Joubert syndrome

Last updated
Joubert syndrome
Other namesCPD IV [1]
Syndrome de Joubert IRM PAMJ-22-127-g001.jpg
(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
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Differential diagnosis Dandy–Walker malformation, ataxia with oculomotor apraxia, 3C syndrome, Meckel–Gruber syndrome [2]
FrequencyBetween 1:80,000 and 1:100,000 [3]

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

Contents

Joubert syndrome is one of the many genetic syndromes associated with syndromic retinitis pigmentosa. [4] 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. [5]

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. [6] 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 or palate, tongue abnormalities, and seizures may also occur. Developmental delays, including cognitive, are always present to some degree. [7] Severe forms have been noted to include hypoplasia of the corpus callosum. [8] [9] [10]

Those with this syndrome often exhibit specific facial features such as a broad forehead, arched eyebrows, 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 to other organ systems such as retinal dystrophy, kidney diseases, liver diseases, skeletal deformities and endocrine (hormonal) problems. [11]

Genetics

A number of mutations have been identified in individuals with Joubert syndrome (JBTS) which allowed for classification of the disorder into subtypes. [12]

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 defected, it can cause various genetic disorders among individuals. This mutation of primary cilia can disrupt significant signaling pathways during the development of the fetus. [13]

Mutations in these various genes are known for causing around 60-90% of Joubert Syndrome cases. In the remaining cases, the cause is unknown if not linked to a mutation of known genes. [14]

Type OMIM Gene Locus Inheritance Remarks
JBTS1 213300 INPP5E 9q34.3 Autosomal recessive Also known as Cerebellooculorenal syndrome 1 (CORS1)
JBTS2 608091 TMEM216 11q12.2 Autosomal recessive Also known as Cerebellooculorenal syndrome 2 (CORS2)
JBTS3 608629 AHI1 6q23.3 Autosomal recessive
JBTS4 609583 NPHP1 2q13
JBTS5 610188 CEP290
NPHP6 		12q21.32 Autosomal recessive
JBTS6 610688 TMEM67 8q22.1 Autosomal recessive
JBTS7 611560 RPGRIP1L 16q12.2
JBTS8 612291 ARL13B 3q11.1
JBTS9 612285 CC2D2A 4p15.32 Autosomal recessive
JBTS10 300804 OFD1 Xp22.2 X-linked recessive
JBTS11– TTC21B 2q24.3
JBTS12– KIF7 15q26.1Overlapping phenotype with acrocallosal syndrome [15]
JBTS13 614173 TCTN1 12q24.11
JBTS14 614424 TMEM237 2q33.1 Autosomal recessive
JBTS15 614464 CEP41 7q32.2 Autosomal recessive
JBTS16 614465 TMEM138 11q12.2 Autosomal recessive
JBTS17 614615 C5ORF42 5p13.2
JBTS18 614815 TCTN3 10q24.1
JBTS19– ZNF423 16q12.1 Autosomal dominant
JBTS20 614970 TMEM231 16q23.1 Autosomal recessive
611654 CSPP1 , [16] [17] [18] 8q13.2 Autosomal recessive
- ARMC9 2q37.1 Autosomal recessive
FAM149B1 10q22.2 Autosomal recessive

Diagnosis

The disorder is characterized by 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 head MRI scan. [19] 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. [6]

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 under-diagnosed. 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. [14]

Treatment

Treatment for Joubert syndrome is symptomatic and supportive. Infants with abnormal breathing patterns should be monitored. The syndrome is associated with progressive worsening for kidneys, the liver and the eyes and thus requires regular monitoring. [7]

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 are able to achieve standard milestones, although often at a much later age. [20]

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 quotients from 60 to 85. [21]

Research

Research has revealed that a number of genetic disorders, 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 ciliopathies. [22]

The underlying cause of the ciliopathies may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles 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 multi-symptom nature of a large set of syndromes and diseases.[ citation needed ]

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 retinal degeneration. [23]

Joubert syndrome type 2 is disproportionately frequent among people of Jewish descent. [24]

Related Research Articles

Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres in the brain, in the embryo is disrupted. The result of this is that the fibers that would otherwise form the corpus callosum are instead longitudinally oriented along the ipsilateral ventricular wall and form structures called Probst bundles.

Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum, is a rare autosomal recessive congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency and recurrent severe infections. To date, about 50 cases have been reported.

<span class="mw-page-title-main">Acrocallosal syndrome</span> Medical condition

Acrocallosal syndrome is an extremely rare autosomal recessive syndrome characterized by corpus callosum agenesis, polydactyly, multiple dysmorphic features, motor and intellectual disabilities, and other symptoms. The syndrome was first described by Albert Schinzel in 1979. Mutations in KIF7 are causative for ACLS, and mutations in GLI3 are associated with a similar syndrome.

<span class="mw-page-title-main">Ciliopathy</span> Genetic disease resulting in abnormal formation or function of cilia

A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.

<span class="mw-page-title-main">Marden–Walker syndrome</span> Medical condition

Marden–Walker syndrome (MWS) is a rare autosomal recessive congenital disorder. It is characterized by blepharophimosis, microcephaly, micrognathia, multiple joint contractures, arachnodactyly, camptodactyly, kyphoscoliosis and delayed motor development and is often associated with cystic dysplastic kidneys, dextrocardia, Dandy–Walker malformation and agenesis of corpus callosum.

<span class="mw-page-title-main">Orofaciodigital syndrome 1</span> Medical condition

Orofaciodigital syndrome 1 (OFD1), also called Papillon-Léage and Psaume syndrome, is an X-linked congenital disorder characterized by malformations of the face, oral cavity, and digits with polycystic kidney disease and variable involvement of the central nervous system.

<span class="mw-page-title-main">Hydrolethalus syndrome</span> Medical condition

Hydrolethalus syndrome (HLS) is a rare genetic disorder that causes improper fetal development, resulting in birth defects and, most commonly, stillbirth.

<span class="mw-page-title-main">Lujan–Fryns syndrome</span> Medical condition

Lujan–Fryns syndrome (LFS) is an X-linked genetic disorder that causes mild to moderate intellectual disability and features described as Marfanoid habitus, referring to a group of physical characteristics similar to those found in Marfan syndrome. These features include a tall, thin stature and long, slender limbs. LFS is also associated with psychopathology and behavioral abnormalities, and it exhibits a number of malformations affecting the brain and heart. The disorder is inherited in an X-linked dominant manner, and is attributed to a missense mutation in the MED12 gene. There is currently no treatment or therapy for the underlying MED12 malfunction, and the exact cause of the disorder remains unclear.

Genitopatellar syndrome is a rare disorder consisting of congenital flexion contractures of the lower extremities, abnormal or missing patellae, and urogenital anomalies. Additional symptoms include microcephaly, severe psychomotor disability. In 2012, it was shown that mutations in the gene KAT6B cause the syndrome. Genitopatellar syndrome (GTPTS) can be caused by heterozygous mutation in the KAT6B gene on chromosome 10q22. The Say-Barber-Biesecker variant of Ohdo syndrome, which has many overlapping features with GTPTS, can also be caused by heterozygous mutation in the KAT6B gene.

<span class="mw-page-title-main">Kohlschütter–Tönz syndrome</span> Medical condition

Kohlschütter–Tönz syndrome (KTS), also called amelo-cerebro-hypohidrotic syndrome, is a rare inherited syndrome characterized by epilepsy, psychomotor delay or regression, intellectual disability, and yellow teeth caused by amelogenesis imperfecta. It is a type A ectodermal dysplasia.

Xia-Gibbs syndrome, is genetic disorder caused by a heterozygous mutation in the AHDC1 gene on chromosome 1p36.

<span class="mw-page-title-main">Andermann syndrome</span> Medical condition

Andermann syndrome, also known as agenesis of corpus callosum with neuronopathy (ACCPN), Charlevoix disease and KCC3 axonopathy among other names, is a very rare neurodegenerative genetic disorder that damages the nerves used to control muscles and related to sensation and is often associated with agenesis of the corpus callosum.

