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]. / 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 .

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.

Topographical arrangements of feline motor cortical projections onto the pretectum.

The projections from motor cortex to pretectum were traced autoradiographically in 15 cats aimed at revealing a topographical arrangement. The anterior sigmoid and rostral coronal gyrus projected amply onto the ventrolateral part of the nucleus pretectalis anterior and to a large part of the ventrocaudal part of the nucleus pretectalis posterior. The posterior sigmoid gyrus rostral to the postcruciate dimple and the caudal part of the coronal gyrus also projected to the nucleus pretectalis anterior. In the posterior pretectal nucleus their target areas were smaller and located more ventromedially. The strongest projections originated from the coronal gyrus.

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.

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.

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.

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.

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 (GrI) and Reis-Bücklers' corneal dystrophy (R-B). One entity?

This paper maintains that Reis-Bücklers' corneal dystrophy and granular corneal dystrophy Groenouw type I are one and the same disease. Included are some of the technically best photographs of Reis-Bücklers' dystrophy found in the literature, and these are compared with photographs from patients with granular corneal dystrophy examined by the author. It is argued that most of the histological and ultrastructural findings on Reis Bücklers' dystrophy described in the literature are either congruent with what is found in granular corneal dystrophy or unspecific.

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.

Inter-familial variability and intra-familial similarities of granular corneal dystrophy Groenouw type I with respect to biomicroscopical appearance and symptomatology.

140 patients from 8 countries with granular corneal dystrophy Groenouw type I are described, and 21 slit-lamp photographs demonstrate inter-familial differences and intra-familial similarities. The clinical appearance varied from mild, with only a few granules on the cornea, to a monstrous course with an almost opaque cornea. The following diagnostic criteria are suggested for the disease, as these signs are described in extensively quoted key references and meet the descriptions in most papers on this subject: Dominant inheritance, as well as 1) typical slit-lamp appearance and/or 2) granules that stain with Masson trichrome histologically, and/or 3) rod-shaped bodies seen electron microscopically.