Rare Genetic Diseases: Joubert Syndrome

Joubert syndrome is a disorder of the brain development that may affect many parts of the body.

It is characterised by the absence or underdevelopment of the cerebellar verbis (part of the brain that controls balance and coordination) and malformed brain stem (connection between the brain and spinal cord). This causes the appearance of molar tooth sign on MRI, which can be seen in the picture above.

Around 1:100,000 newborns are affected by this disease. The treatment is supportive and depends on the severity of the symptoms.

Typical symptoms include weak muscle tone (hypotonia) which over time can develop into difficulty coordinating movements (ataxia) in early childhood. Newborns may suffer from episodes of unusual fast and slow breathing (hyperpnea), however, this symptom disappears around 6 months of age.

Furthemore, the affected children suffer from abnormal eye movement (oculomotor apraxia) and developmental abilities, such as language and motor skills are delayed with variable severity. The children may also suffer from mild to severe intellectual disability.

Joubert syndrome can also be characterised by distinctive facial features such as broad forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes, low-set ears, and triangular-shaped mouth.

The disease can be caused by 30 mutated genes, the majority of which are still unknown. These mutations are inherited in an autosomal recessive way. The mutations on the genes cause problems with the structure and function of the cilia, likely disrupting important signalling pathways during development.

The primary cilia are projections on the cell surface that play a role in signalling. They are important for many cell types including neurons, liver cells and kidney cells.

In rare cases, Joubert syndrome can be caused by mutations of the OFD1 gene located on the X chromosome. If the disease is inherited in this manner, it usually only affects males, as females have two X chromosomes.

The prognosis of the disease is dependent on the severity of the symptoms. With mild symptoms, children may live past the age of 10. However, if the symptoms are severe, children die before the age of 3.