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Enza Maria Valente - One of the best experts on this subject based on the ideXlab platform.
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Establishment of three Joubert Syndrome-derived induced pluripotent stem cell (iPSC) lines harbouring compound heterozygous mutations in CC2D2A gene
2021Co-Authors: Eltahir Ali, Enza Maria Valente, Rosalba Monica Ferraro, Adele Guglielmi, Gaetana Lanzi, Stefania Masneri, Giovanna Piovani, Elena Laura Mazzoldi, Lidia Pollara, Patrizia AccorsiAbstract:We have developed Joubert Syndrome (JS)-derived induced pluripotent stem cell (iPSC) lines from dermal fibroblasts biopsied from a female patient harbouring novel compound heterozygous mutations in CC2D2A gene. The newly established iPSC lines provide tremendous promises for development of JS-derived neuronal cell lines to uncover the molecular and cellular mechanisms underlying the pathogenesis of JS and to develop therapeutic interventions for treatment of JS
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Production and characterization of human induced pluripotent stem cells (iPSC) CSSi007-A (4383) from Joubert Syndrome
2019Co-Authors: Filomena Altieri, Angela D'anzi, Francesco Martello, Silvia Tardivo, Iolanda Spasari, Daniela Ferrari, Laura Bernardini, Giuseppe Lamorte, Gianluigi Mazzoccoli, Enza Maria ValenteAbstract:Abstract Joubert Syndrome (JS) is an autosomal recessive neurodevelopmental disorder, characterized by congenital cerebellar and brainstem defects, belonging to the group of disorders known as ciliopathies, which are caused by mutations in genes encoding proteins of the primary cilium and basal body. Human induced pluripotent stem cells (hiPSCs) from a patient carrying a homozygous missense mutation (c.2168G > A) in AHI1, the first gene to be associated with JS, were produced using a virus-free protocol.
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macular staphyloma in patients affected by Joubert Syndrome with retinal dystrophy a new finding detected by sd oct
2018Co-Authors: Caterina Toma, Enza Maria Valente, G Ruberto, Federico Marzi, Giulio Vandelli, Sabrina Signorini, M Antonini, Chiara Bertone, Paolo Emilio BianchiAbstract:Purpose Joubert Syndrome (JS) is an inherited autosomal recessive or X-lined disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features. It is estimated that retinal dystrophy is present in association with the typical neurological findings in about one-third of the patients. The aim of this study is to better characterize the macular region in JS patients with and without retinal dystrophy.
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Production and characterization of human induced pluripotent stem cells (iPSCs) from Joubert Syndrome: CSSi001-A (2850).
2018Co-Authors: Jessica Rosati, Filomena Altieri, Silvia Tardivo, Iolanda Spasari, Daniela Ferrari, Laura Bernardini, Giuseppe Lamorte, Elisa Maria Turco, Marina Goldoni, Enza Maria ValenteAbstract:Joubert Syndrome (JS) is a rare autosomal recessive or X-linked condition characterized by a peculiar cerebellar malformation, known as the molar tooth sign (MTS), associated with other neurological phenotypes and multiorgan involvement. JS is a ciliopathy, a spectrum of disorders whose causative genes encode proteins involved in the primary cilium apparatus. In order to elucidate ciliopathy-associated molecular mechanisms, human induced pluripotent stem cells (hiPSCs) were derived from a patient affected by JS carrying a homozygous missense mutation in the AHI1 gene (p.H896R) that encodes a protein named Jouberin.
