Última actualización:
June 14, 2021
Años publicados: 1986, 1988, 1990, 1992, 1997, 1999, 2007, 2008, 2011, 2021
NORD gratefully acknowledges Miles Picus, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling and Hannah Wand, MS, CGC, Clinical Instructor (Affiliated), Dept of Pediatrics, Division of Medical Genetics, Stanford University, for assistance in the preparation of this report.
Summary
Joubert syndrome (JS) is an autosomal recessive genetic disorder that affects the area of the brain that controls balance and coordination known as the cerebellum. This condition 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. The most common features of Joubert syndrome are lack of muscle control (ataxia), abnormal breathing patterns (hyperpnea), sleep apnea, abnormal eye and tongue movements and low muscle tone.
Introduction
Joubert syndrome was originally described by pediatric neurologist, Dr. Marie Joubert, and her colleagues in 1969 in four siblings with underdeveloped cerebellar vermis who had symptoms of hypernea (forced respiration), abnormal eye movements, ataxia and intellectual disability. Several years later, the specific brain malformation, the “molar tooth sign”, was first detected in patients with Joubert syndrome. Since then, a number of genes related to Joubert syndrome have been identified in various populations.
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 intellectual disability. 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.
In addition to these core features, the majority of individuals with JS also have involvement of other body systems including the eye, kidney, liver and skeleton. Therefore, JS is considered a multisystem disorder, and several of the additional features may be progressive. 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.
There are several subtypes of Joubert syndrome depending on clinical signs and symptoms. There is Joubert syndrome with retinal disease (JS-Ret), Joubert syndrome with renal disease (JS-Ren), Joubert syndrome with oculorenal disease (JS-OR), Joubert syndrome with hepatic disease (JS-H), Joubert syndrome with oral-facial-digital features (JS-OFD) and a couple other less common clinical subtypes. Joubert syndrome with retinal disease (JS-Ret) is characterized by a pigmentary retinopathy that may be indistinguishable from classic retinitis pigmentosa. It can occasionally be severe with neonatal onset of congenital blindness; however, the retinal disease may not be progressive and is not always present in infancy or early childhood. Joubert syndrome with renal disease (JS-Ren) has been described traditionally in two forms – nephronophthisis (kidney inflammation and scarring) and polycystic kidney disease; however, these now appear to be part of a continuum with the specific renal manifestation varying by stage of renal disease. In Joubert syndrome with oculorenal disease (JS-OR), retinal disease and renal impairment often occur together in the same individual. Joubert syndrome with hepatic disease (JS-H) usually presents with hepatic (liver) fibrosis that is usually progressive but rarely symptomatic at birth. In Joubert syndrome with oral-facial-digital features (JS-OFD), oral findings can include midline upper-lip cleft, midline groove of tongue, hamartomas of the alveolar ridge and cleft palate. Craniofacial features often include wide-spaced eyes, low-set ears and small jaw (micrognathia).
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”.
More than thirty genes have been identified that cause Joubert syndrome. The proteins produced from these genes are known or suspected to play roles in cell structures called primary cilia. Primary cilia are microscopic, finger-like projections that stick out from the surface of cells and are involved in sensing the physical environment and in chemical signaling. Primary cilia are important for the structure and function of many types of cells, including brain cells (neurons) and certain cells in the kidneys and liver. Primary cilia are also necessary for the perception of sensory input, which is interpreted by the brain for sight, hearing, and smell.
Mutations in the genes associated with Joubert syndrome lead to problems with the structure and function of primary cilia. Defects in these cell structures can disrupt important chemical signaling pathways during development. Although researchers believe that defective primary cilia are responsible for most of the features of these disorders, it is not completely understood how they lead to specific developmental abnormalities.
Mutations in the genes known to be associated with Joubert syndrome have been found in about 60-90% of people with this condition. In the remaining patients, the genetic cause is unknown.
