Clinical and Molecular Delineation of AHI1-Associated Joubert Syndrome in a Consanguineous Pedigree: A Case Report

Joubert syndrome is an autosomal-recessive disorder characterized by cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical and genetic basis of Joubert syndrome is unknown and a specific chromosomal locus for this disorder has not been identified. Review of this disorder and related syndromes suggests that (1) hypoplasia of the cerebellar vermis in Joubert syndrome is frequently associated with a complex brain stem malformation represented as the "molar tooth sign" on magnetic resonance imaging, (2) the "molar tooth sign" could be present in association with the Dandy-Walker malformation and occipital encephalocele, (3) cerebellar hypoplasia is present in conditions related to Joubert syndrome such as Arima syndrome; Senior-Loken syndrome; cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndrome; and juvenile nephronophthisis due to NPH1 mutations, and (4) the brainstem-vermis malformation spectrum is probably caused by at least two and probably several genetic loci. We have ascertained previously a cohort of 50 patients with a putative diagnosis of Joubert syndrome in order to evaluate the presence of associated malformations, and to initiate studies leading to the identification of genes causing Joubert and related syndromes. Among the associated malformations found in patients ascertained as having Joubert syndrome, 8% of patients had polydactyly, 4% had ocular colobomas, 2% had renal cysts, and 2% had soft-tissue tumors of the tongue. The WNT1 gene has been tested as a candidate gene for Joubert syndrome based on its expression in the developing cerebellum and an associated mutation in the swaying mouse. A search for mutations in WNT1 in a series of patients with Joubert syndrome did not detect mutations at this locus. This analysis suggested that mutations in WNT1 might not have a significant role in Joubert syndrome, and other functional candidate genes related to development of the cerebellum need to be examined. A genome-wide linkage analysis carried out in 10 Joubert syndrome pedigrees did not identify a specific chromosomal locus for this disorder. This observation, along with those from clinical studies, provides further evidence that Joubert and related syndromes are genetically heterogeneous.

Neurophysiologic characterization of motor and sensory projections in Joubert syndrome

The Cerebellum and Cerebellar Disorders

Joubert Syndrome (JS) is a congenital cerebellar ataxia typically inherited in an autosomal recessive pattern, although rare X-linked inheritance can occur. It is characterized by hypotonia evolving into ataxia, global developmental delay, oculomotor apraxia, breathing dysregulation, and multiorgan involvement. To date, there are 40 causative genes implicated in JS, all of which encode proteins of the primary cilium. Primary cilia play a crucial role in the normal development and function of many organs, including parts of the brain (cerebellum and brainstem), kidneys, and the retina. This likely explains the multiorgan involvement seen in JS. In this report, we present the first genetically confirmed case of JS in two Filipino adolescent siblings who had early onset ataxia, hepatomegaly, and global developmental delay. A cranial CT scan revealed the Molar Tooth Sign (MTS). Whole Exome Sequencing (WES), performed via buccal swab, showed biallelic pathogenic variants at NM_153704.6:c.2086C > T (NP_714915.3:p.Leu696Phe) and NM_153704.6:c.431del (NP_714915.3:p.Leu144CysfsTer19) in TMEM67, which are associated with Joubert Syndrome 6 (OMIM:610688) in a compound heterozygous state. The prevalence of NM_153704.6:c.2086C > T (NP_714915.3:p.Leu696Phe) in TMEM67 variant is very rare (< 0.001%), and the NM_153704.6:c.431del (NP_714915.3:p.Leu144CysfsTer19) has not been recorded. This case contributes valuable information to the expanding knowledge of JS and its related disorders.

Key features of Joubert syndrome include developmental delay, hypotonia, hyperpnea and apnea, oculomotor apraxia, and the presence of the molar tooth sign on axial imaging through the brainstem isthmus--the junction of the pons and mesencephalon. Interestingly, 1 in 10 patients with Joubert syndrome has abnormal cerebrospinal fluid collections misdiagnosed as Dandy-Walker variants. Because of important differences in patient management, genetic counseling, and prognosis between these conditions, we undertook a study to determine if the brainstem isthmus is normal in Dandy-Walker syndrome. Using standard landmarks, we evaluated development of the isthmus in normal subjects and in subjects with Joubert syndrome and Dandy-Walker syndrome. Four of five brainstem measures increased with age in normal subjects. In subjects with Joubert syndrome, the depth and length of the interpeduncular fossa were increased, and the width of the isthmus was decreased. In subjects with Dandy-Walker syndrome, the width of the brainstem isthmus was normal, and the molar tooth sign was absent. Although the pons can be hypoplastic in Dandy-Walker syndrome, we conclude that the pontomesencephalic junction is normal. Thus, the molar tooth sign can effectively distinguish between Joubert and Dandy-Walker syndromes. Genetic heterogeneity or epigenetic factors may account for abnormal cerebrospinal fluid collections in some cases of Joubert syndrome.

