Genetics

Living with Lowe Syndrome

IV. Genetics
Lowe syndrome is a genetic disease, which means that the condition is always caused by an altered gene. In many families, Lowe syndrome is passed from a carrier mother (which means she carries the altered gene) to her affected son. In that situation, female relatives of the mother may also have the altered gene and may be at risk of having boys with Lowe syndrome. In other situations, the mother of the affected boy is not a carrier of the altered gene. In that situation, the mother and her female relatives are not at risk of having more children with Lowe syndrome.

Families in which Lowe syndrome occurs should understand whether the condition is inherited in their family, the likelihood of reoccurrence of the disease in subsequent children of the same couple, who else in the family could be a carrier and how to determine this, and what resources are available to clarify those risks and to assist with decisions about personal family planning.

A. Understanding how Lowe syndrome is inherited
1. Genes. Lowe syndrome is due to an "inborn error of metabolism." Metabolism refers to the complex physical and chemical processes involved in the maintenance of life and the functions of every cell in our bodies. All these processes are controlled by genes, the basic units of life that we each inherit from our parents. When a mutation (an alteration or a change) occurs in a gene, an imbalance or "error" in metabolism may result, causing a disease or disability.

Most mutations of genes occur spontaneously, usually for unknown reasons. They are not caused by being exposed to drugs or alcohol or emotional events during pregnancy. Once a mutation occurs, however, it becomes "fixed" in a person's genetic material. If that individual survives and grows up, he or she then has the potential to pass or transmit the altered gene to subsequent generations. Thus the disorder becomes hereditary in that family.

2. Chromosomes. Genes are grouped together in packages called chromosomes. Except for red blood cells and the reproductive cells, every human cell contains 23 pairs of chromosomes, or a total of 46 chromosomes. One member of each pair of these chromosomes comes from the father and the other member of each pair comes from the mother. The reproductive cells, the ovum (egg) and the sperm, each contain 23 chromosomes. At the moment of conception, the sperm and the ovum fuse, thus creating a cell with 23 pairs of chromosomes and all the genetic material for another human being.

Twenty-two pairs of chromosomes contain genes that determine general body characteristics, like eye color, stature, and growth. The twenty-third pair is different because it determines the sex of the offspring. This pair includes the "X" and "Y" chromosomes. Females (XX) have two X-chromosomes (one from each parent). Each of the female's ova or eggs will carry either one or the other X-chromosome (but not both). Males (XY) have one X-chromosome (from the mother) and one Y-chromosome (from the father). Therefore, each sperm in the male will carry either an X-chromosome or a Y-chromosome (but not both). If the father passes on a sperm that carries his X-chromosome, the resulting offspring will be female (XX); if he passes on a sperm that carries his Y-chromosome, the offspring will be male (XY).

3. X-Linked inheritance. Since the early 1960's, physicians have known that the gene causing Lowe syndrome is located on the X-chromosome. Diseases caused by genes that are located on the X-chromosome are called "X-linked" and have a distinctive pattern of inheritance. X-linked diseases typically affect only males but are "carried" and passed on by females. Women who are Lowe syndrome carriers have one X-chromosome with the normal gene and one X-chromosome with the Lowe gene.

A male (XY) who happens to inherit his mother's X-chromosome with the Lowe gene will be affected with Lowe syndrome, since that X provides the only genetic information for that gene. (The Y-chromosome contains no equivalent information.)

Figure 4. An X-linked Pedigree.
Males are indicated by squares and females by circles. The horizontal line that connects the male and female indicates a mating. The resulting offspring are shown as branches which come down from this line. Affected individuals are indicated by completely coloring in the square and carriers are indicated by a small black dot within a circle. This pedigree shows the situation seen in Lowe syndrome in which the mother is the carrier. In this instance, half of her daughters are carriers and half of her sons are affected.

The X and Y chromosomes are indicated under each individual. For simplicity in this illustration, the father's X-chromosome is labelled "X." To differentiate the mother's two X-chromosomes, her X-chromosome with the "normal" gene copy has been symbolized as "X+." Her X-chromosome with the Lowe syndrome gene copy has been symbolized as "X-." Thus the daughter who is a carrier has her father's normal X and her mother's abnormal copy, thus "XX-." The affected male child with Lowe syndrome inherited his father's Y (thus making him a male) and his mother's "X-" with the Lowe gene, and thus this boy has Lowe syndrome.

Red text indicates corrections made to published version of Living with Lowe Syndrome booklet.

