Joubert syndrome

Joubert syndrome
ICD-10	Q04.3
ICD-9	742.2
DiseasesDB	30688

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

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:

Phenotype	Location of mutation	Gene involved	Inheritance pattern
JOUBERT SYNDROME 1(JBTS1)	9q34.3	INPP5E	Autosomal recessive
JOUBERT SYNDROME 2(JBTS2)	11q12.2	TMEM216	Autosomal recessive

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

INPP5E

• 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

• JBTS2 gene(TMEM216 ) also plays an important role in Inositol polyphosphate-5-phosphatase E pathway
• The mechanism by which the mutation leads to truncated protein is unknown

AHI1

• JBTS3 gene(AHI1) plays an important role in the formation of jouberin
• Nonsense mutation in the AHI1 leads to truncated protein (Jouberin) and cause the disease

NPHP1

• 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

• 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/MKS3

• 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

• JBTS7 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

• JBTS7 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

Presentation

The disorder is characterized by absence or underdevelopment of a part of the brain called the cerebellar vermis and a malformed brain stem (molar tooth sign). The most common features include ataxia (lack of muscle control), an abnormal breathing pattern called hypernea, 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 retardation.

Treatment

Treatment for Joubert syndrome is symptomatic and supportive. Infant stimulation and physical, occupational, and speech 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 retardation.

Genetics

Multiple genes that are mutated in individuals with Joubert syndrome have been identified:

• Mutations in a gene of unknown function called AHI1 is associated with a subset of Joubert syndrome cases.

• In some rare cases of Joubert syndrome, mutations have been found in NPHP1 which is also associated with nephronophthisis, a cystic kidney disorder.

• The gene CEP290 has been associated with both Joubert syndrome and Leber's congenital amaurosis, type 10.