IC3D classification of corneal dystrophies.

The International Committee for Classification of Corneal Dystrophies (IC3D) has provided an update of our knowledge on corneal dystrophies. This chapter gives the summary of clinical findings, onset, course, genetics, nosology, light and electron microscopy as well as immunohistochemistry for 25 different entities included as corneal dystrophies in this survey. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy.

[The IC3D classification of the corneal dystrophies]. / IC3D-Klassifikation von Hornhautdystrophien.

BACKGROUND: The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE: The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS: The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS: This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS: The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d .

Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

The IC3D classification of the corneal dystrophies.

BACKGROUND: The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE: The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS: The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS: This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS: The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d.

Ophthalmic manifestations of congenital disorder of glycosylation type 1a.

PURPOSE: To present the ophthalmic manifestations of patients with congenital disorder of glycosylation type Ia (CDG-Ia) due to the frequent R141H/F119L PMM2 genotype. METHODS: Ophthalmic records of 23 patients (age: 10 months to 20 years) were evaluated. They had had at least one ophthalmic reexamination. RESULTS: Measurements of refractive error showed that 18 patients were myopic, two were hypermetropic, and three could not be measured. Serial measurements in 12 patients indicated a progression towards myopia of 0.80 diopters (D) per year. Congenital esotropia and delayed visual maturation (DVM) were consistent findings. Two children developed good visual acuity (VA), 16 had low vision, and five were legally blind. Pallor of the optic disc was noted in five patients. Electroretinography (ERG) performed in nine patients showed reduced rod responses, while cone responses were only slightly reduced. CONCLUSIONS: The present study illustrates the difficulties in examining severely disabled children. Consistent ophthalmic manifestations of CDG-Ia patients due to the R141H/F119L genotype were congenital esotropia, DVM, and a reduced rod response in ERG-examined patients. The vast majority of patients had reduced VA and developed myopia. We speculate that there is a relationship between the glycosylation defect in CDG-Ia and the development of myopia. We recommend that CDG-Ia patients be followed annually by an ophthalmologist.

Recurrent ophthalmoplegia in childhood: diagnostic and etiologic considerations.

We present two patients with recurrent painful ophthalmoplegia starting in early childhood. Clinically, both patients fulfilled the criteria for ophthalmoplegic migraine. In one case, magnetic resonance investigations were performed following the second attack, between the third and fourth and during the fourth attack. The left third cranial nerve was significantly thickened in its course from the brainstem through the prepontine cistern to the cavernous sinus during the attacks and moderately thickened between the attacks. In the second case, magnetic resonance imaging was performed during the 14th attack, when the oculomotor nerve dysfunction was almost permanent, and the imaging demonstrated a swollen oculomotor nerve. Whether these findings are pathognomonic of ophthalmoplegic migraine awaits further reports using magnetic resonance imaging in infants showing recurrent painful ophthalmoplegia of early onset.

An unusual presentation of Smith-Magenis syndrome with iris dysgenesis.

A boy who presented with iris dysgenesis is described. He was shown to have Smith-Magenis syndrome with a deletion of 17p11.2.

Assignment of granular corneal dystrophy Groenouw type I (CDGG1) to chromosome 5q.

Granular corneal dystrophy Groenouw type I (CDGG1) is an autosomal dominant disease with complete penetrance. 124 blood samples were collected from a single Danish pedigree of seven generations. Linkage was discovered with markers on chromosome 5q, with IL9 (Z = 15.96; theta M = 0.027, theta F = 0.00) and D5S436 (Z = 11.75; theta M = 0.00, theta F = 0.081) flanking the disease locus most closely. The marker IL9 is located in the region 5q22-q32. By multilocus linkage analysis the most likely position of CDGG1 among 9 markers was: D5S396-IL9-CDGG1-D5S436-D5S210/D5S207++ +-D5S434-D5S119-D5S211 and CDGG1-D5S402-D5S434. In each of two independent small pedigrees, in which a milder form of CDGG1 occurs, the disease gene was also linked to IL9 (Z = 3.02 at theta = 0.0 in males and females); i.e. the severe and the milder forms may be allelic.

Immunoglobulins in granular corneal dystrophy Groenouw type I.

Three patients with granular corneal dystrophy Groenouw type I underwent corneal grafting, and cryostat sections of the corneal buttons were examined immunohistochemically for immunoglobulins. Positive results were obtained for IgG, Kappa-, and Lambda chains with immunofluorescence technique. The reactions were seen exclusively in the same localizations as the Masson trichrome positive deposits.

Differential diagnosis between granular corneal dystrophy Groenouw type I and paraproteinemic crystalline keratopathy.

A case of corneal opacities in a leukemic patient with an M-component in the serum proteins is presented, and a comparison is made to patients with granular corneal dystrophy Groenouw type I. The corneal deposits associated with the two conditions may appear identical with slit-lamp biomicroscopy. Granular dystrophy patients, however, show a normal serum immunoglobulin pattern in contrast to patients with paraproteinemic crystalline keratopathy. The two entities can therefore be distinguished from each other by a serum electrophoresis.

Granular corneal dystrophy Groenouw type I. Clinical aspects and treatment.

The paper describes the comparatively benign nature of granular corneal dystrophy Groenouw type I and the results of treatment of the disease. 71 patients with a classic clinical appearance comprised the largest pedigree in medical literature. The disorder was confined to the eyes only. Visual acuity was close to normal in children; the children had small, superficial, corneal opacities, often arranged in lines, and for the most part with a smooth exterior surface when examined with Javal keratometry. In adult patients visual acuity was around 0.5, the exterior surface uneven, the corneal opacities larger, and distributed superficially as well as deeper in the corneal stroma. In elderly patients visual acuity was between 0.5 and 0.1 and they all had additional cataract. Fourteen patients were treated with corneal grafting during the past 15 years and all grafts remained clear.

Granular corneal dystrophy Groenouw type I. 115 Danish patients. An epidemiological and genetic population study.

An epidemiological and genetic study in Denmark of granular corneal dystrophy Groenouw type I is described. Ninety-one living patients were found. The disease is inherited as an autosomal dominant trait with a 100% penetrance of the gene. The 91 cases could be traced back to 6 different mutations. The mutation rate was estimated to be about 0.3/1,000,000; the possible sources of error of this estimate are discussed. The age distribution of the patients is shown to be similar to that of the Danish population in general.

Granular corneal dystrophy Groenouw type I. A report of a probable homozygous patient.

A case of severe granular corneal dystrophy is described. The patient, who is most probably homozygous for the dominantly inherited dystrophy gene, is the product of a first cousin marriage with both parents mildly affected by the same dystrophy. The case report describes an early onset and a severe course with two grafts in each eye before the age of 17. Pictures of the clinical appearance, histology and transmission electronmicroscopy are shown.

Dystrophy: a revised definition.

Dystrophy is defined as the process and consequences of hereditary progressive affections of specific cells in one or more tissues that initially show a normal function. The term abiotrophy was previously applied to these lesions, but has gone out of use. Degeneration is an equivocal term used for both acquired and hereditary disorders. Aging may or may not be considered as dystrophy. Dysplasias or dyshistogeneses are different from dystrophies. Dyshistogenetic tissues present with abnormal structure and function at birth in contrast to dystrophies, which are genetically programmed for later onset.