4. Carriers. A female who has a mutated Lowe syndrome gene on one of her X-chromosomes is called a "carrier" because she bears or carries this information, in the form of one copy of the mutated Lowe gene, on one of her two X-chromosomes. With each pregnancy, she has a 50% chance (one out of two) of passing on the X-chromosome with the Lowe gene to her child. (Since she has two X-chromosomes, she may pass either one or the other X-chromosome to her offspring, with equal probability.) If the child is a male (because he inherits his father's Y-chromosome), there is a 50% chance that he will inherit the mother's X-chromosome with the mutated Lowe gene, and thus he will have Lowe syndrome. If he inherits his mother's X-chromosome with the normal gene, he will be an unaffected (normal) male. If the child is a female (because she inherits her father's X-chromosome), there is a 50% chance she will inherit the mother's X-chromosome with the mutated Lowe gene and thus be a carrier just like the mother; similarly, there is a 50% chance she will not be a carrier because she will inherit the normal X-chromosome.

In summary, with each pregnancy a carrier female has one chance in four (a 25% risk) of having a boy with Lowe syndrome; one chance in four of having a normal boy; one chance in four of having a carrier daughter; and one chance in four of having a normal daughter.

Obviously, these probabilities apply only to women who are genetic carriers. As discussed in the following section, however, in some families the affected male Lowe child is the first individual in the family with the condition. Determining whether his mother is a carrier or not holds tremendous importance in predicting the outcomes of her future pregnancies and those of her female relatives.

5. New mutations. A number of males with Lowe syndrome occur as the first and only affected individuals in their families. In such cases, it is possible that the mother is not a carrier; that is, her genetic makeup may not include the altered gene. Rather, the gene in the single ovum (egg) which developed into the boy may have become altered. An alteration in a previously normal gene is called a mutation. Since the boy is the first person with this altered gene, he is affected as the result of a new genetic event, a "new mutation."

When Lowe syndrome is the result of a new mutation, the mother is not a carrier. Her risk of having another child with Lowe syndrome is no greater than that faced by non-carrier females in the general population. To determine if a boy with Lowe syndrome is the result of a new mutation, the mother must undergo carrier testing (see "Carrier detection" and "Non-carriers" in the following section).

6. Mosaicism. In a few rare families, a child affected with Lowe syndrome may be neither a new mutation nor an inherited mutation coming from a carrier mother. In these few rare cases, the mother may have had a new mutation occur during her own prenatal development. In this case, the mutation may be present in a minority of the cells, including those from which some of her eggs are derived. The cells of her body, other than the cells in the ovary, do not all carry the mutation and so she may not have any signs on her eye exam of being a carrier. Yet, more than one egg will carry the mutation, so she will be at increased risk for having a son with Lowe syndrome, or a daughter who is a carrier. This situation, in which a woman has some cells carrying a mutation and other cells that do not, is called "mosaicism" (see Figure 5). More than one egg, but fewer than half, will carry a Lowe syndrome mutation. Mosaicism has been documented in Lowe syndrome.

B. Genetic Counseling
Couples who are at-risk for having an affected child with Lowe syndrome should explore their family planning options with the guidance of their physician and/or a genetic counselor. Geneticists and genetic counselors can help determine the chances of having an affected child. Trying to determine whether or not a woman is a carrier is very important because it has substantial impact on the risks for having other affected sons (or grandsons). Her carrier status may also be relevant to the status of her female relatives.

1. Carrier detection. Families at-risk for having a boy with Lowe syndrome may wish to investigate their chances of having an affected child. Women who are at-risk include the mothers and sisters of affected boys, as well as the boy's maternal aunts and their daughters. Thus, determining whether or not a woman is a carrier may also be critically important to extended family members who may wish to plan their own families. Geneticists and genetic counselors can advise couples about their reproductive risks.

In some cases, a woman's carrier status can be determined from her family history. For instance, the mother of a son with Lowe syndrome is presumed to be a genetic carrier if there has been a previous case of Lowe syndrome in her family. If there were no other known cases of Lowe syndrome in the family, however, the mother of an affected boy might not be a carrier, since her son's condition could be the result of a new gene mutation or mosaicism. However, even in the absence of any history of Lowe syndrome in a family, one cannot assume that the mother is not a carrier. The carrier status of the mother must be determined by examination.

