Joubert syndrome is a rare brain malformation characterized by the absence or underdevelopment of the cerebellar vermis - an area of the brain that controls balance and coordination -- as well as a malformed brain stem (molar tooth sign). The most common features of Joubert syndrome in infants include abnormally rapid breathing (hyperpnea), decreased muscle tone (hypotonia), abnormal eye movements, mental retardation, and the inability to coordinate voluntary muscle movements (ataxia). In most other cases, Joubert syndrome is inherited in an autosomal recessive manner (meaning both parents must have a copy of the mutation) via mutation in at least 10 different genes, including NPHP1, AHI1, and CEP290
Children with Joubert’s syndrome can have very variable features and problems, from relatively mild to very severe. All babies are likely to have elements of the following:
- Many infants have a somewhat characteristic appearance, with a relatively large head, prominent forehead, broad nose and a tendency to keep their mouths open and their tongues out.
- Floppiness (hypotonia), unsteadiness (ataxia) and developmental or learning delay are present to some extent in all the children. The combination of these factors make sitting and standing delayed or very difficult to achieve.
- Jerky eye movements are likely to be obvious from early infancy and some babies will have very poor vision, or difficulty moving the eyes to look at an object (oculomotor apraxia).
- Learning difficulties are common, especially surrounding speech, and some children may be severely disabled and/or have difficult behaviour problems.
- Some children may develop epilepsy.
- Some children have kidney cysts, which may affect kidney function.
- An abnormal breathing pattern may be noticed soon after birth. This may improve with age but, sadly, very severely affected infants may die within the first few years of life from breathing problems. This is rare.
All these problems are the result of the brain malformation, rather than part of an ongoing disease process. Therefore, unless they are at risk from breathing problems, the children are likely to have the potential to make positive progress in all areas as they get older.
Joubert syndrome and related disorders can be caused by mutations in at least 10 genes. The proteins produced from these genes are known or suspected to play roles in cell structures called cilia. Cilia are microscopic, finger-like projections that stick out from the surface of cells and are involved in chemical signaling. Cilia are important for the structure and function of many types of cells, including brain cells (neurons) and certain cells in the kidneys and liver. Cilia are also necessary for the perception of sensory input (such as sight, hearing, and smell).
Mutations in the genes associated with Joubert syndrome and related disorders lead to problems with the structure and function of cilia. Defects in these cell structures probably disrupt important chemical signaling pathways during development. Although researchers believe that defective cilia are responsible for most of the features of these disorders, it remains unclear how they lead to specific developmental abnormalities.
Mutations in the 10 genes known to be associated with Joubert syndrome and related disorders only account for about half of all cases of these conditions. In the remaining cases, the genetic cause is unknown.
Changes in these genes are associated with Joubert syndrome.
Joubert syndrome-1 (JBTS1) is caused by homozygous mutation in the INPP5E gene (613037) on chromosome 9q34. JBTS2 (608091), caused by mutation in the TMEM216 gene (613277) on chromosome 11q13; JBTS3 (608629), caused by mutation in the AHI1 gene (608894) on chromosome 6q23; JBTS4 (609583), caused by mutation in the NPHP1 gene (607100) on chromosome 2q13; JBTS5 (610188), caused by mutation in the CEP290 gene, also called NPHP6 (610142), on chromosome 12q21.32; JBTS6 (610688), caused by mutation in the TMEM67 gene (609884) on chromosome 8q21; JBTS7 (611560), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12.2; JBTS8 (612291), caused by mutation in the ARL13B (608922) on chromosome 3q11.2; JBTS9 (612285), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15.3; JBTS10 (300804), caused by mutation in the CXORF5 gene (300170) on chromosome Xp22.3; JBTS11 (see 613820), caused by mutation in the TTC21B gene (612014) on chromosome 2q24; JBTS12 (see 200990), caused by mutation in the KIF7 gene (611254) on chromosome 15q26; JBTS13 (614173), caused by mutation in the TCTN1 gene (609863) on chromosome 12q24; JBTS14 (614424), caused by mutation in the TMEM237 gene (614423) on chromosome 2q33; JBTS15 (614464), caused by mutation in the CEP41 gene (610523) on chromosome 7q32; JBTS16 (614465), caused by mutation in the TMEM138 gene (614459) on chromosome 11q; JBTS17 (614615), caused by mutation in the C5ORF42 gene (614571) on chromosome 5p13; JBTS18 (614815), caused by mutation in the TCTN3 gene (613847) on chromosome 10q24; JBTS19 (see 614844), caused by mutation in the ZNF423 gene (604577) on chromosome 16q12; JBTS20 (614970), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; JBTS21 (615636), caused by mutation in the CSPP1 gene (611654) on chromosome 8q13; and JBTS22 (615665), caused by mutation in the PDE6D gene (602676) on chromosome 2q37.
The diagnosis of "classic" or “pure” Joubert syndrome is based on the presence of the following three primary criteria:
- The molar tooth sign. The MRI appearance of hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities in an axial plane through the junction of the midbrain and pons (isthmus region). The molar tooth sign comprises an abnormally deep interpeduncular fossa; prominent, straight, and thickened superior cerebellar peduncles; and hypoplasia of the vermis, the midline portion of the cerebellum
- Hypotonia in infancy with later development of ataxia
- Developmental delays/intellectual disability
Additional features often identified in individuals with Joubert syndrome include:
- Abnormal breathing pattern (alternating tachypnea and/or apnea);
- Abnormal eye movements, typically oculomotor apraxia or difficulty in smooth visual pursuit and jerkiness in gaze and tracking
The prognosis for infants with Joubert syndrome depends on whether or not the cerebellar vermis is partially developed or entirely absent, as well as on the extent and severity of other organ involvement, such as the kidneys and liver.. Some children have a mild form of the disorder, with minimal motor disability and good mental development, while others may have severe motor disability, moderate mental retardation, and multi-organ impairments.