Joubert syndrome
Joubert syndrome is a rare neurological disorder characterized by the improper development of the cerebellum, a brain region essential for coordination and balance. It is often identified through specific imaging findings known as the "molar tooth sign," which indicates distinct malformations in the brain stem. The incidence of Joubert syndrome is estimated to be between 1 in 80,000 and 1 in 100,000 newborns, although cases may be underdiagnosed. Some instances are inherited in an autosomal recessive pattern, typically requiring both parents to carry a mutated gene. Symptoms of the syndrome can vary widely, including respiratory problems in newborns, developmental delays, and potential complications affecting other body systems such as the eyes and kidneys. While there is no cure, treatment focuses on managing symptoms and improving quality of life through supportive therapies. Genetic counseling is recommended for families with a history of the syndrome, allowing for informed reproductive choices in future pregnancies. The prognosis for affected individuals largely depends on the severity of cerebellar malformation.
Joubert syndrome
ALSO KNOWN AS: Cerebelloparenchymal disorder IV (CPD IV); cerebellar vermis agenesis; Joubert-Boltshauser syndrome; JBTS
DEFINITION Joubert syndrome is a rare disorder in which the cerebellum (a part of the brain that controls automatic movements, balance, and coordination) fails to develop properly during gestation. Some cases are inherited in the autosomal recessive pattern.
Risk Factors
The only consistently reported risk factor is consanguinity.
Etiology and Genetics
A diagnosis of Joubert syndrome is indicated if magnetic resonance imaging (MRI) reveals a molar tooth sign, a complex malformation of the brain stem defined by three factors: the absence or incomplete development of the cerebellar vermis (the middle region that normally develops between the two hemispheres of the cerebellum), a thickening and elongation of two bundles of nerve fibers—one on each side of the brain—that run from the cerebellum to the fourth ventricle of the brain, and a deeper-than-normal depression between those nerve bundles.
The US National Library of Medicine's Genetics Home Reference reported in 2014 that the estimated incidence of Joubert syndrome is between 1 in 80,000 and 1 in 100,000 newborns, but cautioned that this estimate may be too low due to underdiagnosis. Most cases of Joubert syndrome cannot be shown to be inherited. They may result from a spontaneous mutation or from some unidentified factor affecting embryological development. In some families, however, Joubert is inherited as autosomal recessive; both parents carry a mutated gene on a non-sex chromosome. In such cases, the chance of bearing an affected child is 1 in 4 with each pregnancy.
Multiple genes on multiple chromosomal sites are involved in the inheritance of Joubert syndrome. AHI1 is the gene that codes for the protein AHI1 (also called jouberin), which may direct nerve fibers to their proper places during brain development. The protein may also play a role in carrying nerve signals, moving substances in and out of neurons, and processing ribonucleic acid (RNA).
The gene NPHP1 codes for the protein nephrocystin-1. The protein’s function is not known, but it may be similar to that of jouberin. CEP290 (NPHP6) codes for nephrocystin-6, a protein known to act as a regulator in normal development of the brain, kidneys, and eyes.
IFT88 and several other genes are cilia genes. Cilia are hair-like structures that normally develop on the surfaces of most types of cells. Research in mice suggests that the loss of certain cilia genes leads to impaired growth and formation of the cerebellum because the progenitor (parent) cells of granule cells (a particular type of interneuron) fail to respond to a signaling protein called sonic hedgehog. That protein normally guides the direction in which nerve fibers grow, thus playing a prominent role in brain organization. One such gene is TMEM67 (formerly MKS3). It codes for the protein meckelin, which is important in the development of cilia. In 2020, researchers at Newcastle University identified that the gene BSND is tied to the severity of kidney disease in individuals with Joubert Syndrome.
Symptoms
Symptoms vary widely among individuals. Extremely rapid breathing, sometimes followed by a cessation of breathing, is often (but not always) observed in newborns. A bluish skin tone, slow heart rate, poor muscle tone, and characteristic facial anomalies may be noted. Other symptoms may include jerky movements of the eyes and limbs.
Over time, evidence of developmental delays and mental retardation may accumulate, as may observations of behaviors related to autism. Breathing abnormalities may lessen with time. Delays in hand-eye coordination, deficits in language and communication, various behavioral impairments, and associated complications involving other body systems (such as the eyes, heart, liver, and kidneys) are sometimes reported, as are extra fingers or toes, cleft lip or palate, tongue abnormalities, and seizures.
Screening and Diagnosis
Molecular genetic testing is available for NPHP1, CEP290, AHI1, and TMEM67. The tests involve analysis of DNA extracted from fetal cells obtained by amniocentesis or chorionic villus sampling. For couples in which the Joubert mutations have been identified, preimplantation genetic diagnosis (PGD) may be employed.
Genetic counseling is advised for parents who already have a child with Joubert syndrome or have reason to suspect a family history of the disorder. Joubert can be diagnosed in utero in at-risk pregnancies. One protocol suggests frequent ultrasound exams beginning at eleven to twelve weeks of gestation, combined with fetal MRI at twenty to twenty-two weeks.
Treatment and Therapy
The syndrome is treated symptomatically. A cardiorespiratory monitor may be used to assess breathing rate and heart rate in newborns. Caffeine, supplemental oxygen, and mechanical support may assist breathing. Parents should learn emergency procedures, including cardiopulmonary resuscitation (CPR). Neurological and neurobehavioral development should be assessed regularly, as should the progression of eye, liver, and kidney complications. Corrective lenses and eye surgery may be needed. Supportive physical, speech, and occupational therapy should be provided as appropriate.
Prevention and Outcomes
Spontaneous cases of Joubert syndrome cannot be prevented, but genetic and may allow parents of an affected child to make choices about future births. The prognosis for children with Joubert syndrome depends, in part, on the degree of cerebellar malformation. Children with incomplete development of the cerebellar vermis typically show milder levels of motor and mental impairment than do those in which the structure is absent.
Bibliography
"Discovery of Gene That Modifies Severity of Inherited Kidney Disease." Newcastle University, 9 Jan. 2020, www.ncl.ac.uk/press/articles/archive/2020/01/joubertsyndromeresearch/#:~:text=Significant%20breakthrough,CEP290%20mutations%20of%20Joubert%20syndrome. Accessed 6 Sept. 2024.
Genetics Home Reference. "Joubert Syndrome." Genetics Home Reference. USNLM, 28 July 2014. Web. 30 July 2014.
McKusick, Victor A., and Cassandra L. Kniffin. "#213300 Joubert Syndrome 1; JBTS1." OMIM.org. Johns Hopkins U, 1 Nov. 2012. Web. 30 July 2014.
Merritt, Linda. “Recognition of the Clinical Signs and Symptoms of Joubert Syndrome.” Advances in Neonatal Care 3.4 (2003): 178–186. Print.
National Institute of Neurological Disorders and Stroke. "NINDS Joubert Syndrome Information Page." NIH National Institute of Neurological Disorders and Stroke. NIH/NINDS, 23 Dec. 2013. Web. 30 July 2014.
Parisi, Melissa, and Ian Glass. "Joubert Syndrome and Related Disorders." GeneReviews. Ed Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 11 Apr. 2013. Web. 30 July 2014.
Valente, Enza Maria, Francesco Brancati, and Bruno Dallapiccola. “Genotypes and Phenotypes of Joubert Syndrome and Related Disorders.” European Journal of Medical Genetics 51 (2008): 1–23. Print.