New findings from the University of California, San Diego (UCSD) School of Medicine have identified chromosome 11 as a second site for a gene or genes that cause Joubert syndrome, a disorder that affects about 1 in 30,000 individuals. Prior to this study, chromosome 9 had been the only known site with gene mutations causing the disorder.

The new study, published online in the September issue of the American Journal of Human Genetics, focused on three Middle Eastern families whose relatives had inter-married and passed the genetic defect to several family members.

Characterized by absence or underdevelopment of a brain region called the cerebellar vermis, and by a malformed brain stem, Joubert syndrome affects individuals to varying degrees across the spectrum of motor and mental development. Its most common features include lack of muscle control and decreased muscle tone; an abnormal breathing pattern called hypernea, in which babies pant; abnormal eye and tongue movements; and mild or moderate retardation. The type of Joubert syndrome now traced to chromosome 11 also includes eye or kidney problems, in addition to the classical symptoms associated with the disorder.

“The hunt for genes for this syndrome has been extremely slow and none are currently known, due to the rarity of the syndrome,” said the study’s senior author, Joseph Gleeson, M.D., UCSD assistant professor of neurosciences. “The main problem in identifying genes has been the small number of patients appropriate for genetic analysis.”

This led Gleeson’s team to an intensive patient recruiting effort and a change in the way the analysis was being performed.

Joubert syndrome is inherited in an autosomal recessive manner, which means that both parents carry the mutant version of the gene, while showing no signs of the disease themselves. To increase their subject pool for research, the Gleeson team focused on the Middle East, where families are larger and inter-marriage between cousins is an accepted custom. Working with collaborators in Oman, the United Arab Emirates, Saudi Arabia, Jordan and Pakistan, the UCSD researchers obtained DNA samples from affected and unaffected individuals in 20 families.

Using sophisticated genetic screening tools, the researchers identified a common genetic region in seven children from three affected families who displayed the form of Joubert syndrome with eye and kidney problems. These patients included a northern Pakistani child of first cousins, who displayed visual impairment and kidney cysts in addition to the characteristic breathing abnormality and muscle coordination problem. Two of six children of first cousins from the United Arab Emirates, exhibited Joubert features such as brain malformations (as revealed on an MRI scan), impaired vision, jerky eye movements and a malformed retina. Three children from another United Arab Emirates family experienced panting respirations, balance problems, retinal dystrophy and moderate visual impairment.

The study’s authors noted that the variability of symptoms in the affected individuals suggests that there may be genetic modifiers that influence the disease severity and expression of symptoms.

Gleeson, who has studied Joubert syndrome for several years, noted “parents of affected children are just craving for information, to understand the basis for this disorder and something about the prognosis. The most heart wrenching thing is parents who are reluctant to get pregnant again because they have had a single child with this condition.”

He added that the possibility of developing a genetic screening test gives his group an additional incentive to discover the gene as soon as possible.

“We don’t yet know the exact genes involved; this is an incremental step,” Gleeson said. “But, we’re getting closer to providing the information these parents so desperately want.”

In addition to Gleeson, additional researchers include first-author Lesley C. Keeler, M.S., Sarah E. Marsh, M.S., Esther P. Leeflang, Ph.D., Neurogenetics Laboratory, UCSD Division of Pediatric Neurology; Christopher G. Woods, M.D., Molecular Medicine Unit and Yorkshire Clinical Genetics Service, St. James’ University Hospital, Leeds, United Kingdom; and Aithala Gururaj, Lihadh Al-Gazali, DCH, Laszlo Sctriha, M.D., Ph.D., Department of Pediatrics, United Emirates University, Al Ain, UAE.

The study was performed collaboratively with the Marshfield Center for Genetics in Wisconsin and funded by the March of Dimes.

A San Diego child’s story

A sweet little girl who smiles when people talk to her, 4-year-old Saily Vargas of Paradise Hills in San Diego, is severely affected with Joubert syndrome. She cannot sit or walk or talk. In addition to her significant problems with muscle control and breathing difficulty, Saily has cysts in her kidneys and eye abnormalities.

Shortly after her birth, her parents, Carmen and Alberto Vargas, began to worry about Saily’s breathing problems and almost daily seizures. With a referral to Mark Nespeca, M.D., a neurologist at San Diego’s Children’s Hospital, they learned about this rare disorder and an anticipated short life span for their beloved first child. It was devastating.

“We were told there is a 25 percent chance that any other children we might have will have this condition, so we don’t plan to have other children,” Mrs. Vargas sadly said.

Links:

Dr. Joseph Gleeson’s Joubert syndrome information page http://gleesongenetics.ucsd.edu/

Joubert Syndrome Foundation http://www.joubertsyndrome.org/index.htm

National Institute of Neurological Disorders and Stroke, Joubert syndrome information http://www.ninds.nih.gov/health_and_medical/disorders/joubert.htm

Note: If no author is given, the source is cited instead.

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