Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants

Background Joubert syndrome (JS) is a group of rare congenital disorders characterized by cerebellar vermis dysplasia, developmental delay, and retina dysfunctions. Herein, we reported a Chinese patient carrying a new variant in the AHI1 gene with mild JS, and the 3D structure of the affected Jouberin protein was also predicted. Case presentation The patient was a 31-year-old male, who presented difficulty at finding toys at the age of 2 years, night blindness from age of 5 years, intention tremor and walking imbalance from 29 years of age. Tubular visual field and retina pigmentation were observed on ophthalmology examinations, as well as molar tooth sign on brain magnetic resonance imaging (MRI). Whole exome sequence revealed two compound heterozygous variants at c.2105C>T (p.T702M) and c.1330A>T (p.I444F) in AHI1 gene. The latter one was a novel mutation. The 3D protein structure was predicted using I-TASSER and PyMOL, showing structural changes from functional β-sheet and α-helix to non-functional D-loop, respectively. Conclusions Mild JS due to novel variants at T702M and I444F in the AHI1 gene was reported. The 3D-structural changes in Jouberin protein might underlie the pathogenesis of JS.

Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

Patients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and a hindbrain malformation described as the “molar tooth sign” due to its appearance on an MRI. This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation and axon guidance through vertebrate Hedgehog signaling. In patients, mutations in ARL13B cause Joubert syndrome. In order to understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. Additionally, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally, showed normal tract targeting and vermis width. Taken together, our data indicate that ARL13B is critical for control of cerebellar vermis width as well as superior cerebellar peduncle axon guidance, likely via Hedgehog signaling. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology.

Periventricular nodular heterotopias an atypical manifestation of Joubert syndrome

Joubert syndrome (JS) is characterized by varying degrees of mid and hindbrain malformations. A thickened superior cerebellar peduncle (“molar tooth sign”), varying degree of cerebellar vermian clefting, and an oddly shaped (“bat-wing”) fourth ventricle are essential diagnostic cues on imaging. When JS is associated with renal, ocular, hepatobiliary, or oro-facial abnormalities, the term Joubert syndrome and related disorders (JSRD) is used. We report a classic case of this rare disease in a 5 month old male child who presented to our department for assessment of developmental delay. MRI revealed molar-tooth appearance of midbrain, an abnormally shaped fourth ventricle, and vermian aplasia. Additional findings present in our case were corpus callosum dysgenesis, colpocephaly, generalized cortical atrophy, and periventricular nodular heterotopia. Subsequently, an ultrasound of the abdomen was performed to look for any associated anomalies. It revealed diffuse bilateral echogenic kidneys with attenuated corticomedullary differentiation (likely due to micro cysts in medulla) and few thin-walled peripheral renal cortical cysts. Callosal dysgenesis, colpocephaly, cortical atrophy and cortical heterotopias are less common manifestations of JS/JSRD and periventricular nodular heterotopia has been infrequently reported in cases of Joubert syndrome. Key-words: Joubert Syndrome, MRI, Molar Tooth Sign, Periventricular Nodular Heterotopia, Bilateral Echogenic Kidneys

Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

Patients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and are diagnosed by the hindbrain “molar tooth sign” malformation. This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles, which create a deepened interpeduncular fossa. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation and axon guidance through vertebrate Hedgehog signaling. In patients, point mutations in ARL13B cause Joubert syndrome. In order to understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. Additionally, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally, showed normal tract targeting and vermis size. Taken together, our data indicate that ARL13B is critical for superior cerebellar peduncle targeting, likely via Hedgehog signaling, as well as control of cerebellar vermis size. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology.Summary statementJoubert syndrome is diagnosed by the hindbrain “molar tooth sign” malformation. Using mouse models, we show loss of the ciliary GTPase ARL13B, mutations in which lead to Joubert syndrome, result in two features of the molar tooth sign: hypoplasia of the cerebellar vermis and inappropriate targeting of the superior cerebellar peduncles. Furthermore, we demonstrate that loss of vertebrate Hedgehog signaling may be the underlying disrupted mechanism as we extend its role in axon guidance to the superior cerebellar peduncles.

Joubert’s syndrome: a case report

Joubert syndrome is an autosomal recessive genetic disorder that affects the area of the brain that controls balance and coordination. This syndrome is difficult to diagnose clinically because of its variable phenotype. Signs and symptoms commonly include hypotonia abnormal breathing patterns; abnormal eye movements; ataxia; distinctive facial features; and intellectual disability. Various other abnormalities may also be present. This condition is characterized by a specific finding on an magnetic resonance imaging (MRI) called a "molar tooth sign" in which the cerebellar vermis of the brain is absent or underdeveloped and the brain stem is abnormal. The exact diagnosis is often not made for several years after birth.We present a case of Joubert syndrome in a thirteen year old male with developmental delay, ataxia, mild hypotonia, nystagmus and molar tooth sign on MRI. Awareness of the characteristic clinical and radiological findings in Joubert syndrome will help in early diagnosis, appropriate counselling and proper rehabilitation.

Joubert Syndrome Diagnosed at 16+6 Weeks Gestation and Molar Tooth Sign by 3D Modality

Joubert’s syndrome is a rare genetic disorder. It is an autosomal recessive neuro-developmental disorder involving mid and hind brain. This report describes a fetus at gestational age 16weeks+ 6 days, who presented with characteristic Molar tooth sign on the antenatal scan. This sign is a salient feature of Joubert syndrome (JS). Mostly the diagnosis of JS is made after birth. Few cases are diagnosed prenatally by ultrasound.