Motor endplate disease affects neuromuscular junction maturation.

Postnatal formation of the neuromuscular synapse requires complex interactions among nerve terminal, muscle fibres and terminal Schwann cells. In motor endplate disease (med) mice, neuromuscular transmission is severely impaired without alteration of axonal conduction and a lethal paralytic phenotype occurs during the postnatal period. The med phenotype appears at a crucial stage of the neuromuscular junction development, corresponding to the increase in terminal Schwann cell number, the elimination of the multiple innervations and the pre- and postsynaptic maturation.

Current concepts in the treatment of retinitis pigmentosa.

Inherited retinal degenerations, including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), affect 1 in 4000 individuals in the general population. A majority of the genes which are mutated in these conditions are expressed in either photoreceptors or the retinal pigment epithelium (RPE). There is considerable variation in the clinical severity of these conditions; the most severe being autosomal recessive LCA, a heterogeneous retinal degenerative disease and the commonest cause of congenital blindness in children.

Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays.

Purpose: Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) cause severe visual impairment early in life. Thus far, mutations in 13 genes have been associated with autosomal recessive LCA and juvenile RP. The purpose of this study was to use homozygosity mapping to identify mutations in known LCA and juvenile RP genes.

Expression of Nav1.6 sodium channels by Schwann cells at neuromuscular junctions: role in the motor endplate disease phenotype.

In addition to their role in action potential generation and fast synaptic transmission in neurons, voltage-dependent sodium channels can also be active in glia. Terminal Schwann cells (TSCs) wrap around the nerve terminal arborization at the neuromuscular junction, which they contribute to shape during development and in the postdenervation processes. Using fluorescent in situ hybridization (FISH), immunofluorescence, and confocal microscopy, we detected the neuronal Nav1.

Symmetrical bilateral lens colobomas in two brothers.

True lens coloboma is a rare developmental disorder usually caused by missing lens zonules in the equatorial area of the lens. Bilateral cases are rare. We report bilateral superonasal lens colobomas in two brothers whose parents are first cousins.

Ocular genetics: current understanding.

Over the past decade, there has been an exponential increase in our knowledge of heritable eye conditions. Coincidentally, our ability to provide accurate genetic diagnoses has allowed appropriate counseling to patients and families. A summary of our current understanding of ocular genetics will prove useful to clinicians, researchers, and students as an introduction to the subject.

Mutation screening of patients with Leber Congenital Amaurosis or the enhanced S-Cone Syndrome reveals a lack of sequence variations in the NRL gene.

Purpose: To determine if mutations in the retinal transcription factor gene NRL are associated with retinopathies other than autosomal dominant retinitis pigmentosa (adRP).

Methods: Genomic DNA was isolated from blood samples obtained from 50 patients with Leber Congenital Amaurosis (LCA), 17 patients with the Enhanced S-Cone Syndrome (ESCS), and a patient with an atypical retinal degeneration that causes photoreceptor rosettes with blue cone opsin. The 5' upstream region (putative promoter), untranslated exon 1, coding exons 2 and 3, and exon-intron boundaries of the NRL gene were analyzed by direct sequencing of the PCR-amplified products.

A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa.

X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP.

Molecular genetics of macular degeneration.

Macular degeneration is a leading cause of blindness that affects the aged population. The complexity of the molecular basis of macular disease is now beginning to be elucidated with the identification of disease-causing genes. For example, mutations in the ABCR gene, (recently identified in cones as well) which codes for retinal rod-specific ABCR protein is responsible for Stargardt macular dystrophy/fundus flavimaculatus, an autosomal recessive macular dystrophy with juvenile onset, which accounts for 7% of human retinal degenerative diseases.

An infant with Turner-Down aneuploidy and massive capillary hemangioma of the orbit: a case report with review.

We report on a case of double aneuploidy involving Down and Turner cell lines in a female child with a massive capillary hemangioma of the left orbit and mild clinical features of Down syndrome. Cytogenetic findings with G-banding revealed mosaicism in her peripheral blood, i.e.

Patient with Bardet-Biedl syndrome presenting with nystagmus at fifteen months of age.

Bardet-Beidl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by dysmorphic distal extremities, obesity, renal abnormalities, hypogenitalism, and varying degrees of mental retardation. Other less common abnormalities are cardiac and hepatic diseases, anal atresia, cerebellar dysfunction, and, in rare cases, nystagmus. This is a report of a child with Bardet-Biedl syndrome who presented at 15 months of age with a horizontal and rotary nystagmus as the initial sign of this disorder.

Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness.

During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of illumination. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal pathways, causing either progressive degeneration or stationary deficits.

Mutations in MKKS cause Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with locus heterogeneity. None of the 'responsible' genes have previously been identified. Some BBS cases (approximately 10%) remain unassigned to the five previously mapped loci.

Mutation analysis of 3 genes in patients with Leber congenital amaurosis.

Objective: To assess the frequency of mutations in the CRX, GUCY2D, and RPE65 genes in patients with Leber congenital amaurosis (LCA).

Patients: One hundred seventy-six probands with a clinical diagnosis of LCA were from 9 countries, with the largest subgroup being 39 probands from India.

Methods: Samples were screened with single-strand conformation polymorphism analysis followed by DNA sequencing of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA.

First African-American child with juvenile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses are among the most common forms of progressive neurodegenerative disease of childhood. They appear to be panethnic, but there is a special predilection of the infantile subtype in Finland. In the United States, the Batten disease registry of 731 cases shows that juvenile neuronal ceroid lipofuscinosis (JNCL) is the most common form.

Novel trabecular meshwork inducible glucocorticoid response mutation in an eight-generation juvenile-onset primary open-angle glaucoma pedigree.

Objective: This study aimed to update a large kindred with juvenile-onset primary open-angle glaucoma (POAG) first described in 1940 and to identify the underlying genetic cause of the disease.

Design: Molecular genetic study of a single kindred, including clinical examination, retrospective review of clinical and family history records, linkage analysis, and mutation screening.

Participants: The retrospective review included 957 members of a single large family.

Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. Two distinct clinical entities of X-linked CSNB have been proposed. Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function.

Evidence for genetic heterogeneity in X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by disturbed or absent night vision; its clinical features may also include myopia, nystagmus, and impaired visual acuity. X-linked CSNB is clinically heterogeneous, and it may also be genetically heterogeneous. We have studied 32 families with X-linked CSNB, including 11 families with the complete form of CSNB and 21 families with the incomplete form of CSNB, to identify genetic-recombination events that would refine the location of the disease genes.

OA1 mutations and deletions in X-linked ocular albinism.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al.

Summary of ocular genetic disorders and inherited systemic conditions with eye findings.

Of the close to 10,000 known inherited disorders that affect humankind, a disproportionately high number affect the eye. The total number of genes responsible for the normal structure, function, and differentiation of the eye is unknown, but the list of these genes is rapidly and constantly growing. The objective of this paper is to provide a current list of mapped and/or cloned human eye genes that are responsible for inherited diseases of the eye.

Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa.

The RPGR (retinitis pigmentosa GTPase regulator) gene for RP3, the most frequent genetic subtype of X-linked retinitis pigmentosa (XLRP), has been shown to be mutated in 10%-15% of European XLRP patients. We have examined the RPGR gene for mutations in a cohort of 80 affected males from apparently unrelated XLRP families, by direct sequencing of the PCR-amplified products from the genomic DNA. Fifteen different putative disease-causing mutations were identified in 17 of the 80 families; these include four nonsense mutations, one missense mutation, six microdeletions, and four intronic-sequence substitutions resulting in splice defects.

Analysis of three deletion breakpoints in Xp21.1 and the further localization of RP3.

The gene responsible for X-linked retinitis pigmentosa (xlRP) in Xp21.1 (RP3) was initially localized by deletion analysis to within a 150- to 170-kb region between the CYBB locus and the proximal deletion junction (BBJPROX) from a patient, BB, who suffered from Duchenne muscular dystrophy (DMD), McLeod syndrome, chronic granulomatous disease (CGD), and xlRP. This gene has recently been isolated and was found to be located outside and 400 kb proximal to the BB deletion.

Characterization of the ocular phenotype of Duchenne and Becker muscular dystrophy.

Purpose: Dystrophin, the Duchenne muscular dystrophy gene product, has been localized to the outer plexiform layer of normal human retina. The purpose of this study is to define completely the ocular phenotype associated with mutations at Xp21, the Duchenne muscular dystrophy gene locus.

Methods: Twenty-one patients with a diagnosis of Duchenne muscular dystrophy and five patients with Becker muscular dystrophy had ophthalmologic examinations, including electroretinograms (ERGs).