Lowe Syndrome (LS) is a rare genetic condition that causes varying levels of physical and mental handicaps, and medical problems. It was first described in 1952 by Drs. Lowe, Terrey, and MacLachlan at the Massachusetts General Hospital in Boston. LS is caused by a single defective gene (an alteration or “mutation”) in a gene called OCRL1. Because of this defective gene, an essential enzyme called PIP2-5-phosphatase is not produced. This is the underlying cause of Lowe syndrome.
The condition became known as “Lowe syndrome” named after Dr. Charles Lowe, the senior member of the group that described it. Because of the three major organ systems involved (eyes, brain, and kidney), it is also known as OCRL (oculo-cerebro-renal) syndrome. Much research has taken place in the last few years. The gene has been mapped and the deficient enzyme has been identified, although its role is not fully understood. A very detailed medical description of Lowe Syndrome can be found on GeneReviews. This article is suggested for medical professionals and researchers who need to learn more about Lowe Syndrome, including the technical details of the genetics involved.
Lowe syndrome virtually always presents only in males, however exceptionally rare cases have been documented in females.
Individuals with Lowe Syndrome are born with cataracts in both eyes, which are usually removed at a few months of age. Most are fitted with glasses, contacts, or a combination of the two. Glaucoma is present in about 50% of Lowe syndrome cases, though usually not at birth. Prescription eye drop and/or surgery is required to maintain appropriate eye pressure in these cases.
While not present at birth, many Lowe Syndrome individuals develop kidney problems at approximately one year of age. This is characterized by the abnormal loss of certain substances into the urine, including bicarbonate, sodium, potassium, amino acids, organic acids, albumin and other small proteins, calcium, phosphate, glucose, and L-carnitine. This problem is known as Fanconi-type renal tubular dysfunction and can also be seen in certain other diseases and syndromes. In Lowe syndrome, the Fanconi syndrome may be mild and involve only a few substances or may be severe and involve large losses of many substances. Medications can be prescribed to replace the lost substances.
Lowe syndrome is caused by a defective gene that results in the deficiency of an enzyme called phosphatidylinositol 4,5-biphosphate. This enzyme is essential to normal metabolic processes that take place in a certain part of the cell called the Golgi apparatus. Because of the enzyme deficiency, cell functions that are regulated by the Golgi are abnormal, leading to various developmental defects in LS including cataracts and kidney and brain problems. How the enzyme deficiency leads to these defects is not yet completely understood.
There is no cure, but many of the symptoms can be effectively treated through medication, surgery, physical and occupational therapies, and special education.
Generally, they are affectionate and sociable, love music, and have a great sense of humor.
In 1992 the gene that causes LS was found. In 1995 researchers discovered that the gene defect causes an enzyme deficiency. Researchers are continuing to investigate the function of the gene and the complicated biochemistry and cellular mechanisms of LS. Other areas that researchers have investigated in recent years include behavior problems and clinical care.
While extremely rare, Lowe syndrome can occur in females. There are known cases of Lowe Syndrome presenting in a female, but the number is very, very small. Lowe syndrome in females can occur either by non-random X inactivation or X:autoxome translocation. Each of these situation is discussed in technical detail below.
In order to prevent females from expressing double the amount of the genes on the X chromosome compared to males who have one X and one Y, one X in females is randomly inactivated early in development. Because the process is random, a female will have, on average, about half of her cells with one X active and other half of her cells with the other X active. In some very rare cases the process may be disrupted so that a female has only one of her X chromosomes active in most or all of her cells. If this occurs and she is a carrier for an X-linked recessive disorder, like Lowe syndrome, and the X chromosome with the mutation is the active one, she will express only the gene with the mutation and will not express a normal gene to compensate, and she could have Lowe syndrome.
Balanced X chromosome:autosome translocation involves the concept of X-inactivation. A chromosomal translocation is a chromosome defect that occurs due to an error of chromosome segregation. If it occurs during the formation of the egg or sperm all the cells in the offspring will have the abnormality. Essentially what happens in a translocation event is that one chromosome can break and “stick” to a different chromosome. In the case of a balanced translocation a piece of one chromosome gets broken and stuck to another broken chromosome, and vice versa, so that the chromosomes actually switch ends. It is called balanced, because all the genetic material is still there (so you could get a piece of one of your chromosome 1’s stuck onto one of your chromosome 2’s and vice versa). People can be balanced translocation carriers are often normal themselves, depending on where the break occurs. Remember that even if the break disrupts a gene, they also have the possibility of having a normal copy on their full-length non-translocated chromosome, to compensate for the gene disrupted by the break. However, if there is a balanced translocation that occurs in the egg, involving the X and an autosome (non-sex chromosome) this creates a problem, since normally one of the X’s in females becomes inactive.
The process of inactivation, travels all down the chromosome, so that if the X with the balanced translocation was inactive, you would not only lose the X chromosome genes, but also the genes from the autosome that is translocated onto the X,–big problem– the fetus would likely not survive with a large loss of all the genes from the translocated autosome. What happens in the case of an X:autosome translocation is that another mechanism kicks in to compensate for this. The X with the translocation will be the one that stays active (overriding the “random X-inactivation” process). The result of the X with the translocation being active is that there may be genes that are disrupted at the breakpoint, the place where the two chromosomes are joined, and there is not another active X chromosome with a normal gene to compensate. If the break were to occur in the Lowe syndrome gene, that female would have only one active X, the translocated one, which has the mutation in the Lowe syndrome gene. Therefore she would have Lowe syndrome, since she would have one copy of the mutated gene in all of her cells, just like a boy with Lowe syndrome. This is an extremely rare event, since the break would have to occur within the OCRL1 gene.