A group of disorders with disparate symptomatology, including congenital cerebellar ataxia, retinal blindness, liver fibrosis, polycystic kidney disease, and polydactyly, have recently been united under a single disease mechanism called 'ciliopathies'. The ciliopathies are due to defects of the cellular antenna known as the primary cilium, a microtubule-based extension of cellular membranes found in nearly all cell types. Key among these ciliopathies is Joubert syndrome, displaying ataxia, oculomotor apraxia, and mental retardation* with a pathognomonic 'molar tooth sign' on brain magnetic resonance imaging. The importance of ciliary function in neuronal development has been appreciated only in the last decade with the classification of Joubert syndrome as a ciliopathy. This, together with the identification of many of the clinical features of ciliopathies in individuals with Joubert syndrome and the localization of Joubert syndrome's causative gene products at or near the primary cilium, have defined a new class of neurological disease. Cilia are involved in diverse cellular processes including protein trafficking, photoreception, embryonic axis patterning, and cell cycle regulation. Ciliary dysfunction can affect a single tissue or manifest as multi-organ involvement. Ciliary defects have been described in retinopathies such as retinitis pigmentosa and Leber congenital amaurosis (defects in photoreceptor ciliary protein complexes), renal syndromes with nephronophthisis and cystic dysplastic kidneys, and liver conditions such as fibrosis and biliary cirrhosis. Recognizing the diverse presentations of the ciliopathies and screening strategies following diagnosis is an important part of the treatment plan of children with cilia-related disorders.

Joubert syndrome (JS) is a rare autosomal recessive ciliopathy characterized by a distinctive molar tooth sign (MTS) on brain imaging and with variable multisystem involvement, including developmental delay, ataxia, and oculomotor abnormalities. The AHI1 gene plays a critical role in ciliary function and neurodevelopment, with pathogenic variants implicated in JS and related ciliopathies. A 3-year-old boy underwent comprehensive clinical evaluation, including developmental assessments, neurological and ophthalmological examinations, and systemic investigations. Magnetic resonance imaging (MRI) of the brain was performed to confirm the diagnosis. Genomic DNA was extracted, and exome-sequencing was employed to identify pathogenic variants, which was followed by in silico analyses, structural modeling, and protein-protein interaction (PPI) studies. Variant validation and segregation analysis were conducted using polymerase chain reaction (PCR) and Sanger sequencing. Evolutionary conservation of the variant residue was evaluated using comparative genomics. The proband exhibited hallmark JS features, including generalized hypotonia, ataxia, developmental delay, and the MTS on MRI. Systemic evaluations revealed no extracerebral organ involvement. Exome-sequencing identified a novel AHI1 variant, c.2941C&gt;G; p.Gln981Glu, absent in public population databases. In silico prediction tools supported pathogenicity, with high conservation of the mutated residue across species. Structural modeling and PPI analysis revealed conformational changes and disrupted interactions in ciliary function-related pathways. Sanger sequencing confirmed autosomal recessive inheritance, with the proband homozygous for the variant, while both parents were heterozygous carriers. This study expands the mutational spectrum of AHI1 and demonstrates the clinical utility of exome-sequencing in diagnosing JS, especially in consanguineous populations. Findings emphasize the importance of genetic counseling, risk assessment, and advanced reproductive technologies to reduce the risk of recurrence in affected families. The integration of clinical, genetic, and computational analyses enhances our understanding of JS pathogenesis and supports personalized care for affected families.

Joubert syndrome is a relatively rare autosomal recessive congenital disorder; it is characterized by cerebellar vermis hypoplasia or aplasia. Characteristic clinical symptoms and signs include motor and respiratory abnormalities. It is currently included in the malformation spectrum of cerebello-oculo-renal syndromes (CORS). An image known as a "molar tooth sign" is typically observed in cerebral magnetic resonance imaging (MRI) and is characterised by a deep posterior interpeduncular fossa, thickened and elongated superior cerebellar peduncles, as well as hypoplasia or agenesis of the cerebellar vermis. We report the case of a 4-year-old male, referred to our rehabilitation unity with a history of hypotonia and delayed psychomotor development. Physical examination found macrocephaly, frontal bossing and triangular upper lip and arched palate. Ocular examination revealed a bilateral divergent squint and inability to track objects with eyes. All aspects of his development were delayed. He had a generalized hypotonia but deep tendon reflexes were normal. There were important negative signs including: Regular breathing pattern, no organomegaly and no polydactyly or syndactyly. With these findings, a brain MRI was requested, which showed the classic "molar tooth sign" which led to the clinical diagnosis of Joubert syndrome. In complementary studies, the audiogram revealed a bilateral sensorineural hearing loss, the ophthalmology assessment and laboratory studies were normal .We have prescribed a stander and hearing aid. A rehabilitation program was started consisting of: joint mobilization, muscle strengthening, occupational and speech therapy.