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Joubert Syndrome and related disorders
2013Co-Authors: Enza Maria Valente, Bruno Dallapiccola, Enrico BertiniAbstract:Joubert Syndrome (JS) is a rare autosomal recessive condition characterized by a peculiar midbrain-hindbrain malformation, known as the molar tooth sign (MTS). The neurological presentation of JS includes hypotonia that evolves into ataxia, developmental delay, abnormal eye movements, and neonatal breathing abnormalities. This picture is often associated with variable multiorgan involvement, mainly of the retina, kidneys, and liver, defining a group of conditions termed Joubert Syndrome and related disorders (JSRDs), that share the MTS. To date, 16 causative genes have been identified, all encoding for proteins expressed in the primary cilium or its apparatus. Indeed, JSRD present clinical and genetic overlap with a growing field of disorders due to mutations in ciliary proteins, that are collectively known as "ciliopathies." These include isolated nephronophthisis, Senior-Loken Syndrome, Bardet-Biedl Syndrome and, in particular, Meckel Syndrome, which is allelic at JSRD at seven distinct loci. Significant genotype-phenotype correlates are emerging between specific clinical presentations and mutations in JSRD genes, with relevant implications in terms of molecular diagnosis, clinical follow-up, and management of mutated patients. Moreover, the identification of mutations allows early prenatal diagnosis in couples at risk, while fetal neuroimaging may remain uninformative until the late second trimester of pregnancy.
Dan Doherty - One of the best experts on this subject based on the ideXlab platform.
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casting a wide net to find the molar tooth a study on Joubert Syndrome
2020Co-Authors: Keith A Coffman, Dan DohertyAbstract:Joubert Syndrome is a genetically heterogeneous group of congenital ataxias that share a distinctive cerebellar and hindbrain malformation referred to in the literature as the molar tooth sign.1,2 Based largely on unpublished data, the prevalence of Joubert Syndrome is estimated as 1:80,000 to 500,000.3,4 In this issue of Neurology ®, Nuovo et al.5 present the first population-based estimate of age and sex prevalence of Joubert Syndrome in Italy. The overall prevalence was 0.47 per 100,000 population, while in children 0 to 19 years of age, the prevalence was 1.7 per 100,000, 2- to 10-fold higher than prior estimates. To achieve these more accurate results, the authors created a nationwide network of centers with expertise in Joubert Syndrome that partnered with a disease-specific nonprofit organization dedicated to congenital ataxias. Through this collaboration, the network identified 284 patients with Joubert Syndrome based on clinical and neuroradiologic findings. Next-generation sequencing confirmed a genetic cause in ≈60% of individuals tested, consistent with prior publications examining the genetics of Joubert Syndrome.6
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Prospective Evaluation of Kidney Disease in Joubert Syndrome
2017Co-Authors: Leah R. Fleming, Ian A. Glass, Dan Doherty, Melissa A Parisi, Joy Bryant, Roxanne Fischer, Baris Turkbey, Peter L. Choyke, Kailash Daryanani, Meghana VemulapalliAbstract:Background and objectives Joubert Syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. Design, setting, participants, & measurements We evaluated 97 individuals with Joubert Syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. Results Patients were ages 0.6–36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). Conclusions Kidney disease occurs in up to one third of patients with Joubert Syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert Syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease–like enlarged kidneys with early-onset hypertension can be part of the Joubert Syndrome kidney phenotype.
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Joubert Syndrome neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause
2017Co-Authors: Joseph Snow, Andrea Poretti, Angela C Summers, Aylin Tekes, Thierry A G M Huisman, Nafi Aygun, Kathryn A Carson, Dan DohertyAbstract:Background Joubert Syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert Syndrome in correlation with molecular genetic cause and cognitive function. Methods Brain MRI of 110 patients with Joubert Syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients. Results The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was. Conclusions The spectrum of neuroimaging findings in Joubert Syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert Syndrome.
