View source for Joubert syndrome

{{Short description|Autosomal recessive genetic disorder}}
{{Infobox medical condition
| image = Photo-of-the-person-with-Joubert-syndrome.webp
| name = 
| synonyms = CPD IV<ref>{{cite web |title=Orphanet: Joubert syndrome |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=475 |website=www.orpha.net |access-date=24 October 2019 |language=en}}</ref>
| caption = Photo of a person with Joubert syndrome, with hypertelorism, ptosis, arched eyebrows, and a broad forehead. Also, [[Duane syndrome]] can be seen.
| pronounce = 
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| complications = 
| onset = 
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| risks = 
| diagnosis = 
| differential = [[Dandy–Walker malformation]], ataxia with oculomotor apraxia, [[3C syndrome]], [[Meckel–Gruber syndrome]]<ref>{{Cite web |title=Orphanet: Joubert syndrome |url=https://www.orpha.net/en/disease/detail/475 |access-date=2024-06-11 |website=www.orpha.net}}</ref>
| prevention = 
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| frequency = Between 1:80,000 and 1:100,000<ref>{{Cite web |title=Joubert syndrome: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/joubert-syndrome/ |access-date=2024-06-11 |website=medlineplus.gov |language=en}}</ref>
| deaths = 
}}

'''Joubert syndrome''' is a rare autosomal recessive [[genetic disorder]] that affects the [[cerebellum]], an area of the [[Human brain|brain]] that controls balance and coordination.

Joubert syndrome is one of the many genetic syndromes associated with syndromic [[retinitis pigmentosa]].<ref>{{cite journal | vauthors = Saraiva JM, Baraitser M | title = Joubert syndrome: a review | journal = American Journal of Medical Genetics | volume = 43 | issue = 4 | pages = 726–31 | date = July 1992 | pmid = 1341417 | doi = 10.1002/ajmg.1320430415 }}</ref> The syndrome was first identified in 1969 by pediatric neurologist [[Marie Joubert]] in [[Montreal]], Quebec, Canada, while working at the [[Montreal Neurological Institute]] and [[McGill University]].<ref name="Joubert, 1969">{{cite journal | vauthors = Joubert M, Eisenring JJ, Robb JP, Andermann F | title = Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation | journal = Neurology | volume = 19 | issue = 9 | pages = 813–25 | date = September 1969 | pmid = 5816874 | doi = 10.1212/wnl.19.9.813 | doi-access = free }}</ref>

== Signs and symptoms ==
Most of the signs and symptoms of the Joubert syndrome appear very early in infancy with most children showing delays in gross motor milestones.<ref name=":1">{{Cite news|url=https://rarediseases.org/rare-diseases/joubert-syndrome/|title=Joubert Syndrome - NORD (National Organization for Rare Disorders)|newspaper=NORD (National Organization for Rare Disorders)|language=en-US|access-date=2016-12-19}}</ref> Although other signs and symptoms vary widely from individual to individual, they generally fall under the hallmark of cerebellum involvement or in this case, lack thereof. Consequently, the most common features include [[ataxia]] (lack of muscle control), [[hyperpnea]] (abnormal breathing patterns), [[sleep apnea]], abnormal eye and tongue movements, and [[hypotonia]] in early childhood. Other malformations such as [[polydactyly]] (extra fingers and toes), [[Cleft lip and cleft palate|cleft lip or palate]], tongue abnormalities, and [[seizure]]s may also occur. Developmental delays, including cognitive, are always present to some degree.<ref name=":0">{{cite journal | vauthors = Parisi MA, Doherty D, Chance PF, Glass IA | title = Joubert syndrome (and related disorders) (OMIM 213300) | journal = European Journal of Human Genetics | volume = 15 | issue = 5 | pages = 511–21 | date = May 2007 | pmid = 17377524 | doi = 10.1038/sj.ejhg.5201648 | doi-access = free }}</ref> Severe forms have been noted to include [[hypoplasia of the corpus callosum]].<ref>{{Cite web|url=https://www.omim.org/entry/213300|title=OMIM Entry - # 213300 - JOUBERT SYNDROME 1; JBTS1|website=www.omim.org|access-date=2019-12-22}}</ref><ref>{{cite journal | vauthors = Zamponi N, Rossi B, Messori A, Polonara G, Regnicolo L, Cardinali C | title = Joubert syndrome with associated corpus callosum agenesis | journal = European Journal of Paediatric Neurology | volume = 6 | issue = 1 | pages = 63–6 | date = 2002 | pmid = 11993957 | doi = 10.1053/ejpn.2001.0542 }}</ref><ref>{{cite journal | vauthors = Bader I, Decker E, Mayr JA, Lunzer V, Koch J, Boltshauser E, Sperl W, Pietsch P, Ertl-Wagner B, Bolz H, Bergmann C, Rittinger O | display-authors = 6 | title = MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum | journal = European Journal of Medical Genetics | volume = 59 | issue = 8 | pages = 386–91 | date = August 2016 | pmid = 27377014 | doi = 10.1016/j.ejmg.2016.06.007 }}</ref>