Depending on the gene involved, various clinical presentations of Joubert syndrome can occur in an affected individual. A mutation in the AHI1 (JBTS3) gene is responsible for this condition in approximately ~7%-10% of families. Affected individuals with this gene mutation often have impaired vision due to retinal dystrophy. A mutation in the NPHP1 (JBTS4) 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 (JBTS5) gene causes about 7-10% of Joubert syndrome. Mutations in the CPLANE1, CC2D2A, INPP5E, KIAA0586, MKS1, RPGRIP1L TCTN2, TMEM67 and TMEM216 genes, along with other less common genetic causes are also associated with Joubert syndrome.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working 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 working genes from both parents is 25%. The risk is the same for males and females.
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.
Rare cases of Joubert syndrome (caused by mutations in the OFD1 gene) are inherited in an X-linked recessive pattern. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The birth prevalence of JS is estimated to be between 1/80,000 and 1/100,000 live births, but JS may be underdiagnosed and the true prevalence may be higher.
The diagnosis of Joubert syndrome is based on physical symptoms and the “molar tooth sign” as seen on an MRI. Diagnostic criteria for JS continue to evolve but most experts agree that the neuroradiologic finding of the molar tooth sign is necessary to make the diagnosis. The diagnosis of Joubert syndrome is based on the presence of the following three primary criteria:
A molecular diagnosis of Joubert syndrome can be confirmed via molecular genetic testing, which is available for the many genes that have been shown to cause Joubert syndrome. A molecular diagnosis can be established in about 60% to 90% of patients. Carrier testing and prenatal diagnosis are available if one of these gene mutations has been identified in an affected family member.
Clinical Testing and Work-Up
Because Joubert syndrome is a multisystem disorder, and the diagnosis is often made initially in the setting of a neurology, genetics or developmental pediatrics clinic, the frequent involvement of other organ systems means that monitoring for complications is required, with referral to the corresponding subspecialists when specific organ involvement is suspected. The following baseline evaluations to identify the extent of disease are recommended by a consensus panel:
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. Children 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.
Infants and children with abnormal breathing patterns should be considered for apnea monitoring and supportive therapy may require stimulatory medications or supplemental oxygen; mechanical support; or tracheostomy in rare cases. Other interventions may include speech therapy for oromotor dysfunction; occupational and physical therapy; educational support, including special programs for the visually impaired; and feedings by gastrostomy tube. Surgery may be required for polydactyly and symptomatic ptosis and/or strabismus. Corrective lenses may be required for optic refractive errors. Nephronophthisis, end-stage renal disease, liver failure and/or fibrosis are treated with standard approaches, which may include dialysis and/or kidney transplantation.
Genetic counseling is recommended for individuals with Joubert syndrome and their families.
Precision treatments are treatments specifically targeting the genetic cause or biological mechanism of a disorder. Currently, precision treatments for Joubert syndrome are only available as part of research studies (investigational). Gene therapy has been used to improve visual function for specific types of retinal dystrophy by direct retinal injection of expression vectors in humans. Future trials are likely to involve the CEP290 gene, a major cause of Leber congenital amaurosis and Joubert syndrome. Alternatively, antisense oligonucleotides can augment gene function by blocking aberrant splicing or by causing exons with deleterious variants to be skipped. These treatments are still in early development for Joubert syndrome but have been used for other disorders in humans such as spinal muscular atrophy. Future medications targeting specific pathways that are disrupted in Joubert syndrome may be beneficial, but this work is also in its infancy.
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 NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Acosta MT, Pearl PL. Joubert syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:542.
JOURNAL ARTICLES
Bachmann‐Gagescu, R, Dempsey, JC, Bulgheroni, S, et al. Healthcare recommendations for Joubert syndrome. Am J Med Genet Part A. 2020; 182: 229– 249.
Brancati F, Dallapiccola B, Valente EM. Joubert syndrome and related disorders. Orphanet J Rare Dis. 2010; 5:20. https://doi.org/10.1186/1750-1172-5-20
INTERNET
MedlinePlus. Bethesda (MD): National Library of Medicine (US); Last updated 8/18/20; Available from: https://medlineplus.gov/genetics/condition/joubert-syndrome/#causes Accessed May 13, 2021.
Parisi M, Glass I. Joubert Syndrome. 2003 Jul 9 [Updated 2017 Jun 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1325/ Accessed May 13, 2021.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Joubert Syndrome; JBTS. Entry No: 213300. Last Edited 02/22/2021. Available at: https://www.omim.org/entry/213300 Accessed May 13, 2011.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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