In most cases, especially in women after puberty, carrier status can be determined by an eye examination performed by an ophthalmologist (a physician specializing in diseases of the eye). The examination must be done with the pupils dilated (with eye drops). Approximately 95% of all carriers of the gene for Lowe syndrome have subtle changes in the lenses of their eyes, especially in the teenage and adult years. These changes, which appear as tiny dots and flecks in the lens in a characteristic distribution and pattern, typically cause no effect on vision and, if not looked for diligently, may be mistakenly dismissed as normal variations. Therefore, the geneticist should insist that the examination only be made by an ophthalmologist with substantial experience with the subtle variations of the lens opacities of Lowe syndrome carriers.

If a reliable examination detects these characteristic lens opacities in an at-risk female of any age, then she is a carrier. If the opacities are not present in an adult female, she is probably not a carrier. This conclusion cannot be made with absolute certainty, however, especially if she is less than 15 years old.

There is no chemical or laboratory test to determine carrier status for all at-risk females at this time. However, genetic analysis may be possible for some family members (see V. Research).

2. Non-carriers. When a careful eye examination of the mother of a child with Lowe syndrome is normal (that is, the characteristic lens opacities are not present), there are three possible explanations for the Lowe syndrome in her child. First, and most commonly, the child is the result of a new genetic mutation in the egg that developed into him. In this case, the mother does not carry any other mutated Lowe syndrome genes in the rest of her eggs. She is not a carrier and she is no more likely to have another child with Lowe syndrome than any other non-carrier female in the general population. Second, and more rarely, is that she really is a carrier but falls into the group of 5% of all carriers who fail to show significant changes in their lenses. Her probability of having a child with Lowe syndrome is 25% with each pregnancy (50% for each male pregnancy).

Third, and most rarely, the mother may be mosaic for the mutation in her ovaries. In this case, she may have additional eggs carrying the Lowe syndrome mutation without showing signs in the lenses of her eyes. Her risk of having another child with Lowe syndrome or a daughter who is a carrier would be much greater than that of the general population, but not the full risk that a true carrier female has (see Carriers).

Unfortunately, there is no reliable biochemical or molecular test to diagnose mosaicism. For that reason, even women with normal eye exams can be offered prenatal testing because of the risk of unsuspected mosaicism. However, whether the mother of a child with Lowe syndrome is a non-carrier or represents a mosaic situation, her sisters or other female relatives (except for her daughters) are not at risk for being carriers because, in either case, the mutation occurred as a new genetic event in the mother herself.

3. Family planning options. At-risk couples have a wide range of options available to them. Some may choose to "take their chances" with a pregnancy, while others may consider prenatal testing. Some couples may be interested in adoption or in techniques that would use a donor egg from a non-carrier female. Others may be interested in methods to increase their chances of conceiving a female since females, even if carriers, do not develop the disease.

If prenatal testing is an option, testing to determine if the fetus is male or female is a well-established procedure and is widely available. If the fetus is male, prenatal enzyme analysis identical to the test used to diagnose Lowe syndrome in patients is available. Enzyme analysis can be used for prenatal diagnosis even if carrier status has not been established firmly. It can also be used whether or not gene analysis has succeeded in identifying the family's specific gene alteration.

Prenatal testing can be accomplished by one of two methods: CVS (chorionic villus sampling), which is done at 11-13 weeks, or amniocentesis, which is done at 15-18 weeks. Although the procedure itself can be performed in the local community, at the present time the analysis for the OCRL enzyme test can only be carried out at the Biochemical Genetics Laboratory in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas. To make arrangements for the test, physicians may call 1-800-246-2436 or 713-798-4982 or e-mail: bioc@bcm.tmc.edu. As with any prenatal diagnosis, the testing should be planned well in advance of the pregnancy.

An experimental technique called preimplantation genetic diagnosis has been suggested as another option for some couples. This technique involves in vitro fertilization and then testing the DNA in one cell of the fertilized eggs for the presence of a disease-causing gene alteration. Any embryo that is found to lack the disease-causing alteration (and by inference is normal) could be implanted into the womb. Preimplantation genetic diagnosis has been used successfully in a few genetic disorders but has not been tested rigorously in Lowe syndrome and therefore remains only a theoretical possibility. Preimplantation genetic diagnosis is a DNA test that would require accurate knowledge of the family's specific gene alteration. It cannot be used for the enzyme diagnosis for Lowe syndrome because the amount of material available for study is too small.

Many factors will affect a couple's family planning decisions, including their personal, family, ethical, and religious views, as well as financial, educational, and geographical considerations. Ultimately, the right decision for any individual or family is the one with which they are comfortable now and will remain comfortable with as they look back from the future.