Joubert syndrome

Joubert syndrome (JS) is a disorder defined by three primary findings:

1. A specific abnormality in the part of the brain characterized by underdevelopment of the cerebellar vermis and additional brain stem differences giving the appearance of the molar tooth sign (MTS)
2. Hypotonia (low muscle tone)
3. Developmental delays/intellectual disabilities of varying degrees

Additional features often include an abnormal breathing pattern demonstrated by rapid/panting-like breathing (tachypnea) followed by pauses in breathing (apnea), eye movement differences (including ocular motor apraxia causing jerky eye movements), and ataxia (uncoordinated movements).

Joubert syndrome and related disorders (JSRD) refers to individuals who have JS with additional findings such as eye, kidney (renal), and liver (hepatic) problems. Many children diagnosed with Joubert syndrome in infancy or childhood develop additional findings of JSRD over time. For more information about this family of conditions, please refer to the Joubert Syndrome & Related Disorders Foundation website at www.jsrdf.org.

Additional features present in some individuals with JSRD (Many of these features are not present at birth.)

• Rapid, involuntary movements of the eyes (nystagmus).
• Severe visual impairment or Leber congenital amaurosis
• Retinal dystrophy, particularly increased pigmentation of the retina or flattened electroretinogram (ERG).
• A gap in the retina or other regions of the eye (coloboma)
• Renal insufficiency, particularly juvenile nephronophthisis or cystic dysplastic kidneys.
• Abnormalities of the liver, including hepatic (liver) fibrosis, also known as the ductal plate malformation in infants.
• Extra fingers and/or toes (polydactyly).
• Extra strands of tissue between the gums, tongue, and mouth (oral frenulae) or nodules on the tongue.
• Speech apraxia, autistic behaviors, and other behavioral problems

Clinical description
Individuals diagnosed with JS have an absence or underdevelopment of part of the brain called the cerebellar vermis which controls balance and coordination. The severity of the resulting ataxia (uncoordinated movements) varies from person to person.

Delay in gross motor, fine motor and speech development is seen in almost all individuals with JS. Delays can be due to low muscle tone and impaired arm, leg, eye and mouth coordination. Some children have also been noted to have visual impairment due to abnormal eye movements. Developmental delays are usually treated with physical therapy, occupational therapy, speech therapy, and infant stimulation. Most children diagnosed with JS are able to achieve standard milestones, although often at a much later age.

Mild to moderate intellectual disability is typical, but cognitive abilities can range from normal to severe intellectual disability. Overall health and growth are not typically affected in patients without pituitary, kidney and liver involvement.

Management and treatment
Presently, there is no cure for Joubert syndrome. Individuals with JS should see the appropriate specialists necessary to help monitor their various clinical issues. Suggested specialists include a nephrologist (kidney doctor), ophthalmologist (eye doctor), geneticist, and neurologist, as well as any others recommended by your primary care provider.

Screening for some of the complications associated with JSRD, such as liver, retinal, or kidney involvement that may become progressive over time, is recommended on an annual basis. Please refer to the Joubert Syndrome & Related Disorders Foundation website’s recommended evaluation for a complete listing of recommended annual tests.

The genetics of JSRD
There are multiple genes associated with JSRD. Alterations in these genes however, are not the cause in many individuals with JS, indicating that additional genetic causes remain to be identified. To learn more about genetics and the genes presently associated with JSRD, please go to the scientific information section of this website.

JS is a member of an emerging class of diseases called ciliopathies. Primary cilia are microscopic, antenna-like structures that stick out from the surface of cells and are important for sensing external cues. Cilia are present on almost all cell types including brain cells (neurons), certain cells within the kidney and liver, and cells involved in sensory input such as sight, hearing, and smell. Alterations in genes associated with JSRD can disrupt proper functioning of the cilia resulting in the clinical features of the disorder (including brain differences, kidney and liver disease, eye abnormalities, hearing loss, and lack of smell (anosmia)). The details of how changes in cilium function cause these features remain the focus of research efforts.

Inheritance and recurrence
JSRD is typically inherited in an autosomal recessive manner, in which an affected individual has mutations in both copies of a gene, preventing the gene from working correctly. Almost always, parents of an affected individual are both unaffected carriers, because they “carry” one nonworking copy of a JSRD gene and one working copy of the gene. When both parents are carriers for mutations in the same JSRD gene, there is a 1 in 4 (25%) chance with each pregnancy that the baby will be affected by JSRD. It is important to note that the severity of JSRD may be quite different between individuals, even within the same family.

Mutations in the OFD1 gene are associated with an X-linked pattern of inheritance. Fathers of an affected male with an OFD1 mutation are not affected and are not carriers. Mothers may be unaffected carriers of an OFD1 mutation or the mutation may be new in the affected male (not inherited from the mother). Mothers who are carriers have a 50% chance with each pregnancy of passing the OFD1 mutation to their children. Males that inherit the OFD1 mutation from their mother have JS; females are usually unaffected.

Digenic inheritance has been proposed to be a cause in patients with single mutations in two different genes; however, this is difficult to prove, since it is always possible that a second mutation in one of the genes has been missed. Further researc is required to determine if and when digenic inheritance might take place.

Medical knowledge has come a long way since JS was first described in 1969. Further research is underway to develop a greater understanding of JSRD and eventually, design disease-specific treatments. For more information about genetic research, please contact the Joubert Syndrome & Related Disorders Foundation.

For more information, additional resources, or to find a JSRDF family in your area, please visit www.jsrdf.org

The information presented is intended to summarize this condition as it is presently understood by medical professionals. The statements included in this document are for information only and should not be considered as medical advice. Please always consult your physician for medical advice.

This information was developed by the Joubert Syndrome Foundation & Related Cerebellar Disorders.

Joubert Syndrome Foundation & Related Cerebellar Disorders. Joubert Syndrome (Cerebellar vermis agenesis/hypoplasia). Available at: https://jsrdf.org/what-is-js/. Accessed September 5, 2018.

The information in this document is for general educational purposes only. It is not intended to substitute for personalized professional advice. Although the information was obtained from sources believed to be reliable, MedLink Corporation, its representatives, and the providers of the information do not guarantee its accuracy and disclaim responsibility for adverse consequences resulting from its use. For further information, consult a physician and the organization referred to herein.