Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028738 (nystagmus)
 7,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aniridia is a rare panocular disorder which primarily involves not only the iris, but also the retina, optic nerve, lens and cornea. Visual acuity deteriorates as a result of nystagmus, glaucoma, cataract, corneal opacities and retinal hypoplasia. Aniridia may appear as an isolated disorder, most often familial with autosomal dominance or sporadically in association with at least 12 syndromes. Both familial isolated and Wilms tumour, bilateral sporadic aniridia, genitourinary abnormalities and mental retardation syndrome-associated aniridia have been traced to a mutation of the PAX6 gene on band 11p13. Since genetic diagnosis of this disorder is already possible, counselling affected families should be preceded by karyotype studies and linkage analysis in familial cases of isolated aniridia. In sporadic cases of isolated aniridia or WAGR syndrome, we suggest that PAX6 mutation analysis be employed.
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PMID:Aniridia: recent achievements in paediatric practice. 852 75

Mutations of the human PAX6 gene underlie aniridia (congenital absence of the iris), a rare dominant malformation of the eye. The spectrum of PAX6 mutations in aniridia patients is highly biased, with 92% of all reported mutations leading to premature truncation of the protein (nonsense, splicing, insertions and deletions) and just 2% leading to substitution of one amino acid by another (missense). The extraordinary conservation of the PAX6 protein at the amino acid level amongst vertebrates predicts that pathological missense mutations should in fact be common even though they are hardly ever seen in aniridia patients. This indicates that there is a heavy ascertainment bias in the selection of patients for PAX6 mutation analysis and that the 'missing' PAX6 missense mutations frequently may underlie phenotypes distinct from textbook aniridia. Here we present four novel PAX6 missense mutations, two in association with atypical phenotypes: ectopia pupillae (displaced pupils) and congenital nystagmus (searching gaze), and two in association with more recognizable aniridia phenotypes. Strikingly, all four mutations are located within the PAX6 paired domain and affect amino acids which are highly conserved in all known paired domain proteins. Our results support the hypothesis that the under-representation of missense mutations is caused by ascertainment bias and suggest that a substantial burden of PAX6 -related disease remains to be uncovered.
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PMID:Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations. 993 24

PAX6, a paired box transcriptional factor, is considered as the master control gene for morphogenesis of the eye. Human PAX6 mutations have been associated with a range of eye abnormalities, including aniridia, various anterior segment defects and foveal hypoplasia. We carried out a mutational analysis of the PAX6 gene in 54 unrelated patients with aniridia or related syndromes. A deleterious variation was evidenced in 17 sporadic cases (50%) and in 13 (72%) familial cases. Twenty-four different mutations, 17 of which are novel, were found. The spectrum of PAX6 mutations was highly homogeneous: 23 mutations (96%) leading to premature stop codons (eight nonsense and four splice site mutations, 11 insertions and deletions) and only one (4%) missense mutation. Twenty-two mutations were associated with aniridia phenotypes whereas two were associated with atypical phenotypes. These latter encompassed a missense mutation (R19P) in an individual with a microphthalmia-sclerocornea and a splice site mutation (IVS4+5G > C) in a family presenting with a congenital nystagmus. Both represented the most probably hypomorphic alleles. Aniridia cases were associated with nonsense or frameshifting mutations. A careful examination of the phenotypes did not make it possible to recognise significant differences whenever the predicted protein was deprived of one or another of its functional domains. This strongly suggested that most of the truncating mutations generated null alleles by nonsense mediated mRNA decay. Our observations support the concept of dosage effects of the PAX6 mutations as well as presenting evidence for variable expressivity.
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PMID:Screening for PAX6 gene mutations is consistent with haploinsufficiency as the main mechanism leading to various ocular defects. 1263 64