Those with this syndrome often exhibit specific facial features such as a broad forehead, arched eyebrows, [[Ptosis (eyelid)|ptosis]] (droopy eyelids), [[hypertelorism]] (widely spaced eyes), low-set ears, and a triangle shaped mouth. Additionally, this disease can include a broad range of other abnormalities in other organ systems such as retinal dystrophy, kidney diseases, liver diseases, skeletal deformities, and endocrine (hormonal) problems.<ref>{{Cite web|url=https://medlineplus.gov/genetics/condition/joubert-syndrome/|title=Joubert syndrome |website=MedlinePlus Genetics|access-date=|publisher = National Institutes of Health}}</ref>

== Genetics ==
Several [[mutation]]s have been identified in individuals with Joubert syndrome (JBTS) which allowed for classification of the disorder into subtypes.<ref>{{Citation|last1=Parisi|first1=Melissa|title=Joubert Syndrome|date=1993|url=https://www.ncbi.nlm.nih.gov/books/NBK1325/|work=GeneReviews®|editor-last=Adam|editor-first=Margaret P.|place=Seattle (WA)|publisher=University of Washington, Seattle|pmid=20301500|access-date=2022-02-11|last2=Glass|first2=Ian|editor2-last=Ardinger|editor2-first=Holly H.|editor3-last=Pagon|editor3-first=Roberta A.|editor4-last=Wallace|editor4-first=Stephanie E.}}</ref>

This disorder can be caused by mutations in more than 30 genes within genetic makeup.  The [[primary cilia]] play an important role in the structure and function of cells.  When primary cilia are mutated and defective, it can cause various genetic disorders among individuals.  This mutation of primary cilia can disrupt significant signaling pathways during the development of the fetus.<ref>{{cite journal | vauthors = Waters AM, Beales PL | title = Ciliopathies: an expanding disease spectrum | journal = Pediatric Nephrology | volume = 26 | issue = 7 | pages = 1039–56 | date = July 2011 | pmid = 21210154 | pmc = 3098370 | doi = 10.1007/s00467-010-1731-7 }}</ref>

