Joubert Syndrome And Related Disorders Research Articles

Epilepsy in Joubert Syndrome: A Still Few Explored Matter

AbstractEpilepsy is rarely associated with Joubert's syndrome and related disorders (JSRD), being reported only in 3% of cases. Few patients have been described, moreover, with poor evidences of specific seizures' semiology or standard of practice for pharmacological treatment. Epilepsy is likely to be related to brain malformations in ciliopathies. Beyond the typical hindbrain malformation, the molar tooth sign, other cerebral anomalies variably reported in JSRD, such as generalized polymicrogyria, hamartomas, periventricular nodular heterotopia, and hippocampal defects, have been described. Herein, we aimed to revise the main clinical and etiopathogenetic characteristics of epilepsy associated with JSRD.

Prenatal Ultrasonographic Molar Tooth Sign: Case Reports and Review of Literature

AbstractJoubert Syndrome and Related Disorders (JSRD) refers to all disorders presenting as “molar tooth sign” (MTS) on brain imaging. Fetuses with JSRD present with relatively nonspecific signs on prenatal ultrasound varying from increased nuchal translucency, enlarged cisterna magna, cerebellar vermian agenesis, occipital encephalocele, ventriculomegaly, renal disease and polydactyly. However, the hallmark sign in the diagnosis is MTS and MRI is the imaging modality of choice. We report two cases in which MTS was identified on prenatal ultrasound at 22 and 21 weeks (wk) of gestational age respectively. The other prenatal findings on ultrasound included polydactyly and anteroposteriorly enlarged 4th ventricle and vermian hypoplasia in both, and, aortic stenosis evolving to hypoplastic left heart in the former. Prenatal MRI was not done. Amniocentesis was done in the one with associated cardiac anomaly which was reported as normal. In both cases, the couple opted for termination of pregnancy and declined fetal autopsy and further mutation analysis. Only a few cases of JSRD diagnosed on prenatal ultrasound, have been reported. Due to the autosomal recessive inheritance (with 25% recurrence) JSRD has to be differentiated from Dandy-Walker malformation and cranio-cerebello-cardiac syndrome. As definitive prenatal genetic testing may not be conclusive in Joubert syndrome (JBTS) due to the large number of pathogenic variants and genetic heterogenicity, the ability to identify the MTS sonographically early provides a valuable adjunct to prenatal diagnosis.

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

Unilateral, frontal polymicrogyria and supratentorial white matter microcysts in fetus with Joubert syndrome and related disorders: Prenatal diagnosis with magnetic resonance imaging

Introduction. Joubert syndrome (JS) and related disorders (JSRD) are a group of rare multiple congenital anomalies syndromes, defined by complex midbrain-hindbrain malformation that creates the ?molar tooth sign? (MTS) on brain imaging and may be associated with multisystem organ pathology, mainly of the retina, kidney, liver and skeleton. Prenatal diagnosis of JSRD has proved difficult because of the rarity of the condition and low sensitivity of ultrasound in evaluation of the fetal posterior fossa (PF) in most affected fetuses. Case report. We presented an unusual case of JSRD, pure Joubert syndrome with unilateral frontal polymicrogyria and supratentorial white matter microcysts, diagnosed by magnetic resonance imaging (MRI), in fetus aged 30 gestational weeks. The distinctive MRI features of this rare ciliopathy were confirmed by 6-months postnatal MRI study. The postnatal outcome was poor; clinical follow- up in the first 6 months of life confirmed hypotonia, developmental delay, oculomotor apraxia and seizures. Conclusion. To the best of our knowledge, fetal MRI features of the coexistence of pure JS and supratentorial abnormalities leading to postnatal cerebellar dysfunction and epilepsy, have never been reported before. Presented case may contribute to the broadening of the spectrum of sparse prenatal features of JRSD, and support the stand that presence of neuronal migration abnormalities can affect the clinical outcome and prognosis of fetuses with JSRD.

Newborn with multiple congenital anomalies in newborn, intensive care unit suggestive of joubert syndrome and related disorder with an atypical presentation

Joubert syndrome (JS) is a rare autosomal recessive disorder with key finding of cerebellar vermis hypoplasia with a complex brainstem malformation that comprises the molar tooth sign on axial magnetic resonance images. This syndrome is difficult to diagnose clinically because of its variable phenotype. Molar tooth sign is not specific for JS. Another entity is termed as Joubert syndrome and related disorders (JSRD). Although the molar tooth sign and other important clinical features of the JS may be seen in these syndromes, they usually have supplementary prominent features. Author present a case of Joubert syndrome and related disorder in a term newborn delivered in the hospital of Government Medical College, Haldwani with multiple congenital anomalies. Macrocephaly, facial dysmorphism, polydactyly left hand and bilateral ballotable lumbar lump (multicystic dysplastic kidney). MRI showed molar tooth configuration of superior cerebellar peduncles, dilatation of lateral and third ventricles with aqueductal stenosis with arachnoid cyst (unusual association).