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mortality in Joubert Syndrome
2017Co-Authors: Jennifer C. Dempsey, Ian A. Glass, Ian G. Phelps, Dan Doherty, Ruxandra Bachmanngagescu, Hannah M TullyAbstract:Joubert Syndrome (JS) is a rare, recessively inherited neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. Little is known about mortality in affected individuals. Identifying the timing and causes of death will allow for development of healthcare guidelines for families and providers and, thus, help to prolong and improve the lives of patients with JS. We evaluated information on 40 deceased individuals with JS to characterize age and cause of death. We compared this population with 525 living individuals with JS to estimate associations between risk of death and extra-neurological features. Genetic causes were examined in both groups. Mean age of death in this cohort was 7.2 years, and the most prevalent causes of death were respiratory failure (35%), particularly in individuals younger than 6 years, and kidney failure (37.5%), which was more common in older individuals. We identified possible associations between risk of death and kidney disease, liver fibrosis, polydactyly, occipital encephalocele, and genetic cause. This work highlights factors (genetic cause, extra-neurological organ involvement, and other malformations) likely to be associated with higher risk of mortality in JS, which should prompt increased monitoring for respiratory issues, kidney disease, and liver fibrosis.
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molecular genetic findings and clinical correlations in 100 patients with Joubert Syndrome and related disorders prospectively evaluated at a single center
2017Co-Authors: Thierry Vilboux, Ian A. Glass, Ian G. Phelps, Dan Doherty, Melissa A Parisi, Andrew R Cullinane, Wadih M ZeinAbstract:Molecular genetic findings and clinical correlations in 100 patients with Joubert Syndrome and related disorders prospectively evaluated at a single center
Joseph G. Gleeson - One of the best experts on this subject based on the ideXlab platform.
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Mutation spectrum of Joubert Syndrome and related disorders among Arabs
2014Co-Authors: Salma Ben-salem, Joseph G. Gleeson, Aisha M Al-shamsi, Bassam R Ali, Lihadh Al-gazaliAbstract:Joubert Syndrome (JS) is a rare autosomal recessive (AR), neurological condition characterized by dysgenesis of the cerebellar vermis with the radiological hallmark of molar tooth sign, oculomotor apraxia, recurrent hyperventilation and intellectual disability. Most cases display a broad spectrum of additional features, including polydactyly, retinal dystrophy and renal abnormalities, which define different subtypes of JS-related disorders (JSRDs). To date, 23 genes have been shown to cause JSRDs, and although most of the identified genes encode proteins involved in cilia function or assembly, the molecular mechanisms associated with ciliary signaling remain enigmatic. Arab populations are ethnically diverse with high levels of consanguinity (20–60%) and a high prevalence of AR disorders. In addition, isolated communities with very-high levels of inbreeding and founder mutations are common. In this article, we review the 70 families reported thus far with JS and JSRDs that have been studied at the molecular level from all the Arabic countries and compile the mutations found. We show that JS and the related JSRDs are genetically heterogeneous in Arabs, with 53 mutations in 15 genes. Thirteen of these mutations are potentially founder mutations for the region.
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the ciliopathies in neuronal development a clinical approach to investigation of Joubert Syndrome and Joubert Syndrome related disorders
2011Co-Authors: Shifteh Sattar, Joseph G. GleesonAbstract: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.
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Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert Syndrome
2011Co-Authors: Madeline A Lancaster, Jennifer L Silhavy, Maha S Zaki, Carrie M. Louie, Dipika J. Gopal, Joon Kim, Sahar N. Saleem, Bryan E. Thacker, Yuko Williams, Joseph G. GleesonAbstract:The ciliopathy Joubert Syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear. To investigate Joubert Syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert Syndrome-associated gene. These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert Syndrome-associated gene, Cep290. Furthermore, fetal magnetic resonance imaging (MRI) of human subjects with Joubert Syndrome reveals a similar midline cleft, suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1-mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert Syndrome that can be overcome with Wnt stimulation.
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Genetic basis of Joubert Syndrome and related disorders of cerebellar development.