Mutations in these various genes are known to cause around 60-90% of Joubert Syndrome cases.  In the remaining cases, the cause is unknown if not linked to a mutation of known genes.<ref name=":2">{{Cite web|url=https://medlineplus.gov/genetics/condition/joubert-syndrome/|title=Joubert syndrome|website=Genetics Home Reference|language=en|access-date=2017-09-13}}</ref>
{| class="wikitable" style="width: 90%; margin-left: auto; margin-right: auto;"
|-
! style="width:4em;"|Type
! style="width:5em;"|[[OMIM]]
! style="width:6em;"|[[Gene]]
! style="width:5em;"|[[Locus (genetics)|Locus]]
! style="width:10em;"|[[Mendelian inheritance|Inheritance]]
! Remarks
|-
| JBTS1
| {{OMIM|213300||none}}
| ''[[INPP5E]]''
| 9q34.3
| [[Autosomal recessive]]
| Also known as ''Cerebellooculorenal syndrome 1'' (''CORS1'')
|-
| JBTS2
| {{OMIM|608091||none}}
| ''[[TMEM216]]''
| 11q12.2
| [[Autosomal recessive]]
| Also known as ''Cerebellooculorenal syndrome 2'' (''CORS2'')
|-
| JBTS3
| {{OMIM|608629||none}}
| ''[[AHI1]]''
| 6q23.3
| [[Autosomal recessive]]
|
|-
| JBTS4
| {{OMIM|609583||none}}
| ''[[NPHP1]]''
| 2q13
|
|
|-
| JBTS5
| {{OMIM|610188||none}}
| ''[[CEP290]]''<br />''[[NPHP6]]''
| 12q21.32
| [[Autosomal recessive]]
|
|-
| JBTS6
| {{OMIM|610688||none}}
| ''[[TMEM67]]''
| 8q22.1
| [[Autosomal recessive]]
|
|-
| JBTS7
| {{OMIM|611560||none}}
| ''[[RPGRIP1L]]''
| 16q12.2
|
|
|-
| JBTS8
| {{OMIM|612291||none}}
| ''[[ARL13B]]''
| 3q11.1
|
|
|-
| JBTS9
| {{OMIM|612285||none}}
| ''[[CC2D2A]]''
| 4p15.32
| [[Autosomal recessive]]
|
|-
| JBTS10
| {{OMIM|300804||none}}
| ''[[OFD1]]''
| Xp22.2
| [[X-linked recessive]]
|
|-
| JBTS11
| –
| ''[[TTC21B]]''
| 2q24.3
|
|
|-
| JBTS12
| –
| ''[[KIF7]]''
| 15q26.1
|
| Overlapping phenotype with [[acrocallosal syndrome]]<ref>{{OMIM|200990}}</ref>
|-
| JBTS13
| {{OMIM|614173||none}}
| ''[[TCTN1]]''
| 12q24.11
|
|
|-
| JBTS14
| {{OMIM|614424||none}}
| ''[[TMEM237]]''
| 2q33.1
| [[Autosomal recessive]]
|
|-
| JBTS15
| {{OMIM|614464||none}}
| ''[[CEP41]]''
| 7q32.2
| [[Autosomal recessive]]
|
|-
| JBTS16
| {{OMIM|614465||none}}
| ''[[TMEM138]]''
| 11q12.2
| [[Autosomal recessive]]
|
|-
| JBTS17
| {{OMIM|614615||none}}
| ''[[C5ORF42]]''
| 5p13.2
|
|
|-
| JBTS18
| {{OMIM|614815||none}}
| ''[[TCTN3]]''
| 10q24.1
|
|
|-
| JBTS19
| –
| ''[[ZNF423]]''
| 16q12.1
| [[Autosomal dominant]]
|
|-
| JBTS20
| {{OMIM|614970||none}}
| ''[[TMEM231]]''
| 16q23.1
| [[Autosomal recessive]]
|
|-
|
| {{OMIM|611654||none}}
| ''[[CSPP1]]'',<ref name="Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans">{{cite journal | vauthors = Shaheen R, Shamseldin HE, Loucks CM, Seidahmed MZ, Ansari S, Ibrahim Khalil M, Al-Yacoub N, Davis EE, Mola NA, Szymanska K, Herridge W, Chudley AE, Chodirker BN, Schwartzentruber J, Majewski J, Katsanis N, Poizat C, Johnson CA, Parboosingh J, Boycott KM, Innes AM, Alkuraya FS | display-authors = 6 | title = Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans | journal = American Journal of Human Genetics | volume = 94 | issue = 1 | pages = 73–9 | date = January 2014 | pmid = 24360803 | pmc = 3882732 | doi = 10.1016/j.ajhg.2013.11.010 }}</ref><ref name="Mutations in CSPP1 Lead to Classical Joubert Syndrome">{{cite journal | vauthors = Akizu N, Silhavy JL, Rosti RO, Scott E, Fenstermaker AG, Schroth J, Zaki MS, Sanchez H, Gupta N, Kabra M, Kara M, Ben-Omran T, Rosti B, Guemez-Gamboa A, Spencer E, Pan R, Cai N, Abdellateef M, Gabriel S, Halbritter J, Hildebrandt F, van Bokhoven H, Gunel M, Gleeson JG | display-authors = 6 | title = Mutations in CSPP1 lead to classical Joubert syndrome | journal = American Journal of Human Genetics | volume = 94 | issue = 1 | pages = 80–6 | date = January 2014 | pmid = 24360807 | pmc = 3882909 | doi = 10.1016/j.ajhg.2013.11.015 }}</ref><ref name="Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy">{{cite journal | vauthors = Tuz K, Bachmann-Gagescu R, O'Day DR, Hua K, Isabella CR, Phelps IG, Stolarski AE, O'Roak BJ, Dempsey JC, Lourenco C, Alswaid A, Bönnemann CG, Medne L, Nampoothiri S, Stark Z, Leventer RJ, Topçu M, Cansu A, Jagadeesh S, Done S, Ishak GE, Glass IA, Shendure J, Neuhauss SC, Haldeman-Englert CR, Doherty D, Ferland RJ | display-authors = 6 | title = Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy | journal = American Journal of Human Genetics | volume = 94 | issue = 1 | pages = 62–72 | date = January 2014 | pmid = 24360808 | pmc = 3882733 | doi = 10.1016/j.ajhg.2013.11.019 }}</ref>
| 8q13.2
| [[Autosomal recessive]]
|
|-
|
| -
| ''[[ARMC9]]''
| 2q37.1
| [[Autosomal recessive]]
|
|-
|
|
| ''[[FAM149B1]]''
| 10q22.2
| [[Autosomal recessive]]
|
|-
|}