<span class="mw-page-title-main">Strømme syndrome</span> Rare genetic condition involving intestinal atresia, eye abnormalities and microcephaly

Strømme syndrome is a very rare autosomal recessive genetic condition characterised by intestinal atresia, eye abnormalities and microcephaly. The intestinal atresia is of the "apple-peel" type, in which the remaining intestine is twisted around its main artery. The front third of the eye is typically underdeveloped, and there is usually moderate developmental delay. Less common features include an atrial septal defect, increased muscle tone or skeletal abnormalities. Physical features may include short stature, large, low-set ears, a small jaw, a large mouth, epicanthic folds, or fine, sparse hair.

<span class="mw-page-title-main">Chudley–Mccullough syndrome</span> Medical condition

Chudley–Mccullough syndrome is a rare genetic disorder which is characterized by bilateral congenital hearing loss associated with brain malformations. It is a type of syndromic deafness.

<span class="mw-page-title-main">Waardenburg anophthalmia syndrome</span> Medical condition

Waardenburg anophthalmia syndrome is a rare autosomal recessive genetic disorder which is characterized by either microphthalmia or anophthalmia, osseous synostosis, ectrodactylism, polydactylism, and syndactylism. So far, 29 cases from families in Brazil, Italy, Turkey, and Lebanon have been reported worldwide. This condition is caused by homozygous mutations in the SMOC1 gene, in chromosome 14.

Proud syndrome is a very rare genetic disorder which is characterized by severe intellectual disabilities, corpus callosum agenesis, epilepsy, and spasticity. It is a type of syndromic X-linked intellectual disability.

Curry–Jones syndrome is a rare genetic disorder characterized by congenital brain, osseous, cutaneous, ocular, and intestinal anomalies.

Holoprosencephaly-ectrodactyly-cleft lip/palate syndrome, also simply known as Hartsfield syndrome, is a rare genetic disorder characterized by the presence of variable holoprosencephaly, ectrodactyly, cleft lip and palate, alongside generalized ectodermal abnormalities. Additional findings include endocrine anomalies and developmental delays.

<span class="mw-page-title-main">Severe intellectual disability-progressive spastic diplegia syndrome</span> Medical condition

Severe intellectual disability-progressive spastic diplegia syndrome is a rare novel genetic disorder characterized by severe intellectual disabilities, ataxia, craniofacial dysmorphisms, and muscle spasticity. It is a type of autosomal dominant syndromic intellectual disability.

<span class="mw-page-title-main">X-linked complicated corpus callosum dysgenesis</span> Medical condition

X-linked complicated corpus callosum dysgenesis is a genetic disorder characterized by dysplasia, hypoplasia or agenesis of the corpus callosum alongside variable intellectual disability and spastic paraplegia. Only 13 cases have been described in medical literature. Transmission is X-linked recessive. It is the mildest subtype of L1 syndrome.