Aniridia, Wilms tumor, genitourinary abnormalities, growth and mental retardation are the cardinal features of the WAGR 11p13 deletion syndrome. The Potocki-Schaffer syndrome or proximal 11p deletion syndrome (previously DEFECT11 syndrome) is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses and enlarged parietal foramina. Mental handicap, facial dysmorphism and craniosynostosis may also be associated. We report a patient with combined WAGR and Potocki-Shaffer syndromes, and obesity. She presented with aniridia, cataract, nystagmus, corneal ulcers and bilateral congenital ptosis. A left nephroblastoma was detected at 15 months. Other features included moderate developmental delay, growth deficiency, facial dysmorphism, multiple exostoses and cranial lacunae. High-resolution and molecular cytogenetics confirmed a del(11)(p11.2p14.1) deletion with a proximal breakpoint between the cosmid DO8153 and the BAC RP11-104M24 to a distal breakpoint between cosmids CO8160 (D11S151) and F1238 (D11S1446). The deletion therefore includes EXT2, ALX4, WT1 and PAX6. This case appears to be the second patient reported with this combined deletion syndrome and confirms the association of obesity in the WAGR spectrum, a feature previously reported in four cases, and for which the acronym WAGRO has been suggested. Molecular and follow-up data on the original WAGRO case are briefly presented.
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PMID:Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion. 1570 31

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, Aniridia, Genito-urinary abnormalities, and growth and mental retardation which is invariably associated with an 11p13 deletion. We report two monozygotic twins and a third, unrelated patient with WAGR syndrome and additional clinical features not usually associated with WAGR. Both twins had developmental delay, growth deficiency, severe ocular involvement (nystagmus, aniridia, cataracts), atrial septal defect and two uncommon findings: agenesis of the corpus callosum and duplication of the halluces. One twin developed Wilms tumors aged 19 months while her sister remained tumor free by the age of 6.5 years. The singleton patient showed typical WAGR syndrome and preaxial hallucal polydactyly. Molecular cytogenetic studies refined the identification of the extent of the deleted segments, which were not identical in the two families. The two deletions included the PAX6 and WT1 genes as previously reported in typical WAGR patients. The unusual anomalies described in this report, may represent the expression of low penetrant traits associated with haploinsufficency of one or more of the genes present in the deletion (PAX6 is expressed in CNS) or may indicate epistatic influences of modifier genes on the expression of gene(s) present in the WAGR region.
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PMID:Three patients with hallucal polydactyly and WAGR syndrome, including discordant expression of Wilms tumor in MZ twins. 1577 23

Aniridia usually occurs in isolation, but may also occur as part of the WAGR contiguous gene deletion syndrome, which includes Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. The aniridia and predisposition for Wilms tumor seen in WAGR are caused by haploinsufficiency for PAX 6 and WT1, respectively. We present a female infant with aniridia, bilateral ptosis, bilateral posterior capsular cataracts, nystagmus, left-sided glaucoma, microcephaly, mild unilateral hydronephrosis, poor linear growth, and gross motor delay consistent with a clinical diagnosis of WAGR syndrome. In addition, weight-for-height ratio at 12 months is at the 94th centile, raising the possibility of a diagnosis of WAGRO (WAGR + Obesity). Chromosome analysis revealed a translocation (11;15)(p13;p11.2) which has not been previously associated with a diagnosis of WAGR. Subsequent clinical WAGR fluorescent in situ hybridization (FISH) analysis demonstrated a deletion of 11p13 including PAX6 and WT1. A complete FISH-mapping of the breakpoints on chromosome 11 revealed a 7 Mb deletion within 11p13-11p14. The patient is examined in light of other reported patients with deletions and/or translocations involving the regions between 11p12 --> 11p14 including patients with WAGR + obesity (WAGRO) as well as with other reported patients with aniridia and congenital ptosis.
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PMID:WAGR(O?) syndrome and congenital ptosis caused by an unbalanced t(11;15)(p13;p11.2)dn demonstrating a 7 megabase deletion by FISH. 1664 34