== Diagnosis ==
[[File:Syndrome de Joubert IRM PAMJ-22-127-g001.jpg|frame|(A) MRI Brain, axial T2 sequence showing enlarged superior cerebellar peduncles and vermian hypoplasia resulting in characteristic "molar tooth" appearance; (B) MRI Brain, sagittal T2 (a) and T1 (b) sequences showing vermian hypoplasia, predominantly at the superior aspect]]
The disorder is characterized by the absence or underdevelopment of the [[cerebellar vermis]] and a malformed [[brain stem]] (molar tooth sign), both of which can be visualized on a transverse view of the head [[Magnetic resonance imaging|MRI scan]].<ref name="Brancati, 2010">{{cite journal | vauthors = Brancati F, Dallapiccola B, Valente EM | title = Joubert Syndrome and related disorders | journal = Orphanet Journal of Rare Diseases | volume = 5 | article-number = 20 | date = July 2010 | pmid = 20615230 | pmc = 2913941 | doi = 10.1186/1750-1172-5-20 | doi-access = free }}</ref> Together with this sign, the diagnosis is based on the physical symptoms and [[genetic testing]] for mutations. If the gene mutations have been identified in a family member, prenatal or carrier diagnosis can be pursued.<ref name=":1" />

Joubert Syndrome is known to affect 1 in 80,000-100,000 newborns.  Due to the variety of genes this disorder involves, it is likely to be underdiagnosed.  It is commonly found in [[Ashkenazi Jewish]], [[French-Canadians]], and [[Hutterite]] ethnic populations.  Most cases of Joubert syndrome are autosomal recessive; in these cases, both parents are either carriers or affected. Rarely, Joubert syndrome is inherited in an X-linked recessive pattern. In these cases, males are more commonly affected because they must have one X chromosome mutated, while affected females must have mutated genes on both X chromosomes.<ref name=":2" />

== Treatment ==
Treatment for Joubert syndrome is symptomatic and supportive. Infants with abnormal breathing patterns should be monitored. The syndrome is associated with progressive worsening of the kidneys, the liver, and the eyes and thus requires regular monitoring.<ref name=":0" />

Delays in gross motor skills, fine motor skills, and speech development are seen in almost all individuals with Joubert syndrome. Delays can be due to low muscle tone as well as impaired motor 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, and speech therapy interventions. Most children diagnosed with Joubert syndrome can achieve standard milestones, although often at a much later age.<ref>{{cite web |title=Joubert Syndrome {{!}} MedLink Neurology |url=https://www.medlink.com/index.php/handout/joubert_syndrome |website=www.medlink.com |access-date=3 April 2020 }}{{Dead link|date=April 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

== Prognosis ==
In a sample of 19 children, a 1997 study found that 3 died before the age of 3, and 2 never learned to walk. The children had various levels of delayed development with [[developmental quotient]]s from 60 to 85.<ref>{{cite journal | vauthors = Steinlin M, Schmid M, Landau K, Boltshauser E | title = Follow-up in children with Joubert syndrome | journal = Neuropediatrics | volume = 28 | issue = 4 | pages = 204–11 | date = August 1997 | pmid = 9309710 | doi = 10.1055/s-2007-973701 | s2cid = 260241632 }}</ref>

