Joubert syndrome
Synonyms and Keywords: Cerebelloparenchymal disorder 4; Cerebellar vermis agenesis; Joubert-Boltshauser syndrome; JBTS1; CPD4; Cerebellooculorenal syndrome 1; CORS1; Joubert syndrome 1

# Overview
Joubert syndrome is a rare genetic disorder that affects the areas of the cerebellar vermis and brain stem in the brain that controls balance and coordination. Joubert syndrome follows autosomal recessive pattern of inheritance. In The United States of America in order to categorise a condition as a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed on 1983 by congress for the rare diseases. Today an average of 25-30 million americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number.

# Historical perspective
- In year 1955, the first reported cases of Joubert syndrome which are partial agenesis of the vermis of the cerebellum was collected by De Haene.
- In year 1969,  Joubert syndrome was first discovered in in four siblings by Dr. Marie Joubert et al.
- In year 1977, Joubert syndrome name was first suggested by Boltshauser and Isler.
- In year 1978, Friede and Boltshauser are the first to describe neuropathologic findings in one patient with joubert syndrome.
- In year 1978,  Boltshauser et al are the first first to describe two sisters who are having joubert syndrome whose parents were consanguineous.

# Classification
- Joubert syndrome may be classified according to gene location of the mutation into many subtypes of these JBTS1 and JBTS2 are the most common and important subtypes:

# Pathophysiology
- It is understood that Joubert syndrome is most commonly caused by mutation in basal body genes in INPP5E and TMEM216 gene on chromosome 9q34 and 11q12.2 respectively.
- Other genes involved in developing of joubert syndrome are as follows:
AHI1, NPHP1, CEP290, RPGRIP1L, ARL13B, and CC2D2A
- AHI1, NPHP1, CEP290, RPGRIP1L, ARL13B, and CC2D2A
INPP5E (Inositol polyphosphate-5-phosphatase E)
- JBTS1 gene(INPP5E) plays an important role in Inositol polyphosphate-5-phosphatase E pathway on chromosome 9q34.3.
- Missense mutation in Inositol polyphosphate-5-phosphatase E pathway leads to truncated protein
TMEM216(Transmembrane protein 216)
- JBTS2 gene(TMEM216 ) also plays an important role in Inositol polyphosphate-5-phosphatase on chromosome 11q12.2
- The mechanism by which the mutation leads to truncated protein is unknown
AHI1(Abelson Helper Integration Site 1)
- JBTS3 gene(AHI1) plays an important role in the formation of jouberin on chromosome 6q23.
- Nonsense mutation in the AHI1 leads to truncated protein (Jouberin) and cause the disease
NPHP1(Nephrocystin 1)
- JBTS4 gene(NPHP1) on chromosome 2q13 plays an important role in the formation of nephrocystin-1 protein
- Missense mutation in the NPHP1 leads to truncated protein (Nephrocystin-1 protein) and cause the disease
CEP290(Centrosomal protein 290)
- JBTS5 gene(CEP290) on chromosome12q21.3 plays an important role in the formation of centrosomal protein of 290 kDa protein
- Nonsense mutation in the CEP290 leads to truncated protein (Centrosomal protein of 290 kDa protein) and cause the disease
TMEM67(Transmembrane protein 67) / MKS3(Transmembrane protein meckelin)
- JBTS6 gene(TMEM67/MKS3) on chromosome 8q21.1-q22.1 plays an important role in the formation of meckelin protein
- Missense, splice mutation leads to truncated protein (meckelin protein) and cause the disease
RPGRIP1L
- JBTS7 gene(RPGRIP1L) on chromosome 16q12.2 plays an important role in the formation of RPGR-interacting protein 1-like protein
- Missense, nonsense, splice mutation leads to truncated protein (RPGR-interacting protein 1-like protein) and cause the disease
ARL13B
- JBTS8 gene(ARL13B) on chromosome 3q11.2 plays an important role in the formation of ADP-Ribosylation factor-like 13B protein
- Missense mutation leads to truncated protein (ADP-Ribosylation factor-like 13B protein) and cause the disease
CC2D2A
- JBTS9 gene(CC2D2A) on chromosome 4p15.3 plays an important role in the formation of coiled-coil and C2 Domains-containing protein 2A protein
- Missense, nonsense, splice, frame shift mutation leads to truncated protein(C2 Domains-containing protein 2A protein) and cause the disease

# Causes

### Genetic Causes
- Joubert syndrome is caused by mutations in the following genes INPP5E, TMEM216, AHI1, NPHP1, CEP290, RPGRIP1L, ARL13B, and CC2D2A.

# Differentiating joubert syndrome from other Diseases
- Joubert syndrome must be differentiated from acrocallosal syndrome (ACLS), bardet-Biedl syndrome (BBS), cogan syndrome, hydrolethalus syndrome (HLS), jeune asphyxiating thoracic dystrophy (JATD), leber congenital amaurosis (LCA), mainzer-Saldino syndrome (MZSDS), meckel syndrome, MORM (mental retardation, truncal obesity, retinal dystrophy, micropenis) syndrome and oral-facial-digital syndrome.