2005Co-Authors: Carrie M. Louie, Joseph G. GleesonAbstract:Over three decades have passed since Marie Joubert described the original proband for Joubert Syndrome, a rare neurological disorder featuring absence of the cerebellar vermis (i.e. midline). Efforts at deciphering the molecular basis for this disease have been complicated by the clinical and genetic heterogeneity as well as extensive phenotypic overlap with other Syndromes. However, progress has been made in recent years with the mapping of three genetic loci and the identification of mutations in two genes, AHI1 and NPHP1. These genes encode proteins with some shared functional domains, but their role in brain development is unclear. Clues may come from studies of related Syndromes, including Bardet-Biedl Syndrome and nephronophthisis, for which all of the encoded proteins localize to primary cilia. The data suggest a tantalizing connection between intraflagellar transport in cilia and brain development.
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linkage analysis in families with Joubert Syndrome plus oculo renal involvement identifies the cors2 locus on chromosome 11p12 q13 3
2003Co-Authors: Lesley C Keeler, Sarah E. Marsh, László Sztriha, Aithala Gururaj, Esther P Leeflang, Christopher G Woods, Lihadh Algazali, Joseph G. GleesonAbstract:Joubert Syndrome (JS) is an autosomal recessive developmental brain condition characterized by hypoplasia/dysplasia of the cerebellar vermis and by ataxia, hypotonia, oculomotor apraxia, and neonatal breathing dysregulation. A form of JS that includes retinal dysplasia and cystic dysplastic kidneys has been differentiated from other forms of JS, called either "JS type B" or "cerebello-oculo-renal Syndrome" (CORS), but the genetic basis of this condition is unknown. Here, we describe three consanguineous families that display CORS. Linkage analysis defines a novel locus on chromosome 11p12-q13.3, with a maximum two-point LOD score of Z=5.2 at the marker D11S1915. Therefore, the cerebello-oculo-renal form of JS is a distinct genetic entity from the Joubert Syndrome 1 (JBTS1) locus described elsewhere, in which there is minimal involvement of retina or kidney. We suggest the term "CORS2" for this new locus.
Mary K. Colvin - One of the best experts on this subject based on the ideXlab platform.
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Cerebellar cognitive affective Syndrome: insights from Joubert Syndrome
2018Co-Authors: Chelsea L. Hickey, Janet C. Sherman, Paula Goldenberg, Amy Kritzer, Paul Caruso, Jeremy D. Schmahmann, Mary K. ColvinAbstract:Background Joubert Syndrome (JS) is a rare, autosomal recessively inherited genetic disorder characterized morphologically by unique developmental malformations of the cerebellum and brainstem (the molar tooth sign), and clinically by impaired motor functions and intellectual disability. Patients with JS often face multiple cognitive challenges, but the neuropsychological profile of this condition has not been well characterized. Methods We performed comprehensive neurological and neuropsychological evaluations in three adult brothers with JS, ages 32, 27, and 25 years. Results They all exhibited impaired motor control, global developmental delay most evident in executive function, affect regulation, and social skill set, and similar patterns of neuropsychiatric symptoms. Conclusions These findings provide new insights into the intellectual and neurobehavioral phenotype of JS, which we regard as a developmental form of the cerebellar cognitive affective / Schmahmann Syndrome (CCAS). These observations have direct clinical relevance for the diagnosis and care of patients with JS, and they help further the understanding of the multiple manifestations of atypical cerebrocerebellar development.
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cerebellar cognitive affective Syndrome insights from Joubert Syndrome
2018Co-Authors: Chelsea L. Hickey, Janet C. Sherman, Paula Goldenberg, Amy Kritzer, Jeremy D. Schmahmann, Paul A Caruso, Mary K. ColvinAbstract:Joubert Syndrome (JS) is a rare, autosomal recessively inherited genetic disorder characterized morphologically by unique developmental malformations of the cerebellum and brainstem (the molar tooth sign), and clinically by impaired motor functions and intellectual disability. Patients with JS often face multiple cognitive challenges, but the neuropsychological profile of this condition has not been well characterized. We performed comprehensive neurological and neuropsychological evaluations in three adult brothers with JS, ages 32, 27, and 25 years. They all exhibited impaired motor control, global developmental delay most evident in executive function, affect regulation, and social skill set, and similar patterns of neuropsychiatric symptoms. These findings provide new insights into the intellectual and neurobehavioral phenotype of JS, which we regard as a developmental form of the cerebellar cognitive affective / Schmahmann Syndrome (CCAS). These observations have direct clinical relevance for the diagnosis and care of patients with JS, and they help further the understanding of the multiple manifestations of atypical cerebrocerebellar development.
