RESEARCH
The University of Washington Joubert center is engaged in genetic research to understand cerebellar conditions, including Joubert syndrome.
A GENE FOR JOUBERT SYNDROME HAS NOW BEEN IDENTIFIED!
Our group in Seattle, working in conjunction with Drs. Bill Dobyns and Joseph Gleeson, has identified the first gene change associated with Joubert syndrome. This has been published in the July issue of the American Journal of Human Genetics (Parisi et al., "The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals of with Joubert syndrome," Am. J. Hum. Genet., 2004, 75:82-91). The gene, called NPHP1, has been known to cause a kidney disease known as juvenile nephronophthisis. Approximately 60-80% of children with nephronophthisis are missing both copies of the NPHP1 gene. Because some children with Joubert syndrome develop nephronophthisis, we tested children with kidney involvement for deletions in this gene. We found this change in 1 out of 25 children who were tested, and this child had nephrophthisis and a mild form of Joubert syndrome. When we tested 80 children with Joubert syndrome whether or not they kidney involvement, we found a total of 2 children with this deletion. This result has been confirmed by Dr. Valente's group in Italy in a child with Joubert syndrome, retinal dystrophy, and nephronophthisis.
Nephronophthisis is a form of kidney disease that is also known as medullary cystic kidney disease. It can be progressive. The symptoms may not be apparent until late childhood or early teenage years. The first symptoms are usually difficulty with concentrating the urine and sometimes anemia (low red blood cell count). This is why we recommend a complete blood count (to check hematocrit for evidence of anemia) as well as blood tests to check for kidney function (creatinine and BUN) and ultrasound examination. We also recommend a urine test to check its concentration in a sample collected when a child first wakes up (when it should be most concentrated). Later in the disease, there may be ultrasound changes such as scarring of the kidneys. Sometimes, very small cysts can be visualized in the middle of the kidney that may suggest this condition. Treatments can include medications, dialysis, and sometimes, a kidney transplant. Nephrologists or kidney doctors are the best doctors to manage this condition.
Therefore, we believe that the NPHP1 deletion represents the first molecular defect identified in a subset of children with Joubert syndrome. Children with nephronophthisis and retinal disease are at greater risk to have this genetic cause. It may also be more likely in children with milder neurologic symptoms of Joubert syndrome. However, it is important to remember that this is a very uncommon cause of Joubert syndrome, as probably less than 5% of children will have this gene deletion. We are developing recommendations for screening children with Joubert syndrome for this gene deletion. Genetic testing is probably warranted, particularly for those families interested in prenatal diagnosis, since the presence of an NPHP1 gene deletion in an older affected child would allow prenatal DNA testing as an option for first trimester diagnosis in subsequent pregnancies. We recommend annual blood and urine screening tests and ultrasound exam as outlined above for all children with Joubert syndrome. Please contact us or refer to the Health Care Recommendations for further details.
Click here to download the research publication.
May 2006
Dear Participants and Families in Joubert Syndrome Research,
The University of Washington Joubert Research Center has recently published two articles on Joubert syndrome. In one article, Drs. Doherty, Glass, Parisi, Chance, and others review the prenatal ultrasound and fetal MRI findings in two pregnancies at 25% risk of having an affected baby with Joubert syndrome. In one case, the fetus was suspected of having Joubert syndrome on the basis of prenatal imaging findings, which was later confirmed. In the other pregnancy, imaging results suggested that the cerebellum was intact, and an unaffected infant was born several months later. A proposed protocol for monitoring pregnancies is now available for those families wishing to have as much prenatal diagnostic information as possible.
This protocol may be accessed through the Joubert Syndrome Foundation website at http:://www.joubertsyndrome.org/ PrenatalDiagnosis.asp. A Powerpoint presentation on prenatal diagnosis in Joubert syndrome was given by Drs. Doherty and Glass at the last biennial conference in St. Louis, and can be downloaded from our website Prenatal Diagnosis presentation.
A second article by Drs. Parisi, Doherty, Glass, Chance, Dobyns, and others is available on-line. This article describes the clinical findings in 13 families with mutations identified in the AHI1 gene, a gene recently reported for Joubert syndrome. We identified a strong correlation between a child having Joubert syndrome due to AHI1 gene changes and the development of retinal dystrophy in those individuals. In addition, a few of the older subjects had kidney disease similar to nephronophthisis, but with a slower progression than typical juvenile nephronophthisis. Information is limited regarding the significance of this finding for younger children with Joubert syndrome due to AHI1 mutations. On the basis of testing 117 individuals, we found that overall, only 1-2% had Joubert syndrome related to the NPHP1 gene (which also causes classic juvenile nephronophthisis) and 11% had mutations in the AHI1 gene. This means that more genes that cause Joubert syndrome remain to be identified. In fact, this is the major focus of our research currently.
On a separate issue, over the course of this year, the Institutional Review Board (IRB) at the University of Washington has been reviewing human research studies, including our Joubert syndrome research, and making important updates and amendments to our documentation process. As we near the completion of our IRB review, we realize that we will need to re-contact some of you for additional information. If you or members of your family previously gave samples for our research, we may need you to sign new, updated consent forms. These forms will give us permission to store and study your or your family's samples long-term through the Neurogenetics Laboratory Repository, which has been created solely for this purpose. We anticipate that these forms, along with a general cover letter, will be mailed within the next 1-2 months. Please note that not all families will need to be re-contacted. If you have any questions about this process, please let us know.
We are sad to say goodbye to Melissa Eckert who has helped us make such tremendous progress on Joubert syndrome research over the past few years. We would like to welcome the following new members to our team: Jonathan Adkins, Nick Gorden and students Eugene Lee and Nell Niewiadomski.
Thank you very much for participating in our Joubert syndrome research studies. Best wishes for 2006!
Sincerely,
Phillip F. Chance, MD
Melissa A. Parisi, MD, PhD
Ian A. Glass, MD
Daniel Doherty, MD, PhD
Craig L. Bennett, PhD
Dana Knutzen, MS, CGC
Jonathan Adkins , BS
Nick Gorden, BS
Eugene Lee
Nell Niewiadomski
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