# Epidemiology and Demographics
Incidence
- The incidence of joubert syndrome is approximately 1 per 80,000 individuals to 1 per 100,000 individuals worldwide.
- Till now only 200 cases of joubert syndrome were published in the literature.

### Prevalence
- The prevalence of joubert syndrome is approximately 1 per 100,000 in the United States.
Age
- Joubert syndrome commonly affects newborns in the first 6 months of life.

# Risk Factors
- There are no established risk factors for joubert syndrome.

# Physical Examination
HEENT
- Facial features: Facial features in patients with joubert syndrome are very prominent and have a significant importance in diagnosis.
Broad forehead
High rounded eyebrows
Epicanthal folds
Ptosis
Widely spaced eyes
Upturned nose with evident nostrils
Low-set ears
Triangular-shaped mouth(Rhomboid appearance)
Tongue protrusion
- Broad forehead
- High rounded eyebrows
- Epicanthal folds
- Ptosis
- Widely spaced eyes
- Upturned nose with evident nostrils
- Low-set ears
- Triangular-shaped mouth(Rhomboid appearance)
- Tongue protrusion
- Oculomotor apraxia(OMA): Patients with oculomotor apraxia in joubert syndrome have difficulty in moving the eyes from one side to another side.
Ocular coloboma
Retinal dystrophy
- Ocular coloboma
- Retinal dystrophy
Lungs
- Episodic apnea
Neuromuscular
- Ataxia: Very prominent and most common physical findings in patients with joubert syndrome
- Intellectual impairment
- Gross motor milestones delays 
- Hypotonia

# Natural History, Complications, and Prognosis
Natural History
- The symptoms of joubert syndrome usually develop in the first decade of life, and start with symptoms such as episodic apnea, ataxia and intellectual disability.
Complications
Common complications of joubert syndrome include:
- Developmental delay
- Abnormal eye movements
- Hypotonia
- Cystic dysplasia
- Nephronophthisis
Prognosis
- The development or underdevelopment of cerebellar vermis is the main prognostic factor in patients with joubert syndrome.
- Involvement of other organs such as kidney and liver also plays a significant role in prognosis.
- The extent of breathing dysregulation also determines the prognosis in a patient with joubert syndrome.

# Diagnostic Study of Choice
- Magnetic resonance imaging(MRI) is the gold standard test for the diagnosis of joubert syndrome, shows the following features on MRI
Molar tooth sign: Pathognomonic of joubert syndrome
Vermian dysgenesis and horizontal superior cerebellar peduncle elongation represents the molar tooth sign
Hypoplastic posterior cerebellar vermis
Deformed midbrain and pontomesencephalic junction
Prenatal MRI of the fetal brain can help in diagnosis of joubert syndrome
- Molar tooth sign: Pathognomonic of joubert syndrome
Vermian dysgenesis and horizontal superior cerebellar peduncle elongation represents the molar tooth sign
Hypoplastic posterior cerebellar vermis
Deformed midbrain and pontomesencephalic junction
Prenatal MRI of the fetal brain can help in diagnosis of joubert syndrome
- Vermian dysgenesis and horizontal superior cerebellar peduncle elongation represents the molar tooth sign
- Hypoplastic posterior cerebellar vermis
- Deformed midbrain and pontomesencephalic junction
- Prenatal MRI of the fetal brain can help in diagnosis of joubert syndrome

# Medical therapy
- There is no treatment for joubert syndrome; the mainstay of therapy is supportive care.
- In patients with joubert syndrome opioids should be used with caution as they lead to respiratory depression .
- Nonsteroidal anti-inflammatory drugs(NSAIDS) should be avoided if the patient with joubert syndrome have renal impairment.
- Hepatotoxic drugs should be avoided in case of liver failure.
- Caffeine may be helpful with respiratory problems in some patients with joubert syndrome.
- Nitrous oxide which is an anaesthetic agents should be avoided in patients with joubert syndrome.
- In patients with joubert syndrome, neuropsychological support and rehabilitation should be provided to deal with the cognitive and behavioral abnormalities.
- The use of dexmedetomidine along with remifentanil maybe effective in some patients with joubert syndrome who might need surgery.

# Surgery
- Surgical intervention is not recommended for the management of joubert syndrome.
- Surgery is usually reserved for patients with either:
Respiratory problems which can be managed by tracheostomy
Feeding problems which can be managed by gastrostomy tube
Polydactyly patients
Symptomatic ptosis and/or strabismus patients
- Respiratory problems which can be managed by tracheostomy
- Feeding problems which can be managed by gastrostomy tube
- Polydactyly patients
- Symptomatic ptosis and/or strabismus patients