Joubert syndrome

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	Joubert Syndrome and Related Disorders
Orphanet	475

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

Diagnosis

The disorder is characterized by absence or underdevelopment of the cerebellar vermis and a malformed brain stem (molar tooth sign).^[1] The most common features include ataxia (lack of muscle control), hyperpnea (abnormal breathing patterns), sleep apnea, abnormal eye and tongue movements, and hypotonia. Other malformations such as extra fingers and toes, cleft lip or palate, tongue abnormalities, and seizures may also occur. There may be mild or moderate intellectual disabilities. Joubert syndrome is one of the many genetic syndromes associated with syndromic retinitis pigmentosa.^[2] The syndrome was first identified by pioneering pediatric neurologist Marie Joubert in Montreal, Canada, while working at the Montreal Neurological Institute and McGill University.^[3]

Treatment

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

Prognosis

The prognosis for individuals with Joubert syndrome varies. Some patients have a mild form with minimal motor disability and good mental development, while others may have severe motor disability and moderate mental developmental delays.

Genetics

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,^[4]^[5]^[6]	8q13.2	Autosomal recessive

Ciliopathy

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.^[7]

References

↑ Brancati F, Dallapiccola B, Valente EM (2010). "Joubert Syndrome and related disorders". Orphanet J Rare Dis 5: 20. doi:10.1186/1750-1172-5-20. PMC 2913941. PMID 20615230.
↑ Saraiva, JM; Baraitser, M (1992). "Joubert syndrome: a review". American Journal of Medical Genetics 43 (4): 726–731. doi:10.1002/ajmg.1320430415. PMID 1341417.
↑ 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.
↑ 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. doi:10.1016/j.ajhg.2013.11.010. PMID 24360803.
↑ 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. doi:10.1016/j.ajhg.2013.11.015. PMID 24360807.
↑ 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. doi:10.1016/j.ajhg.2013.11.019. PMID 24360808.
↑ 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. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. Retrieved 2008-06-15.

External links

Diseases of cilia

Structural	receptor: Polycystic kidney disease cargo: Asphyxiating thoracic dysplasia basal body: Bardet–Biedl syndrome mitotic spindle: Meckel syndrome centrosome: Joubert syndrome

Signaling	Nephronophthisis

Other/ungrouped	Alström syndrome Primary ciliary dyskinesia Senior–Løken syndrome Orofaciodigital syndrome 1 McKusick–Kaufman syndrome Autosomal recessive polycystic kidney

See also: ciliary proteins

Deficiencies of intracellular signaling peptides and proteins

GTP-binding protein regulators

GTPase-activating protein	Neurofibromatosis type I Watson syndrome Tuberous sclerosis

Guanine nucleotide exchange factor	Marinesco–Sjögren syndrome Aarskog–Scott syndrome Juvenile primary lateral sclerosis X-Linked mental retardation 1

G protein

Heterotrimeic	cAMP/GNAS1: Pseudopseudohypoparathyroidism Progressive osseous heteroplasia Pseudohypoparathyroidism Albright's hereditary osteodystrophy McCune–Albright syndrome CGL 2

Monomeric	RAS: HRAS Costello syndrome KRAS Noonan syndrome 3 KRAS Cardiofaciocutaneous syndrome RAB: RAB7 Charcot–Marie–Tooth disease RAB23 Carpenter syndrome RAB27 Griscelli syndrome type 2 RHO: RAC2 Neutrophil immunodeficiency syndrome ARF: SAR1B Chylomicron retention disease ARL13B Joubert syndrome 8 ARL6 Bardet–Biedl syndrome 3

MAP kinase

Cardiofaciocutaneous syndrome

Other kinase/phosphatase

Tyrosine kinase	BTK X-linked agammaglobulinemia ZAP70 ZAP70 deficiency

Serine/threonine kinase	RPS6KA3 Coffin-Lowry syndrome CHEK2 Li-Fraumeni syndrome 2 IKBKG Incontinentia pigmenti STK11 Peutz–Jeghers syndrome DMPK Myotonic dystrophy 1 ATR Seckel syndrome 1 GRK1 Oguchi disease 2 WNK4/WNK1 Pseudohypoaldosteronism 2

Tyrosine phosphatase	PTEN Bannayan–Riley–Ruvalcaba syndrome Lhermitte–Duclos disease Cowden syndrome Proteus-like syndrome MTM1 X-linked myotubular myopathy PTPN11 Noonan syndrome 1 LEOPARD syndrome Metachondromatosis

Signal transducing adaptor proteins

Other

NF2
- Neurofibromatosis type II
NOTCH3
- CADASIL
PRKAR1A
- Carney complex
PRKAG2
- Wolff–Parkinson–White syndrome
PRKCSH
- PRKCSH Polycystic liver disease
XIAP
- XIAP2

See also intracellular signaling peptides and proteins

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