In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations

Mutations in CEP290, a transition zone protein in primary cilia, cause diverse ciliopathies, including Leber congenital amaurosis (LCA) and Joubert-syndrome and related disorders (JSRD). We examined cilia biogenesis and function in cells derived from CEP290-LCA and CEP290-JSRD patients. CEP290 protein was reduced in LCA fibroblasts with no detectable impact on cilia; however, optic cups derived from induced pluripotent stem cells (iPSCs) of CEP290-LCA patients displayed less developed photoreceptor cilia. Lack of CEP290 in JSRD fibroblasts resulted in abnormal cilia and decreased ciliogenesis. We observed selectively reduced localization of ADCY3 and ARL13B. Notably, Hedgehog signaling was augmented in CEP290-JSRD because of enhanced ciliary transport of Smoothened and GPR161. These results demonstrate a direct correlation between the extent of ciliogenesis defects infibroblasts and photoreceptors with phenotypicseverity in JSRD and LCA, respectively, and strengthen the role of CEP290 as a selective ciliary gatekeeper for transport of signaling molecules in and out of the cilium.

Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing

Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS.

Prenatal abnormal features of the fourth ventricle in Joubert syndrome and related disorders

Joubert syndrome and related disorders (JSRD) are characterized by absence or underdevelopment of the cerebellar vermis and a malformed brainstem. This family of disorders is a member of an emerging class of diseases called ciliopathies. We describe the abnormal features of the brain, particularly the fourth ventricle, in seven fetuses affected by JSRD. In three cases abnormality of the fourth ventricle was isolated and in four cases there were associated malformations. The molar tooth sign (MTS) was always present and visible on two-dimensional ultrasound and, when performed, on three-dimensional ultrasound and magnetic resonance imaging. The fourth ventricle was always abnormal, in both axial and sagittal views, presenting pathognomonic deformities. It is important to identify JSRD, preferably prenatally or at least postnatally, due to its high risk of recurrence of about 25%. A detailed prenatal assessment of the fourth ventricle in several views may help to achieve this goal.

Mutations in CSPP1 Lead to Classical Joubert Syndrome

Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an invitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.

Molar tooth sign − looking beyond the obvious

The molar tooth sign was initially identified in Joubert syndrome, named after Marie Joubert who first described it in 1968 as a rare autosomal recessive disorder characterised by the neuroradiological hallmark of the molar tooth sign caused by cerebellar vermian hypoplasia. Subsequently, it emerged that the molar tooth sign encompasses many syndromes that are now grouped together and termed Joubert syndrome and related disorders (JSRDs). Knowledge of the newer classification system and the subtypes is important and helps to direct and interpret imaging studies based on clinical signs so as to avoid delay in diagnosis of the hepatic oculorenal and renal subtypes of JSRDs in patients in whom the molar tooth sign is identified on brain MRI.

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

The diagnostic utility of exome sequencing in Joubert syndrome and related disorders

Joubert syndrome (JS) and related disorders (JSRD) are autosomal recessive and X-linked disorders characterized by hypoplasia of the cerebellar vermis with a characteristic 'molar tooth sign' on brain imaging and accompanying neurological symptoms including episodic hyperpnoea, abnormal eye movements, ataxia and intellectual disability. JSRD are clinically and genetically heterogeneous, and, to date, a total of 17 causative genes are known. We applied whole-exome sequencing (WES) to five JSRD families and found mutations in all: either CEP290, TMEM67 or INPP5E was mutated. Compared with conventional Sanger sequencing, WES appears to be advantageous with regard to speed and cost, supporting its potential utility in molecular diagnosis.

Joubert Syndrome and Related Disorders: Implications for Nurse Practitioners

Joubert syndrome (JS) and related disorders (JSRD) are rare autosomal recessive disorders typified by a distinctive cerebellar and brainstem malformation. The diagnosis of JSRD requires the neuroradiological “molar tooth sign” found on magnetic resonance imaging. Many children affected with the disorder die in infancy before diagnosis. Rare diseases or syndromes can pose unique challenges for primary care providers who participate in the day-to-day care of chronically ill and physically and mentally challenged children. This article discusses JS and JSRD to provide insight for primary care providers caring for these special children and adults.