References

  1. ↑ "Orphanet: Joubert syndrome". www.orpha.net. Retrieved 24 October 2019.
  2. ↑ "Orphanet: Joubert syndrome". www.orpha.net. Retrieved 2024-06-11.
  3. ↑ "Joubert syndrome: MedlinePlus Genetics". medlineplus.gov. Retrieved 2024-06-11.
  4. ↑ Saraiva JM, Baraitser M (July 1992). "Joubert syndrome: a review". American Journal of Medical Genetics. 43 (4): 726–31. doi:10.1002/ajmg.1320430415. PMID   1341417.
  5. ↑ Joubert M, Eisenring JJ, Robb JP, Andermann F (September 1969). "Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation". Neurology. 19 (9): 813–25. doi: 10.1212/wnl.19.9.813 . PMID   5816874.
  6. 1 2 "Joubert Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2016-12-19.
  7. 1 2 Parisi MA, Doherty D, Chance PF, Glass IA (May 2007). "Joubert syndrome (and related disorders) (OMIM 213300)". European Journal of Human Genetics. 15 (5): 511–21. doi: 10.1038/sj.ejhg.5201648 . PMID   17377524.
  8. ↑ "OMIM Entry - # 213300 - JOUBERT SYNDROME 1; JBTS1". www.omim.org. Retrieved 2019-12-22.
  9. ↑ Zamponi N, Rossi B, Messori A, Polonara G, Regnicolo L, Cardinali C (2002). "Joubert syndrome with associated corpus callosum agenesis". European Journal of Paediatric Neurology. 6 (1): 63–6. doi:10.1053/ejpn.2001.0542. PMID   11993957.
  10. ↑ Bader I, Decker E, Mayr JA, Lunzer V, Koch J, Boltshauser E, et al. (August 2016). "MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum". European Journal of Medical Genetics. 59 (8): 386–91. doi:10.1016/j.ejmg.2016.06.007. PMID   27377014.
  11. ↑ "Joubert syndrome". MedlinePlus Genetics. National Institutes of Health.
  12. ↑ Parisi, Melissa; Glass, Ian (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Joubert Syndrome", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301500 , retrieved 2022-02-11
  13. ↑ Waters AM, Beales PL (July 2011). "Ciliopathies: an expanding disease spectrum". Pediatric Nephrology. 26 (7): 1039–56. doi:10.1007/s00467-010-1731-7. PMC   3098370 . PMID   21210154.
  14. 1 2 "Joubert syndrome". Genetics Home Reference. Retrieved 2017-09-13.
  15. ↑ Online Mendelian Inheritance in Man (OMIM): 200990
  16. ↑ Shaheen R, Shamseldin HE, Loucks CM, Seidahmed MZ, Ansari S, Ibrahim Khalil M, et al. (January 2014). "Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans". American Journal of Human Genetics. 94 (1): 73–9. doi:10.1016/j.ajhg.2013.11.010. PMC   3882732 . PMID   24360803.
  17. ↑ Akizu N, Silhavy JL, Rosti RO, Scott E, Fenstermaker AG, Schroth J, et al. (January 2014). "Mutations in CSPP1 lead to classical Joubert syndrome". American Journal of Human Genetics. 94 (1): 80–6. doi:10.1016/j.ajhg.2013.11.015. PMC   3882909 . PMID   24360807.
  18. ↑ Tuz K, Bachmann-Gagescu R, O'Day DR, Hua K, Isabella CR, Phelps IG, et al. (January 2014). "Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy". American Journal of Human Genetics. 94 (1): 62–72. doi:10.1016/j.ajhg.2013.11.019. PMC   3882733 . PMID   24360808.
  19. ↑ Brancati F, Dallapiccola B, Valente EM (July 2010). "Joubert Syndrome and related disorders". Orphanet Journal of Rare Diseases. 5: 20. doi: 10.1186/1750-1172-5-20 . PMC   2913941 . PMID   20615230.
  20. ↑ "Joubert Syndrome | MedLink Neurology". www.medlink.com. Retrieved 3 April 2020.[ permanent dead link ]
  21. ↑ Steinlin M, Schmid M, Landau K, Boltshauser E (August 1997). "Follow-up in children with Joubert syndrome". Neuropediatrics. 28 (4): 204–11. doi:10.1055/s-2007-973701. PMID   9309710. S2CID   260241632.
  22. ↑ Sattar S, Gleeson JG (September 2011). "The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders". Developmental Medicine and Child Neurology. 53 (9): 793–798. doi:10.1111/j.1469-8749.2011.04021.x. PMC   3984879 . PMID   21679365.
  23. ↑ Badano JL, Mitsuma N, Beales PL, Katsanis N (September 2006). "The ciliopathies: an emerging class of human genetic disorders". Annual Review of Genomics and Human Genetics. 7: 125–48. doi:10.1146/annurev.genom.7.080505.115610. PMID   16722803.
  24. ↑ Gutkind L, Kennedy P (10 October 2013). An Immense New Power to Heal: The Promise of Personalized Medicine. Underland Press. p. 36. ISBN   978-1-937163-07-5.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.