Joubert syndrome

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Joubert syndrome
Classification and external resources
Specialty medical genetics
ICD-10 Q04.3
ICD-9-CM 742.2
OMIM 213300
DiseasesDB 30688
MeSH C536293
GeneReviews
Orphanet 475

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

Joubert syndrome is one of the many genetic syndromes associated with syndromic retinitis pigmentosa.[1] The syndrome was first identified in 1969 by pioneering pediatric neurologist Marie Joubert in Montreal, Canada, while working at the Montreal Neurological Institute and McGill University.[2]

Signs and symptoms[edit]

Most of the signs and symptoms of the Joubert syndrome appear very early in infancy with most children showing delays in gross motor milestones.[3] 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.[4]

Those suffering from 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.[5]

Genetics[edit]

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

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 15q26.1
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,[6][7][8] 8q13.2 Autosomal recessive
- ARMC9 2q37.1 Autosomal recessive

Diagnosis[edit]

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 MRI scan.[9] 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.[3]

Treatment[edit]

Treatment for Joubert syndrome is symptomatic and supportive.[4] Infant stimulation and physical, occupational, speech and hearing therapy may benefit some patients. Infants with abnormal breathing patterns should be monitored.

The syndrome is associated with progressive worsening for kidneys, the liver and the eyes and thus require regular monitoring.[4]

Prognosis[edit]

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 retarded development with developmental quotients from 60 to 85.[10]

Research/Ciliopathy[edit]

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.

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.

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, Alstrom syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration.[11]

Joubert syndrome type 2 is disproportionately frequent among people of Jewish descent; this has been attributed to the resistance to intermarriage of this population.[12]

References[edit]

  1. ^ Saraiva, JM; Baraitser, M (1992). "Joubert syndrome: a review". American Journal of Medical Genetics. 43 (4): 726–731. PMID 1341417. doi:10.1002/ajmg.1320430415. 
  2. ^ 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. PMID 5816874. doi:10.1212/wnl.19.9.813. 
  3. ^ a b "Joubert Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2016-12-19. 
  4. ^ a b c Parisi, Melissa A.; Doherty, Dan; Chance, Phillip F.; Glass, Ian A. (2007-03-21). "Joubert syndrome (and related disorders) (OMIM 213300)". European Journal of Human Genetics. 15 (5): 511–521. ISSN 1018-4813. doi:10.1038/sj.ejhg.5201648. 
  5. ^ Reference, Genetics Home. "Joubert syndrome". Genetics Home Reference. Retrieved 2016-12-19. 
  6. ^ Shaheen, R.; Shamseldin, H. E.; Loucks, C. M.; Seidahmed, M. Z.; Ansari, S.; Ibrahim Khalil, M.; Al-Yacoub, N.; Davis, E. E.; Mola, N. A.; Szymanska, K.; Herridge, W.; Chudley, A. E.; Chodirker, B. N.; Schwartzentruber, J.; Majewski, J.; Katsanis, N.; Poizat, C.; Johnson, C. A.; Parboosingh, J.; Boycott, K. M.; Innes, A. M.; Alkuraya, F. S. (2013). "Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans". The American Journal of Human Genetics. 94 (1): 73–9. PMC 3882732Freely accessible. PMID 24360803. doi:10.1016/j.ajhg.2013.11.010. 
  7. ^ Akizu, N.; Silhavy, J. L.; Rosti, R. O.; Scott, E.; Fenstermaker, A. G.; Schroth, J.; Zaki, M. S.; 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, J. G. (2013). "Mutations in CSPP1 Lead to Classical Joubert Syndrome". The American Journal of Human Genetics. 94 (1): 80–6. PMC 3882909Freely accessible. PMID 24360807. doi:10.1016/j.ajhg.2013.11.015. 
  8. ^ Tuz, K.; Bachmann-Gagescu, R.; o’Day, D. R.; Hua, K.; Isabella, C. R.; Phelps, I. G.; Stolarski, A. E.; o’Roak, B. J.; Dempsey, J. C.; Lourenco, C.; Alswaid, A.; Bönnemann, C. G.; Medne, L.; Nampoothiri, S.; Stark, Z.; Leventer, R. J.; Topçu, M.; Cansu, A.; Jagadeesh, S.; Done, S.; Ishak, G. E.; Glass, I. A.; Shendure, J.; Neuhauss, S. C. F.; Haldeman-Englert, C. R.; Doherty, D.; Ferland, R. J. (2013). "Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy". The American Journal of Human Genetics. 94 (1): 62–72. PMC 3882733Freely accessible. PMID 24360808. doi:10.1016/j.ajhg.2013.11.019. 
  9. ^ Brancati F, Dallapiccola B, Valente EM (2010). "Joubert Syndrome and related disorders". Orphanet J Rare Dis. 5: 20. PMC 2913941Freely accessible. PMID 20615230. doi:10.1186/1750-1172-5-20. 
  10. ^ Steinlin, M.; Schmid, M.; Landau, K.; Boltshauser, E. (1997-08-01). "Follow-Up in Children with Joubert Syndrome". Neuropediatrics. 28 (04): 204–211. ISSN 0174-304X. PMID 9309710. doi:10.1055/s-2007-973701. 
  11. ^ Badano, Jose L.; Norimasa Mitsuma; Phil L. Beales; Nicholas Katsanis (September 2006). "The Ciliopathies : An Emerging Class of Human Genetic Disorders". Annual Review of Genomics and Human Genetics. 7: 125–148. PMID 16722803. doi:10.1146/annurev.genom.7.080505.115610. Retrieved 2008-06-15. 
  12. ^ Gutkind, Lee; Kennedy, Pagan (10 October 2013). An Immense New Power to Heal: The Promise of Personalized Medicine. Underland Press. p. 36. ISBN 978-1-937163-07-5. 

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