The clinical presentation of children with Joubert syndrome can include nonspecific features such as hypotonia, ataxia, and developmental delay. Careful examination of the face shows a characteristic appearance, and a neuro-ophthalmologic examination shows the presence of oculomotor apraxia. In the neonatal period, most children have hyperpnea intermixed with central apnea. Neuroimaging of the head in the axial plane demonstrates the "molar tooth sign"--deep posterior interpeduncular fossa, thick and elongated superior cerebellar peduncles, and hypoplastic or aplastic superior cerebellar vermis. The central nervous system malformation spectrum observed in radiologic and neuropathologic studies accounts for many clinical features of Joubert syndrome. The developmental delay and cognitive impairment cannot be fully explained by the hindbrain malformation and probably result from dysfunction of the cerebral hemispheres. Although related conditions with vermian hypoplasia or aplasia (including Arima; Senior-Loken; and cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndromes) can mimic Joubert syndrome, detailed imaging data are lacking in such cases. We propose a revision in diagnostic criteria for Joubert syndrome.

Joubert syndrome(JS), was first discovered by Marie Joubert, which is a rare autosomal recessive inherited disease belonging to ciliopathy with the causative mutation of genes. A 27-years-old woman was referred to our clinic for advanced research over the detection of fetal renal cyst.We observed policycstic kidney in detailed examination.INPP5E mutation was detected on chorion villus sampling.We were thought may be this findings will be associated with the syndrome, primarily joubert syndorme (JS),upon detection the vermis hypoplasia, policyctic kidney and molar teeth sign was observed on USG in the 23rd week of pregnancy.The vermis hypoplasia, posterior fossa expansion and bilateral polycystic kidney was seen on MRI and radiologist was reported as Dandy-Walker depend on this findings.They did not pay attention to the molar tooth finding.We were explanied prognosis and suggeted termination to the family.The family was accepted and fetus was terminated. The most common characteristic brain image of JS is the molar tooth sign(MTS) on the axial plane, cerebellar vermis (CV) hypoplasia, and a deepened interpeduncular fossa.The MTS is the key diagnostic feature for this disease. So far, more than 30 causative genes have been found for the various subtypes of JSRD.One of them is INPP5E. Defects of additional extra-nervous systems involve polycystic kidney disease, retinal degeneration, skeletal defects (such as polydactyly), and liver disorder. Joubert Syndrome can be diagnosed in prenatally period.MTS can be seen easily with usg during prenatal period.The vermian hypoplasia and additional organ anomalies must be brought to mind JS and MTS should be searched.

