Information on the following diseases can be found in the Related Disorders section of this report:

• Dandy Walker Syndrome
• Leber's Congenital Amaurosis
• Hydrocephalus

Many of the clinical symptoms of Joubert syndrome are apparent in infancy and most affected children have delays in gross motor milestones. The most common features are lack of muscle control (ataxia), abnormal breathing patterns (hyperpnea), sleep apnea, abnormal eye and tongue movements and low muscle tone. Intellect ranges from normal to severe mental retardation. Joubert syndrome is characterized by a specific finding on an MRI called a "molar tooth sign" in which the cerebellar vermis of the brain is absent or underdeveloped and the brain stem is abnormal.

Joubert syndrome is a very variable condition and the full spectrum of symptoms has not yet been determined. Several conditions have been described in which the "molar tooth sign" and characteristics of Joubert syndrome are present in addition to other findings. It is not yet clear if these conditions are variants of Joubert syndrome or separate syndromes. These conditions have been termed "Joubert syndrome and related disorders". Some of the other problems that may be associated with Joubert syndrome include eye abnormalities such as abnormal development of the retina, abnormality in the iris (coloboma), abnormal eye movements (nystagmus), crossed eyes (strabismus), and drooping eyelids (ptosis). Other problems sometimes associated with Joubert syndrome include kidney and/or liver abnormalities, extra fingers and toes (polydactyly), a gap in the skull with protrusion of the membranes that cover the brain (encephalocele) and hormone abnormalities.

Joubert syndrome is inherited as an autosomal recessive genetic disorder.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Four genes have been identified that cause Joubert syndrome in approximately 40% of affected families. A mutation in the AHI1 gene is responsible for this condition in approximately 11% of families. Affected individuals with this gene mutation often have impaired vision due to retinal dystrophy. A mutation in the NPHP1 gene causes approximately 1-2% of Joubert syndrome. Affected individuals with this gene mutation often develop a progressive kidney disease called nephronophthisis. A mutation in the CEP290 gene causes about 4-10% of Joubert syndrome. A mutation in the TMEM67 gene is also associated with Joubert syndrome. Other genes responsible for this condition are currently unknown.

The prevalence of Joubert syndrome has been estimated to be 1/258,000 but is probably an underestimate of the true prevalence, which may be closer to 1/100,000.

Several conditions have been described in which the "molar tooth sign" and characteristics of Joubert syndrome are present in addition to other findings. It is not yet clear if these conditions are variants of Joubert syndrome or separate syndromes. The following conditions have been termed "Joubert syndrome and related disorders".

Dekaban-Arima syndrome is characterized by vision abnormalities and kidney dysfunction.

Severe retinal dysplasia is characterized by blindness.

COACH syndrome is characterized by mental retardation, coloboma malformation of the retina and liver abnormalities.

Senior-Loken syndrome is characterized by vision abnormalities and a type of kidney dysfunction called nephronophthisis.

Varadi-Papp syndrome is also known as oral-facial-digital syndrome, type VI. This condition is characterized by cleft lip or palate, tongue abnormalities, extra tissue between the gums, tongue and mouth, dental abnormalities, facial abnormalities, extra fingers and toes, poor growth and short stature.

Nephronophphthisis is a specific type of kidney dysfunction.

Cogan oculomotor apraxia syndrome is characterized by an eye movement abnormality.

Symptoms of the following disorders can be similar to those of Joubert syndrome. Comparisons may be useful for a differential diagnosis:

Dandy-Walker malformation is a rare malformation of the brain that is present at birth (congenital). It is characterized by an abnormally enlarged space at the back of the brain (cystic 4th ventricle) that interferes with the normal flow of cerebrospinal fluid through the openings between the ventricle and other parts of the brain. Excessive amounts of fluid accumulate around the brain and cause abnormally high pressure within the skull, swelling of the head (congenital hydrocephalus), and neurological impairment. Motor delays and learning problems may also occur. Dandy-Walker malformation is a form of obstructive or internal noncommunicating hydrocephalus, meaning that the normal flow of cerebrospinal fluid is blocked resulting in the widening of the ventricles. (For more information, choose "Dandy Walker" as your search term in the Rare Disease Database.)

Oral-facial-digital syndrome (OFDS) is an umbrella term for at least 10 apparently distinctive genetic disorders that are characterized by defects and flaws in the development of the structure of the oral cavity including the mouth, tongue, teeth, and jaw; the development of the facial structures including the head, eyes, and nose; and the fingers and toes (digits); along with differing degrees of mental retardation. The presentation of signs and symptoms is extremely varied, making diagnosis difficult. OFDS type I is the most common of all of these disorders, and it is quite rare. Each of the other types is extremely rare. (For more information, choose "oral-facial-digital" as your search term in the Rare Disease Database.)

Meckel syndrome is a rare inherited disorder characterized by abnormalities affecting several organ systems of the body (multisystem). Three classic symptoms are normally associated with Meckel syndrome: protrusion of a portion of the brain and its surrounding membranes (meninges) through a defect in the back or front of the skull (occipital encephalocele), multiple cysts on the kidneys (polycystic kidneys), and extra fingers and/or toes (polydactyly). Affected children may also have abnormalities affecting the head and face (craniofacial area), liver, lungs, and genitourinary tract. Meckel syndrome is inherited as an autosomal recessive trait. (For more information, choose "Meckel" as your search term in the Rare Disease Database.)

TDiagnosis
The diagnosis of Joubert syndrome is based on physical symptoms and the "molar tooth sign" as seen on an MRI. Molecular genetic testing is available for the four genes that have been shown to cause Joubert syndrome in about 40% of cases. Carrier testing and prenatal diagnosis are available if one of these gene mutations has been identified in an affected family member.

Treatment
The treatment for Joubert syndrome is symptomatic and supportive. Developmental delays are usually treated with physical therapy, occupational therapy, speech therapy and infant stimulation. Individuals with Joubert syndrome should be evaluated by appropriate specialists including nephrologists, ophthalmologists, geneticists and neurologists. Annual screening is recommended for liver, kidney and retinal abnormalities.

Genetic counseling is recommended for individuals with Joubert syndrome and their families.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

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