Sex Chromosome Conditions

Sex chromosome defects: There are various defects of the sex chromosomes. Normally a man has XY and a woman XX. But the wrong combinations can arise with extra sex chromosomes or missing ones:

• Turner syndrome (XO syndrome, monosomy X, missing Y): This should just be called the "X syndrome" because the person has an X, but no second sex chromosome. Such people are female, as there is no male Y chromosome. It is a 1-in-5000 syndrome, involving some relatively minor conditions, but usually sterility.
• Klinefelter syndrome (XXY syndrome, also rarely XXXY): a 1-in-1000 disorder where the person is usually male (because of the Y chromosome), but has lower levels of testosterone and may have some female-like features (because there are two X chromosomes), and is usually sterile. The rarer XXXY syndrome may lead to retardation.
• Jacobs syndrome (XYY syndrome): The person has an extra Y male chromosome. He will be male and may be largely normal, or may suffer from minor features such as excess acne and may be very tall, and in some cases behavioral complaints such as aggression. Frequency around 1-in-2000.
• Triple-X (XXX, also XXXX or XXXXX): These people are females with an additional X chromosome. In rarer cases, there can even be 4 or 5 X chromosomes. They can be largely normal, or may suffer from problems such as infertility (some but not all), and reduced mental acuity. Occurs with a frequency around 1-in-700.

Note that there is no ordering, and XYX would be the same as XXY.

So there are viable combinations: XX (male), XY (female), XXY (Klinefelter), XXX, XYY, and XO (Turner). They all contain the X chromosome. Interestingly, there has been no combinations found that contain only Y: YO (Y, missing X), YY, or YYY syndromes. Not even aborted fetal embryo cells with this combination have been found. It has been suggested that there is something fundamental on the X chromosome that is needed for life.

Autosomal Trisomy Chromosome Diseases

The 22 non-sex autosome chromosomes (autosomes) can also exhibit disorders, of which the most common is trisomy (having 3 copies rather than a pair). Because these are disorders of the autosomes and not the sex chromosomes, these disorders can occur with males or females. These chromosome diseases arise rather surprisingly from an extra copy of the DNA, which makes you wonder why having 3 copies of the code bad even when the DNA code on the extra chromosome is actually correct. The condition of having 3 chromosomes is called trisomy and the most common example for autosomes is Down syndrome.

Here is some details about particular autosome disorders:

• Down syndrome (trisomy 21): an extra autosome creating a triplet at chromsome 21. These people are usually mentally retarded, and have physical characteristics such as an enlarged tongue and rounded flattened facial features. Frequency is around 1-in-800 but risk increases with the age of the mother to around 1-in-25 for a 45-year-old mother. The extra chromosome occurs because the mother's egg (or less commonly father's sperm) has wrongly kept both of its autosome 21 pair.
• Edwards syndrome (trisomy 18): an extra autosome at chromosome 18. Most fetuses are aborted before term, but a live birth with this condition occurs with a frequency around 1-in-3000. Edwards syndrome is more severe than Down's syndrome, and includes mental retardation and numerous physical defects that often cause an early death.
• Patau syndrome (trisomy 13): a very severe disorder leading to mental retardation and physical defects, occurring with a frequency around 1-in-5000. It is so severe that many babies die soon after birth.

Miscarriages caused by trisomy: So we have seen trisomies at autosomes 13, 15, 18, and 21. Trisomy at the other autosomes seems to be fatal in embryos leading to spontaneous miscarriage. The high frequency of natural miscarriages, around 1-in-5, occurs to a large extent because of chromosome errors.

Causes of trisomy: Since Down syndrome occurs more frequently in older women, one might theorize of the reason why. The most likely idea is that the problem is not during the pregnancy, but at the start, with more eggs created with poorly separated chromosomes in older women (about 1-in-5 for young women, compared to 3-in-4 for 40-year-old women). However, another possibility is that the female body gradually loses its ability to recognize wrong cells in a fetus. But it is not an immune issue because the uterus is an immune-privileged site during pregnancy.