== Research ==
Research has revealed that a number of [[genetic disorder]]s, not previously thought to be related, may indeed be related as to their root cause. Joubert syndrome is one such disease. It is a member of an emerging class of diseases called [[ciliopathy|ciliopathies]].<ref>{{cite journal | vauthors = Sattar S, Gleeson JG | title = The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders | journal = Developmental Medicine and Child Neurology | volume = 53 | issue = 9 | pages = 793–798 | date = September 2011 | pmid = 21679365 | pmc = 3984879 | doi = 10.1111/j.1469-8749.2011.04021.x }}</ref>

The underlying cause of the ciliopathies may be a dysfunctional molecular mechanism in the primary [[cilia]] structures of the [[Cell (biology)|cell]], [[organelle]]s which are present in many cellular types throughout the [[human]] body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often [[pleiotropic|multi-symptom]] nature of a large set of syndromes and diseases.{{citation needed|date=November 2020}}

Currently recognized ciliopathies include Joubert syndrome, [[primary ciliary dyskinesia]] (also known as Kartagener Syndrome), [[Bardet–Biedl syndrome]], [[polycystic kidney disease]] and [[polycystic liver disease]], [[nephronophthisis]], [[Alström syndrome]], [[Meckel–Gruber syndrome]] and some forms of [[retinopathy|retinal degeneration]].<ref>{{cite journal | vauthors = Badano JL, Mitsuma N, Beales PL, Katsanis N | title = The ciliopathies: an emerging class of human genetic disorders | journal = Annual Review of Genomics and Human Genetics | volume = 7 | pages = 125–48 | date = September 2006 | pmid = 16722803 | doi = 10.1146/annurev.genom.7.080505.115610 }}</ref>

Joubert syndrome type 2 is disproportionately [[Medical genetics of Jews|frequent among people of Jewish descent]].<ref>{{cite book| vauthors = Gutkind L, Kennedy P |title=An Immense New Power to Heal: The Promise of Personalized Medicine|url=https://books.google.com/books?id=MOs7LjBQW40C&pg=PT36|date=10 October 2013|publisher=Underland Press|isbn=978-1-937163-07-5|pages=36}}</ref>

== References ==
{{Reflist}}

== External links ==
{{Medical resources
| DiseasesDB=30688
| ICD10={{ICD10|Q|04|3|q|00}}
| ICD9={{ICD9|742.2}}
| OMIM=213300
| MedlinePlus=
| eMedicineSubj=
| eMedicineTopic=
| MeSH=C536293
| GeneReviewsName=Joubert Syndrome and Related Disorders
| GeneReviewsNBK=NBK1325
| Orphanet=475
}}
* [http://www.ninds.nih.gov/health_and_medical/disorders/joubert.htm NINDS Joubert Syndrome Information Page] {{Webarchive|url=https://web.archive.org/web/20080906232647/http://www.ninds.nih.gov/health_and_medical/disorders/joubert.htm |date=2008-09-06 }}
* [http://www.ninds.nih.gov/news_and_events/news_articles/news_article_Joubert_genes.htm  Researchers Identify Joubert Syndrome Genes] {{Webarchive|url=https://web.archive.org/web/20160704224835/http://www.ninds.nih.gov/news_and_events/news_articles/news_article_Joubert_genes.htm |date=2016-07-04 }}
* [https://web.archive.org/web/20210829200305/https://www.ncbi.nlm.nih.gov/gtr/ GeneReviews: Joubert syndrome]
* [https://www.ncbi.nlm.nih.gov/books/NBK1325/ NCBI Joubert Syndrome]
{{Authority control}}

{{Other genetic disorders by mechanism}}
{{Deficiencies of intracellular signaling peptides and proteins}}

[[Category:Neurological disorders]]
[[Category:Syndromes affecting the nervous system]]
[[Category:Genodermatoses]]
[[Category:Ciliopathy]]
[[Category:Genetic syndromes]]
[[Category:Syndromes with intellectual disability]]
[[Category:Syndromes with craniofacial abnormalities]]
[[Category:Syndromes with dysmelia]]
[[Category:Syndromes affecting the cerebellum]]
[[Category:Rare syndromes]]