Oral-Facial-Digital Syndrome Type VI: Delineation and Diagnostic Criteria

Aims: Oral-Facial-Digital Syndrome type VI (OFD VI) is a subtype of Joubert syndrome and related disorders (JSRD). The originally reported patients had polydactyly, oral findings, intellectual disability and vermian agenesis. Subsequently, MRI showed the “Molar Tooth Sign” (MTS), prompting its inclusion in JSRD. We aim to evaluate the MRI spectrum, characterize neurological/dysmorphic features and cognitive outcome and suggest diagnostic criteria for OFD VI.

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.

Joubert syndrome and related disorders, prenatal diagnosis with ultrasound and magnetic resonance imaging

Joubert syndrome (JBTS) is an autosomal recessive disorder characterized by intellectual disability, hypotonia, ataxia, tachypnea/apnea, and abnormal eye movements. A pathognomonic midbrain-hindbrain malformation seen on cranial magnetic resonance imaging (MRI), which consists of hypoplasia of the midline cerebellar vermis that resembles the cross-section through a molar tooth, has been described previously. The molar tooth sign is defined by a peculiar appearance resembling a molar tooth secondary to an abnormally deep interpeduncular fossa and enlarged superior cerebellar peduncles on axial images at the pontomesencephalic level. The term Joubert Syndrome and Related Disorders (JSRD) has recently been adopted to describe all disorders presenting the "molar tooth sign" (MTS) on brain imaging. JSRD is characterized by lack of decussation of the superior cerebellar peduncles, central pontine tracts and corticospinal tracts suggesting defective axon guidance. Prenatal sonographic findings in fetuses with JSRD are relatively nonspecific and include increased nuchal translucency, enlarged cisterna magna, cerebellar vermian agenesis, occipital encephalocele, ventriculomegaly and polydactyly. We report a case of JSRD detected prenatally at 23 weeks of gestation. The fetus in the present case had a normal karyotype. Sonographic features of the fetus included polydactyly, partial vermian hypoplasia, dilated 4(th) ventricle and mild ventriculomegaly which were also confirmed by prenatal MRI. MTS was demonstrated in a postnatal MRI after pregnancy termination.

Tecto-cerebellar Dysraphism with Occipital Encephalocele: Not a Distinct Disorder, but Part of the Joubert Syndrome Spectrum?

Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) findings in a 4-year-old child with occipital encephalocele, cerebellar vermis hypogenesis, and tectal malformation are presented. The neuroimaging findings are reminiscent of tectocerebellar dysraphism with an occipital encephalocele (TCD-OE). Additionally, elongated, thickened, and horizontally orientated superior cerebellar peduncles, an abnormally deepened interpeduncular fossa, subependymal heterotopia, and focal cortical dysplasia were noted. Color-coded fractional anisotropy (FA) maps revealed an absence of the decussation of the superior cerebellar peduncles. These findings are highly suggestive of Joubert syndrome and related disorders (JSRD). Our report and the review of the published cases suggest that TCD-OE is not a nosological entity, but may represent the structural manifestation of heterogeneous disorders such as the JSRD spectrum. DTI may be very helpful to differentiate between similar midbrain-hindbrain malformations.

Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients

Background and purpose: The key neuroimaging hallmarks of Joubert syndrome and related disorders (JSRD) include vermian hypoplasia and the molar tooth sign (MTS). We aimed to look at the full spectrum of neuroimaging findings in JSRD, pointing out unusual observations in particular.

MRI with fibre tracking in Cogan congenital oculomotor apraxia

Congenital ocular motor apraxia (COMA) occasionally shares with Joubert syndrome (JS) and related disorders (JSRDs) a peculiar malformation, the 'molar tooth sign' (MTS). In JSRDs, the absence of superior cerebellar peduncles (SCP) decussation is reported. To investigate whether COMA demonstrates similar abnormal axonal pathways. Eight healthy age-matched controls, three children with clinical COMA and one child with clinical JSRD underwent examination with a 1.5-T MRI scanner. Diffusion-weighted imaging (DWI), colour-coded fractional anisotropy maps and three-dimensional diffusion tensor imaging (DTI) tractography of the cerebellorubral network were analyzed. On DTI cartography, the 'red dot' originally supposed to represent the SCP decussation in the midbrain was present in controls as well in those with COMA but absent in the single case with JS. In none of the subjects including controls was 3-D FT able to depict the SCP decussation. When seeded, the red dot resulted in the ventral tegmental decussation (VTD). It was normal in controls and in patients with COMA but was absent in our single patient with JSRD. MTS was identified in alla patients with COMA and in the patient with JSRD. MTS can be present in both COMA and JSRD but the underlying anatomy depicted by fibre tracking is distinct. The main difference is the integrity of the VTD in COMA.

NovelTMEM67mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.