Partial trisomy: Down syndrome can be caused not only by a full trisomy, but also by a partial trisomy at autosome 21. Due to errors in a process called "translocation", a part of a chromosome can be wrongly attached to another pair. This creates a partial trisomy.

Another possible variant of Down's syndrome is a translocation between two pairs of chromosomes, usually part of 21 gets add to the 14th. This also causes a variant known as Translocation Down syndrome.

Mosaicism: Yet another chromosome oddity is mosaicism, where a person has different sets of chromosomes in different cells. If some cells are normal and others have trisomy 21, then Down syndrome results. Mosaicism can result from two paths. In the first method, the fetus started with trisomy 21, and then one line of cells lost the trisomy. In the second method, the fetus started normal, but somehow a cell line gained trisomy 21.

So why chromosome 21? It is one of the smaller chromosomes, and has relatively few genes (maybe 200-250). Research continues into determining why having too many of these genes, and consequent gene overexpression, leads to Down syndrome's characteristic mental and physical features.

Monosomy and Autosome Subtraction Disorders

Monosomy occurs when there is only one of a pair of chromosomes and is usually non-viable. For example, the opposite of Down syndrome is monosomy-21, which is fatal. More common are "subtraction disorders" which occur due to missing genetic material within chromosomes, typically when a sequence of a chromosome is missing. The creation of reproductive sperm and egg cells involves a complex process that can sometimes misplace parts of a chromosome, such that one cell has an extra sequence (perhaps leading to one of the trisomy disorders if this cell becomes a child), but if a child is generated from the other cell, it may get a subtraction disorder.

• Cri-du-chat syndrome (cat's cry): a subtraction disorder at autosome 5, with a missing short arm of chromosome 5, but not an entirely missing chromosome. Extremely rare at 1-in-50,000 and exhibiting severe mental retardation and physical defects including larynx problems giving the characteristic cat-like child's cry.
• Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS): These are two separate genetic chromosome subtraction disorders that arise from the deletion of the same sequence on one copy of chromosome 15, specifically the sequence are "15q11-13". Prader-Willi Syndrome arises when it occurs on the father-inherited copy of chromosome 15, and Angelman Syndrome occurs if from the mother-inherited copy. This one-sided distinction between the father and mother's chromosomes is unusual, and quite important, and is discussed in detail later.

One-sided genetic disorders: Prader-Willi Syndrome and Angelman Syndrome

There are several disorders that have an odd characteristic in that it actually matters which of a pair of chromosomes is affected. Different effects arise for the chromosomes from the mother and from the father. This was a totally unexpected discovery since traditional genetic theory, particularly the "law of equivalent crosses", indicated that it did not matter which chromosome a gene was present on. However, it seems that the body does distinguish between the chromosomes that come from the father and the mother within each pair. Some genes are only activated on the chromosome that came from the mother's or father's side. It is like having male and female genes with slightly different effects. They are "imprinted" with some extra information, although exactly how this occurs is as yet unclear.

The best known examples are Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS), which both arise from the same sequence on chromosome 15. They are both rare, arising around 1-in-10,000 to 1-in-15,000 but the two diseases are related in a surprising way. For some reason, the sequence 15q11-13 is likely to be misplaced during reproductive cell creation. Rather than causing a single disease, this error can cause two diseases. If it is deleted from the mother's egg, the child will get Angelman Syndrome; if the deletion occurs in a father's sperm, the child gets Prader-Willi Syndrome.

It is also important to note that both Prader-Willi and Angelman are actually gene disorders, not really chromosome disorders. Although the most common cause is from chromosome deletion (a non-inherited random physical occurrence), both of these diseases can arise rarely from a non-chromosome genetic inheritance. The real cause of the disease is the missing genes, rather than the chromosome-level changes. The gene for Angelman has been identified as the gene that creates the E6AP ubiquitin protein ligase 3A (UBE3A) protein, which is involved in the ubiquitination pathway (whatever that is). Inherited mutations of the UBE3A gene do cause Angelman without any major chromosome error. The exact gene for PWS is not known since there are several genes on the 15q11-13 sequence deleted in PWS and AS. The most likely PWS gene seems to be SNRPN (small nuclear ribonucleoprotein N) gene but it is not yet certain.