Ian A. Glass - One of the best experts on this subject based on the ideXlab platform.
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Prospective Evaluation of Kidney Disease in Joubert Syndrome
2017Co-Authors: Leah R. Fleming, Ian A. Glass, Dan Doherty, Melissa A Parisi, Joy Bryant, Roxanne Fischer, Baris Turkbey, Peter L. Choyke, Kailash Daryanani, Meghana VemulapalliAbstract:Background and objectives Joubert Syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. Design, setting, participants, & measurements We evaluated 97 individuals with Joubert Syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. Results Patients were ages 0.6–36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). Conclusions Kidney disease occurs in up to one third of patients with Joubert Syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert Syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease–like enlarged kidneys with early-onset hypertension can be part of the Joubert Syndrome kidney phenotype.
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mortality in Joubert Syndrome
2017Co-Authors: Jennifer C. Dempsey, Ian A. Glass, Ian G. Phelps, Dan Doherty, Ruxandra Bachmanngagescu, Hannah M TullyAbstract:Joubert Syndrome (JS) is a rare, recessively inherited neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. Little is known about mortality in affected individuals. Identifying the timing and causes of death will allow for development of healthcare guidelines for families and providers and, thus, help to prolong and improve the lives of patients with JS. We evaluated information on 40 deceased individuals with JS to characterize age and cause of death. We compared this population with 525 living individuals with JS to estimate associations between risk of death and extra-neurological features. Genetic causes were examined in both groups. Mean age of death in this cohort was 7.2 years, and the most prevalent causes of death were respiratory failure (35%), particularly in individuals younger than 6 years, and kidney failure (37.5%), which was more common in older individuals. We identified possible associations between risk of death and kidney disease, liver fibrosis, polydactyly, occipital encephalocele, and genetic cause. This work highlights factors (genetic cause, extra-neurological organ involvement, and other malformations) likely to be associated with higher risk of mortality in JS, which should prompt increased monitoring for respiratory issues, kidney disease, and liver fibrosis.
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molecular genetic findings and clinical correlations in 100 patients with Joubert Syndrome and related disorders prospectively evaluated at a single center
2017Co-Authors: Thierry Vilboux, Ian A. Glass, Ian G. Phelps, Dan Doherty, Melissa A Parisi, Andrew R Cullinane, Wadih M ZeinAbstract:Molecular genetic findings and clinical correlations in 100 patients with Joubert Syndrome and related disorders prospectively evaluated at a single center
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co occurrence of Joubert Syndrome and jeune asphyxiating thoracic dystrophy
2010Co-Authors: Anna Lehman, Ian A. Glass, Dan Doherty, Patrice Eydoux, David Chitayat, Bhy Chung, Sylvie Langlois, Siuli Yong, R B LowryAbstract:Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert Syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both Syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune Syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.
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Joubert Syndrome (and related disorders) (OMIM 213300)
2007Co-Authors: Melissa A Parisi, Dan Doherty, Phillip F. Chance, Ian A. GlassAbstract:Joubert Syndrome (JS) and related disorders are characterized by the ‘molar tooth sign’ (cerebellar vermis hypoplasia and brainstem anomalies) on MRI, hypotonia, developmental delay, ataxia, irregular breathing pattern and abnormal eye movements. Combinations of additional features such as polydactyly, ocular coloboma, retinal dystrophy, renal disease, hepatic fibrosis, encephalocele, and other brain malformations define clinical sub-types. Recent identification of the NPHP1 , AHI1 , and CEP290 genes has started to reveal the molecular basis of JS, which may implicate the primary cilium in these disorders. Additional genes remain to be identified.
