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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Joubert syndrome (JS) is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation. Despite the fact that this condition was described >30 years ago, the molecular basis has remained poorly understood. Here, we identify two frameshift mutations and one missense mutation in the AHI1 gene in three consanguineous families with JS, some with cortical polymicrogyria. AHI1, encoding the Jouberin protein, is an alternatively spliced signaling molecule that contains seven Trp-Asp (WD) repeats, an SH3 domain, and numerous SH3-binding sites. The gene is expressed strongly in embryonic hindbrain and forebrain, and our data suggest that AHI1 is required for both cerebellar and cortical development in humans. The recently described mutations in NPHP1, encoding a protein containing an SH3 domain, in a subset of patients with JS plus nephronophthisis, suggest a shared pathway.
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PMID:Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. 1546 82

We have identified a group of 13 patients with a homogeneous radiological pattern at MRI consisting of the molar tooth sign (MTS) and superior vermian dysplasia. The patients represent a relatively heterogeneous clinical group with variable severity of developmental delay, ataxia, hypotonia, and apnea. Careful examination of MRI prompted us to split our series of patients into two groups, based on IVth ventricle dilatation. In 4/13 patients the IVth ventricle was judged to be dilated and those patients were less severely affected while most clinically affected patients had a normal IVth ventricle. DNA samples of blood leukocytes from 6/13 consanguineous patients were genotyped using polymorphic markers encompassing the Joubert syndrome loci. We therefore sequenced AHI1 located in 6q23 in two patients who were homozygous at the locus and in four sporadic cases. Only one homozygous nonsense mutation was identified. Clinically, the patient exhibiting the AHI1 mutation was the most severely affected child with a profound encephalopathy, major hypotonia, ataxia, Leber congenital amaurosis, and normal IVth ventricle at the MRI. The present study suggests that the syndrome associating MTS and dysplasia of the superior vermis of the cerebellum is a clinically and genetically heterogeneous entity and that Jouberin (AHI1) mutations account for a marginal fraction of patients.
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PMID:Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study. 1654 67

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.
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PMID:Joubert syndrome (and related disorders) (OMIM 213300). 1737 24

Joubert syndrome and related cerebellar disorders (JSRD) are a group of recessive congenital ataxia conditions usually showing neonatal hypotonia, dysregulated breathing rhythms, oculomotor apraxia, and mental retardation. The pathognomonic finding in JSRD is the unique molar tooth sign (MTS) on brain imaging. There is a tremendously broad spectrum of signs and symptoms mainly including kidney, retina, and liver disease, along with polydactyly and facial dysmorphisms. Here we propose a new diagnostic classification within JSRD that includes four major subtypes. To test this classification, we performed a systematic recruitment and genetic evaluation from a single referral center in Egypt. Thirteen families were identified, four showed evidence of linkage to one of the four known genetic loci, three showed novel AHI1 mutations, and nine were excluded from known loci. Each family could be classified into one of the four subtypes. This classification may thus be useful in the evaluation of patients with JSRD.
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PMID:The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families. 1826 48

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.
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PMID:CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. 1895 Jul 40

Joubert syndrome (JS) is characterized by hypotonia, ataxia, developmental delay, and a typical neuroimaging finding, the so-called "molar tooth sign" (MTS). The association of MTS and polymicrogyria (PMG) has been reported as a distinct JS-related disorder (JSRD). So far, five patients have been reported with this phenotype, only two of them being siblings. We report on one additional family, describing a living child with JS and PMG, and the corresponding neuropathological picture in the aborted brother. No mutations were detected in the AHI1 gene, the only so far associated with the JS + PMG phenotype. Moreover, linkage analysis allowed excluding all known gene loci, suggesting further genetic heterogeneity.
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PMID:Joubert syndrome with bilateral polymicrogyria: clinical and neuropathological findings in two brothers. 1953 93

Joubert syndrome (JS) is a primarily autosomal recessive condition characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation (the "molar tooth sign"). Variable features include retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly. Recently, substantial progress has been made in our understanding of the genetic basis of JS, including identification of seven causal genes (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B and CC2D2A). Despite this progress, the known genes account for <50% of cases and few strong genotype-phenotype correlations exist in JS; however, genetic testing can be prioritized based on clinical features. While all seven JS genes have been implicated in the function of the primary cilium/basal body organelle (PC/BB), little is known about how the PC/BB is required for brain, kidney, retina and liver development/function, nor how disruption of PC/BB function leads to diseases of these organs. Recent work on the function of the PC/BB indicates that the organelle is required for multiple signaling pathways including sonic hedgehog, WNT and platelet derived growth factor. Due to shared clinical features and underlying molecular pathophysiology, JS is included in the rapidly expanding group of disorders called ciliopathies. The ciliopathies are emerging as models for more complex diseases, where sequence variants in multiple genes contribute to the phenotype expressed in any given patient.
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PMID:Joubert syndrome: insights into brain development, cilium biology, and complex disease. 1977 11

The cerebellum plays a role not only in motor control but also in motor learning and cognition. Joubert syndrome is a rare heterogeneous inherited genetic disorder characterized by ataxia, hypotonia, developmental delay, and at least one of the following features: neonatal respiratory disturbances or abnormal eye movement. The estimated frequency of Joubert syndrome in the United States is around 1 : 100 000. The term Joubert syndrome and related disorders (JSRD) has been recently coined to describe all disorders presenting with molar tooth sign on brain neuroimaging. Joubert syndrome is believed to be a representative of a new group of disorders named ciliopathies. The identification of seven causal genes (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B, CC2D2A) has led to substantial progress in the understanding of the genetic basis of Joubert syndrome. The authors focus on clinical presentation of JSRD, differential diagnosis and molecular background.
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PMID:[Joubert syndrome and related disorders]. 2302 37