PWS and AS are very distinct diseases. They are not two variants of the same disease and have significantly different mental and physical features. This makes sense since they are caused by failures of different genes. The AS gene is mother-sided and the gene(s) causing PWS are father-sided.

PWS has several features, the most notable of which is a total lack of appetite suppression leading sufferers to continual hunger and over-eating. If left uncontrolled, they will literally eat themselves to death via extreme obesity and the consequent heart or organ damage. PWS suffers may have a slightly reduced mental capacity, but are not usually significantly retarded. Other physical features include some facial features, hypogonadism (testes or ovaries), and short stature.

AS is a more several mental disorder causing retardation or at least developmental difficulty. There are usually speech problems and an inappropriately happy smiling child.

AS is caused by one gene only, despite losing several genes in chromosome deletion. Presumably, the other missing genes are compensated for by the genes on the other chromosome in the pair, but for some reason the AS gene is one-sided and cannot be activated on the father's chromosome. The UBE3A gene is only one-sided within brain cells, which explains why AS is a mental disease without physical defects. The UBE3A gene is expressed from both chromosomes in other tissues.

Because AS is a single gene disease, there are in fact several ways to get it:

• Chromosome deletion (most common): loss of the 15q11-13 sequence on the mother's copy of chromosome 15, which deletes the UBE3A gene (and many others as well).
• Uniparental disomy: getting both copies of chromosome 15 from the father (i.e. the pair), so there is no mother's copy of chromosome 15 at all.
• Gene mutations: ordinary localize genetic mutations within the UBE3A gene, causing AS in the same way as other genetic non-chromosome diseases. However, the mutation only causes the disease if on the father's chromosome copy. A mutation in UBE3A on the mother's side does not cause AS, nor does it cause PWS, since PWS and AS involve different genes.
• Imprint disorders: mutations in the genetic code that surrounds the gene, inhibiting the activation of the UBE3A gene.

Another point to note is that both male and female children equally get AS and PWS. The one-sided gender-imprinting of the gene is not affected by the gender of the child with the disease.

Does one-sidedness go back to the gender of grandparents? Must it comes from the mother's mother or father's father, or can it cross gender in the previous generation?

Some traits inherited from only one side? The one-sidedness of these diseases also raises the question of what other traits are inherited from only one parent.

Uniparental disomy: Another strange way to get both PWS or AS is called uniparental disomy. This means getting from one parent (uniparental) both pairs of chromosome (disomy). In a pair, you get two chromosomes from one parent, none from the other. Although the majority of PWS and AS are caused by simple deletions within a chromosome, some cases arise because both copies of chromosome 15 come from the same parent. Somewhere along the path, the egg or sperm kept both of its pair of chromosome 15, and the other parent's copy was discarded. People with two mother-inherited copies of chromosome 15 get PWS and two father-inherited copies cause AS.

Uniparental disomy is interesting because the person theoretically has two good copies of chromosome 15 with no genes missing. However, it doesn't work that way. For full health, you need copies from both parents.

Also interesting is that having the entire chromosome 15 from the mother's side seems to only cause PWS, despite there being hundreds or thousands of genes on the entirety of chromosome 15. Hence, it would seem that very few genes are one-sided. If lots of genes are one-sided, then numerous diseases would arise from uniparental disomy of chromosome 15 rather than just one.

Note that uniparental disomy has been seen on several chromosomes: 4, 6, 7, 11, 14, 15, 16, and 21. Like trisomy, it also occurs more often for an older mother.

One-sided disease genes compared to X-linked recessive carriers: But how is this different from X-linked recessive disorders? Isn't inheriting Prader-Willi as an error from the mother's side the same as inheriting a recessive hemophilia gene from a mother carrier? The answer is no, not really, there are several differences. Firstly, the gender differences in hemophilia arise because it involves a gene on the X sex chromosome, whereas one-sided genes occur on autosomes. Secondly, although X-linked recessive disorders are similar to a maternal one-sided disorder, there is no analogous X-linked or autosomal recessive inheritance pattern that matches paternal one-sided disorders.

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