Joubert syndrome (ORPHA:475)
A rare, autosomal recessive congenital cerebellar ataxia characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia, and delay in achieving motor milestones.
Epidemiology
Prevalence is estimated at approximately 1/100,000.
Clinical description
Disease onset is antenatal, although clinical presentation is typically in the neonatal period with irregular breathing pattern (episodic tachypnea and/or apnea), and nystagmus. During infancy, hypotonia may appear. Cerebellar ataxia (staggering gait and imbalance) may develop later. Delayed acquisition of motor milestones is common. Cognitive abilities are variable, ranging from severe intellectual deficit to normal intelligence. Neuro-ophthalmologic examination may show oculomotor apraxia. In some cases, seizures occur. Careful examination of the face often shows a characteristic appearance: large head, prominent forehead, high rounded eyebrows, epicanthal folds, ptosis (occasionally), an upturned nose with prominent nostrils, an open mouth (which tends to have an oval shape early on, a 'rhomboid' appearance later, and finally can appear triangular with downturned angles), tongue protrusion and rhythmic tongue motions, and occasionally low-set and tilted ears. Other features sometimes present in Joubert syndrome include retinal dystrophy, hepatopathy, nephronophthisis, and polydactyly.
Etiology
JS is due to dysfunction of the primary, non-motile cilium found in most cells. The syndrome is genetically heterogeneous with numerous genes and two loci on chromosomes 9q34 (INPP5E) and 11p12-q13 (TMEM216) associated with the disease so far. Most of these genes encode proteins that constitute the primary cilium or the regulatory proteins and transcription factors involved in its development and function.
Diagnostic methods
Diagnosis is based on the main clinical features (hypotonia, ataxia, development delay and oculomotor apraxia), which must be accompanied by the presence of a neuroradiological hallmark, designated as the ''molar tooth sign'' (MTS) on magnetic resonance imaging (MRI). MTS results from hypoplasia of the cerebellar vermis and midbrain-hindbrain malformations. Moreover the clinical distinct sign is oculomotor apraxia.
Differential diagnosis
Differential diagnoses include Joubert syndrome-related disorders (JSRD), cerebellar vermis malformations without the MTS (which include Dandy-Walker malformation), X-linked cerebellar hypoplasia, ataxia with oculomotor apraxia types 1 and 2 (AOA1, AOA2), congenital disorders of glycosylation (CDG), 3-C syndrome, pontocerebellar hypoplasias/atrophies, orofaciodigital syndromes II and III, and Meckel-Gruber syndrome.
Antenatal diagnosis
Antenatal diagnosis is feasible through genetic testing where both disease-causing mutations have been previously identified in an affected family member. Imaging studies can suggest the disease (fetal ultrasonography and MRI) but cannot be use to conduct any antenatal diagnosis.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is recommended for families with an affected child; the recurrence risk for future offspring is 25%.
Management and treatment
Management is symptomatic and should be multidisciplinary. Education programs, physical, occupational, and speech therapy may improve the hypotonia and reduce the delay in achieving motor milestones. In general, the neurological disability and amaurosis are not progressive. Particularly relevant is the detection of nephronophthisis (NPH) which leads to chronic kidney disease which occurs in about 30% of subjects with all genetic types (with higher risk for mutations in the following genes: CEP290 (12q21.32), RPGRIP1L ( 16q12.2), TMEM216 (11q13.1), TMEM67 (8q22.1), NPHP4 (1p36.31; 1 case), AHI1 (6q23.3). Another aspect that may determine progressivity is the association with a liver disease, and particularly a liver fibrosis that may need liver transplantation.
Prognosis
Prognosis is favorable for moderate forms of the disease. In patients with nephronophthisis (NPH), end stage renal disease occurs in the second decade of life. Management of patients with more severe forms should be carried out by a specialized reference center. Liver disease does not recur in the transplanted liver.

                            Last update: 
                            July 2020


                            - Expert reviewer(s): 
                            Pr Enrico BERTINI  - Pr Enza Maria VALENTE