Joubert syndrome (JS) is 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. In the neonatal period, the disease often manifests by an 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 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, nephronophthisis, and polydactyly. JBTS3 shows minimal extra central nervous system involvement and appears not to be associated with renal dysfunction.
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. 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. Prognosis is favorable for moderate forms of the disease.
In two patients with Joubert syndrome, born to consanguineous Egyptian parents, Valente et al. (2006) identified a homozygous 2-bp deletion (c.3263delGG) in exon 25 of the AHI1 gene. Both children had hypotonia, mental retardation, oculomotor apraxia, and retinitis pigmentosa.
Zaki et al. (2008) performed a systematic recruitment and genetic evaluation from a single referral center in Egypt. Thirteen families were identified with Joubert syndrome, of which three showed novel AHI1 mutations.
[See: Palestine > Dixon-Salazar et al., 2004].
In affected members of two consanguineous families with Joubert syndrome (JS), some with cortical polymicrogyria, Dixon-Salazar et al. (2004) identified missense and frameshift mutation in the AHI1 gene. The frameshift mutation (c.787insC; p.fsX270) was identified in the affected male child of Palestinian family, whereas the missense mutation (c.1328T>A; p.V443D) was detected in the both affected individuals (one male and one female) of Kuwaiti family. Clinically, the patients in both families displayed the clinical hallmarks of JS, including the molar tooth malformation (MTM) and cerebellar vermis hypoplasia. The Palestinian patient and another Turkish patient described in this study did not show evidence of renal involvement, but the two patients, from the same Kuwaiti family, displayed evidence of retinal dysplasia. These data were found to be consistent with previous findings that this locus is not associated with striking retinal or renal involvement, and they suggest a role for this gene in cerebellar development. These patients appear to have a supratentorial phenotype, with both patients in the same Kuwaiti family showing clear evidence of polymicrogyria, a disorder of cerebral cortex development in which there were supernumary small gyri. There was also evidence in these families of corpus callosum abnormalities. Both affected members of the Kuwaiti family displayed a thin corpus callosum and frontal polymicrogyria. The findings of this study led Dixon-Salazar et al. (2004) to suggest that mutations in AHI1 can produce typical JS, JS plus retinal involvement, or JS plus polymicrogyria, but that renal involvement is uncommon among these patients.
Ferland et al. (2004) identified a locus associated with Joubert syndrome on 6q23.2-q23.3 and found three deleterious mutations in the gene encoding Abelson helper integration site-1 (AHI1), the first gene to be associated with Joubert syndrome. These mutations (p.R351X, p.R435X, p.V443D) were identified in three consanguineous Saudi Arabian pedigrees, respectively, from the same geographic region with autosomal recessive Joubert syndrome. Clinical features of the children (three males) with Joubert syndrome in the first pedigree included nystagmus and ocular apraxia (both eye movement abnormalities), hypotonia (weakness), ataxia (clumsiness), developmental delay with mental retardation and mirror movements. In the second pedigree, all of the children with Joubert syndrome were found to have nystagmus or ocular apraxia, hypotonia, ataxia, developmental delay with mental retardation and mirror movements (in one of the two male affected children). The child (male) with Joubert syndrome in the third pedigree were found to have hypotonia, is unable to walk and had developmental delay and mental retardation (no information is available on the presence of eye or mirror movements). Moreover, the parents of this child had two previous children who had mental retardation and died early in infancy (no MRIs are available). The addition of another Saudi Arabian family from another region of Saudi Arabia was included in this study, but no mutation was identified in this family. The affected child in this family had hypotonia, inability to walk, mental retardation, and a seizure disorder (no information is available on the presence of mirror movements).
Parisi et al. (2006) identified a new missense mutation (c.2156A>G; p.D719G) in the AHI1 gene in homozygous state. This mutation was identified in a consanguineous Saudi Arabian family with two affected male siblings (4 and 3 years old) with Joubert syndrome. Both of them were found to have hypotonia, ataxia, and developmental delay with cognitive impairment. They also presented abnormal eye movement with nystagmus and one of them had retinal dystrophy. One of them had breathing abnormalities with tachypnea, and renal problems with left hydronephrosis. The findings of studying this and other families in this investigation led Parisi et al. (2006) to suggest that subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.