We report on the clinical, molecular and biochemical findings of a patient with the rare event (<4.02 x 10(-9) per generation) of coinciding de novo mutations in the nuclear PAX6 (c.1252-1267del16) and the mitochondrial mt.RNA (Lys) (8347A-->G) genes. The boy suffers from exercise intolerance, ptosis, nystagmus, macular hypoplasia and anterior segment abnormalities evocative of Axenfeld-Rieger anomaly. The PAX6 mutation is predicted to cause haploinsufficiency. The novel mt.RNA (Lys) mutation is located close to the classic myoclonic epilepsy with ragged-red-fibers mutation, but the patient exhibits neither myoclonic epilepsy nor ragged-red-fibers. The degree of mutant mtDNA heteroplasmy, as determined by a very accurate pyrosequencing assay, varies between 31% (muscle) and 38% (fibroblasts). We discuss a potential effect of the PAX6 mutation on the mtDNA mutation rate.
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PMID:De novo double mutation in PAX6 and mtDNA tRNA(Lys) associated with atypical aniridia and mitochondrial disease. 1703 79

Aniridia consists in a congenital absence of the iris, with incidence varying from 1/64,000 to 1/96,000. This complex embryologic malformation involves the iris, trabecula, and cornea with limbal stem cell deficiency. Aniridia is a genetic haplo-insufficiency expression of the PAX6 gene located on chromosome 11p13. The associated clinical ocular signs could be congenital cataract, congenital glaucoma (the most common complication), keratopathy, ptosis, nystagmus, foveal aplasia, or microphthalmia. More than half of aniridic patients will develop glaucoma, so a regular complete tensional check-up is recommended. Central pachymetry is thicker than in the general population and overestimates ocular pressure if a corrective coefficient is not used. When glaucoma is diagnosed, medical or surgical treatment should be adapted to the child's age. In younger children, trabeculotomy is preferable to trabeculectomy in the first step if the cornea is clear enough. In older children or teenagers, a classical medical treatment must be initiated first, but surgical treatment will often be needed later. Trabeculectomy is the surgical procedure to choose for these older patients or can be combined with cataract surgery in adults. In severe glaucoma, after failure of trabeculectomy with or without mitomycin C, glaucoma surgery with drainage placement could be necessary to control ocular pressure and preserve vision. The outcome of glaucoma in aniridia is always severe and requires medical and surgical treatment adapted from infancy to adulthood.
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PMID:[Glaucoma in aniridia]. 1731 8

PAX6 is a key regulator of eye development and there are many well recognized ophthalmic sequelae of mutations at this locus. The 14 exon PAX6 gene is well conserved across species and phyla. Coding region mutations manifest in a variety of phenotypes. Predicted premature protein truncations are generally associated with classical aniridia. Missense mutations are often found in cases with variant phenotypes such as ectopia pupillae; isolated foveal hypoplasia; nystagmus and hyaloid vessel proliferation. The locus has also been implicated, through a genome-wide sib-pair scan, to be important in the normal variation of myopia. We investigated the association between identified PAX6 mutations and refractive error in Australian patients from four pedigrees. Two of eight subjects with a 1410delC PAX6 mutation had a mean spherical equivalence < -9D, whilst a mean spherical equivalence < or = -5D was recorded in two from four subjects with an Arg240Stop PAX6 mutation and one of two subjects with a Glu93Stop mutation. One individual identified with a Pro346Ala PAX6 mutation had a mean spherical equivalence of +2.8 D. Thus, our observations generally support other incidental findings, that PAX6 mutation, particularly predicted haploinsufficiency, may be associated with extreme refractive error, although the mechanism by which this occurs is not clear.
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PMID:PAX6 mutations may be associated with high myopia. 1789 18

The combination of optical coherence tomography (OCT) and genetic methods along with other clinical diagnostic tools permit the discrimination of infantile nystagmus subtypes with a precision that has not previously been possible. Analysis of specific diseases, such as albinism and achromatopsia as well as known genetic abnormalities, such as FRMD7 and PAX6 mutations, shows subtle but significant differences between nystagmus subtypes using eye movement recordings. In addition, OCT can be used to chart the progression of retinal diseases with age, for example, as has been shown in achromatopsia. OCT can also be used to predict the level of visual deficit due to retinal abnormalities, as demonstrated for albinism. These findings suggest that the classification of all infantile nystagmus into one single entity is premature.
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PMID:Foveal development and nystagmus. 2195 Oct 7


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