Summary of NPHP1 Gene
Identification
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
“Recommendations for evaluation and monitoring of patients with
Joubert syndrome and related disorders” provided on the Joubert
Syndrome Foundation website for further details.
Submitted by Melissa Parisi, MD, PhD and Ian Glass, MD,
University of Washington, Seattle, WA
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