Introduction A 16-year-old boy presented with complaints of intermittent slurring of speech, occasional swaying of the body, and abnormal eye movements noticed by the relatives, for one month duration. He was born of a consanguineous marriage. Father and mother were third cousins. He had global developmental delay of mile stone and mental retardation. There was no history of similar neurological illness in the family. On examination, he had moderate mental retardation. External ocular movements were full and see-saw nystagmus was present. Right facial palsy was present. Other cranial nerves were normal. He had mild to moderate truncal ataxia and hypotonia. Other neurological examinations were normal. Patient had two siblings, one brother and one sister. A detailed neurological examination on them did not reveal any abnormality. His blood and urine routine examinations including renal function and liver function tests were normal. Ultrasonogram of abdomen was normal. His magnetic resonance imaging (MRI) of brain showed vermian agenesis [Figure 1], which is thick and maloriented superior cerebellar peduncles with deep interpeduncular fossa forming the molar tooth appearance [Figure 2]. Fourth ventricle showed a batwing appearance at the level of pons [Figure 3] and the mid sagittal images showed a high position of the ventricles with curved roof [Figure 4]. On the basis of the clinical and MRI findings, a diagnosis of Joubert syndrome was made.Figure 1: Axial T2 weighted image showing superior vermian dysplasia with agenesis of mid and inferior vermian lobules and apposing cerebellar hemispheres (black arrow)Figure 2: Axial T1 weighted image at the level of mid-brain interpeduncular fossa showing classical molar tooth sign (white arrow)Figure 3: Axial T1 weighted image at the level of the upper pons showing bat-wing morphology of fourth ventricle (white arrow).Figure 4: Mid-sagittal T2 weighted image showing a high position of the fourth ventricle and curved roof (black arrow).Joubert syndrome was first described by a French Neurologist, Marie Joubert in 1969. It is a rare congenital neurological disorder with autosomal recessive inheritance. In this disease, there is agenesis of cerebellar vermis, malformations of several brain stem nuclei, and dysplasia of the structures of pontomesencephalic junction. Classical Joubert syndrome is characterized by Molar tooth sign in MRI, hypotonia, developmental delay/mental retardation, oculomotor apraxia, and breathing abnormalities.[1] Other clinical features define subtypes of the disease and they are termed Joubert syndrome and related diseases. These include occipital encephalocele, polymicrogyria, polydactyly, occular coloboma, retinal dystrophy, cystic kidney disease, nephronophthisis, and hepatic fibrosis.[1] The main oculomotor anomalies described in this syndrome include occulomotor apraxia, decreased smooth pursuit gain and vestibulo-ocular reflexes, hypometric volitional saccades, optic nerve dysplasia, severe visual loss, pendular see-saw nystagmus, gaze-holding nystagmus, and pigmentary changes in the fundus.[2] See-saw nystagmus is an uncommon and interesting eye movement disorder found in this condition characterized by cyclic movement of the eye with conjugate torsional component and disjunctive vertical component. In one-half cycles, one eye will rise and intort and the other eye will fall and extort; and in the next half cycle, the vertical and torsional components are reversed.[2] The pathognomonic neuroradiological finding in Joubert syndrome and related disorders is the molar tooth sign-with its three components; partial or complete absence of vermice, thickened and elongated superior cerebellar peduncles, and deepened interpeduncular fossa.[3] Lack of normal decussation of the superior cerebellar peduncular fibres leads to enlargement of peduncles, which follow a more horizontal course extending perpendicular to the brainstem between the midbrain and cerebellum.[4] The absence of crossing fibres is also responsible for decreased anteroposterior diameter of the brainstem and deep interpeduncular cistern. The absence of normal vermis creates a midline cleft between two normal appearing cerebellar hemispheres resulting in a characteristic ‘batwing’ appearance of the fourth ventricle on axial MR images. Molar tooth sign is useful in differentiating Joubert syndrome and related diseases from other hindbrain malformations and also aids in delineation of genetic factors.[3]

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

A number of oculomotor defects have been described in Joubert syndrome. This study systematically examined the oculomotor systems of 13 individuals previously diagnosed with Joubert syndrome. Twelve had the characteristic "molar tooth sign" seen on magnetic resonance imaging scan. In all individuals, smooth pursuit gain and vestibulo-ocular reflex cancellation were decreased in the horizontal and vertical directions and volitional saccades, when generated, were hypometric. We believe that these defects arise from a disorder in the posterior cerebellar vermis. All individuals also had partial to complete oculomotor apraxia in which initiation of saccades was prolonged or impaired. The oculomotor apraxia in Joubert syndrome differs from congenital idiopathic oculomotor apraxia in that both volitional saccades and quick phases of nystagmus were impaired both in the horizontal and vertical directions, and the defects did not resolve with time. We believe that the oculomotor apraxia arises from a disorder involving the projections from the superior colliculus to the parapontine reticular formation and rostral interstitial nucleus of the medial longitudinal fasciculus. A subset of individuals also had severe visual loss, pendular nystagmus, pigmentary changes in the fundus, and decreased vestibulo-ocular reflexes. We believe that this is a form of Leber's amaurosis occasionally associated with Joubert syndrome. In summary, key oculomotor features of Joubert syndrome are decreased smooth pursuit and vestibulo-ocular reflex cancellation, partial to complete oculomotor apraxia both in the horizontal and vertical directions, and hypometric saccades if oculomotor apraxia is not complete.

In this article, we examine the inter-relationship between moral theory and the unpredictable and complex world of primary health care, where the values of patient and doctor, or groups of...

The CC2D2A gene is essential for primary cilia formation, and its disruption has been associated with Joubert Syndrome-9 (JBTS9), a ciliopathy with typical neurodevelopmental features. Here, we describe an Italian pediatric patient with typical features of Joubert Syndrome (JBTS): "Molar Tooth Sign", global developmental delay, nystagmus, mild hypotonia, and oculomotor apraxia. Whole exome sequencing and segregation analysis identified in our infant patient a novel heterozygous germline missense variant c.3626C > T; p.(Pro1209Leu) inherited from the father and a novel 7.16 kb deletion inherited from the mother. To the best of our knowledge, this is the first report showing a novel missense and deletion variant involving exon 30 of the CC2D2A gene.