Research

Living with Lowe Syndrome

V. Research

A. Early research history
During the first three decades after Lowe syndrome was recognized, research efforts led to a better overall understanding of the syndrome. In 1954 the specific form of kidney involvement associated with the syndrome was recognized. X-linked inheritance was suggested in 1957, and the ability to identify female carriers by eye examination was confirmed in 1976. However, not until the past decade were researchers able to make any significant progress in identifying the underlying defect.

Several factors that have frustrated researchers' efforts over the years have changed. First, because Lowe syndrome is rare, there was a general lack of research projects. This situation changed somewhat in 1983 when the Lowe Syndrome Association (LSA) was founded. With the establishment of the LSA, researchers had access to a large pool of willing participants for the first time. Second, until the 1995 discovery that Lowe syndrome is caused by an enzyme deficiency, the biochemical manifestations in Lowe syndrome were found to be too nonspecific for easy investigation. There was no single abnormal metabolite which would point to a specific pathway to investigate. Third, there are no naturally occurring animal models for the disease. Researchers have been restricted by the necessary limitations placed on investigations that can be done on the patients themselves. This situation is now changing as researchers use genetic cloning to develop laboratory animal models.

B. Discovery of the Lowe syndrome gene and enzyme
The dramatic advances in the field of genetics during the past decade have opened new avenues of research and have led to significant advances in understanding Lowe syndrome. The first big step towards identifying the underlying defect took place in 1986 when Drs. Lewis and Nussbaum and their colleagues at Baylor College of Medicine succeeded in assigning the Lowe syndrome gene to a small region in the middle portion of the long arm of the X-chromosome. Subsequent work by many collaborating scientists ultimately culminated in identifying the exact identification of the gene in 1992. The gene site for Lowe syndrome is known as OCRL1. Three years later, Dr. Nussbaum and his colleagues, then at the National Institutes of Health, announced the discovery that the defective gene causes a deficiency of an enzyme that is essential to inositol metabolism. The enzyme phosphatidylinositol 4,5-biphosphate 5 phosphatase is essential to normal metabolic processes that take place in a part of the cell called the Golgi apparatus. Because this enzyme is deficient in Lowe syndrome, cell functions that are regulated by the Golgi are abnormal, leading to developmental defects such as cataracts and kidney and brain problems.

C. Current biomolecular research
Current research is directed toward understanding how and why the enzyme deficiency causes so many difficulties. The role of phosphatidylinositol metabolism in normal Golgi function and in Lowe syndrome is being investigated in two basic research projects underway at Indiana University and Rutgers University. These projects were funded by the LSA in 1999.

In addition, researchers at the National Institutes of Health are attempting to develop an animal model for Lowe syndrome. In 1998 researchers successfully cloned the Lowe syndrome gene into a laboratory mouse. However, the mouse did not exhibit the expected characteristics of Lowe syndrome. This result has presented researchers with new avenues of investigation that may lead not only to the eventual development of an animal model, but also to a better understanding of the basic biochemistry of the Lowe syndrome gene.

D. Diagnostic and carrier tests
The development of diagnostic and carrier tests have also been the subject of recent and ongoing research projects. The discovery of the enzyme deficiency led to the development of a simple and reliable diagnostic and prenatal diagnostic test. A biochemical test -- a direct assay of the enzyme phosphatidylinositol 4,5-biphosphate 5 phosphatase -- was initially developed in 1996 and has become a standard test in the clinical laboratory at Baylor College of Medicine. The enzyme assay is now commonly used to diagnose affected patients as well as to carry out prenatal diagnosis.

Biochemical testing is not, however, effective for carrier detection. For laboratory carrier testing, the specific change (mutation) in the DNA sequence that causes the disease can be used to identify carriers. To date, nearly forty different mutations have been found in approximately 50 different patients with Lowe syndrome worldwide. Thus, most families typically have a mutation unique to their family. DNA sequencing in a search for the mutation responsible for Lowe syndrome is necessary in each family who decides to pursue this option. This type of genetic mutational analysis is currently still an expensive procedure not commonly available through routine clinical laboratories. In some families with a strong family history of Lowe syndrome, DNA markers near the mutant gene may be used to trace the inheritance of the abnormal gene in the family without knowing the specific mutation in the gene. This approach, called "linkage," is carried out by specialized genetic diagnosis labs. The eye examination of at-risk females (see "Carrier Detection" in IV. Genetics) currently remains the standard method for determining carrier status. However, an applied research project currently underway at the National Institutes of Health and funded by the Lowe Syndrome Association is directed towards streamlining and improving the process of searching for mutations. The LSA hopes that this project will lead to the development of a simple and reliable carrier test that will be available in clinical settings within the near future.

E. Clinical research
Areas other than genetics have also been investigated. Researchers at the National Institutes of Health studied clinical aspects of the syndrome in a large number of individuals over a span of several years during the 1980's and early 1990's. Their discoveries led to a better understanding of the natural course of the syndrome and better treatment techniques for many of the problems. Other important research projects included a study that helped to establish a causal link between the syndrome and behavioral problems. Much work remains to be done in the area of clinical research.

F. The LSA and research
Good medical research is a partnership between scientists, physicians and affected families. Cooperation and sharing of ideas has led to rapid advances in understanding the cause of Lowe syndrome and may lead to more effective therapies. By providing funds for medical and scientific research, the LSA helps to encourage innovative thinking and interest in a rare condition that otherwise might go unnoticed.

Another way the LSA supports research is by encouraging its parent members to register with the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland at Baltimore. The BTB collects relevant tissues after surgery or after death and stores them for future research purposes. Supported by the National Institute of Child Health and Human Development, the BTB is dedicated to the "improved understanding, care and treatment of developmental disorders." LSA families are encouraged to consider registering with the program. For more information contact the LSA, or contact the BTB at:

University of Maryland, Baltimore
Department of Pediatrics, 13-013 BRB
University of Maryland
655 West Baltimore St.
Baltimore MD 21201-1559
Phone: 1-800-847-1539
Web site: http://medschool.umaryland.edu/btbank

One research project tends to lead to another as knowledge increases and new areas for investigation are developed. Although there have been dramatic advances in the understanding of Lowe syndrome during the five decades since it was first recognized, there is much that remains a mystery. With advances in medical and scientific technology and with the strong support of the LSA, the future will undoubtedly see researchers finding more answers to the many profound and baffling questions that remain.