Gerhard W. Cibis

Retinal signal transmission in Duchenne muscular dystrophy: evidence for dysfunction in the photoreceptor/depolarizing bipolar cell pathway.

There have been reports of abnormal retinal neurotransmission determined by electroretinography in boys with Duchenne and Becker muscular dystrophy. Dystrophin may play a role in transmitting signals between photoreceptors and the excitatory synapse of the ON-bipolar cell. These electroretinographic changes appeared to be limited to the rod ON-pathway but we felt there was also similar abnormality in the cone ON-pathway. We used long-duration stimuli to separate ON-(depolarizing bipolar cell) and OFF (hyperpolarizing bipolar cell) contributions to the cone-dominated ERG to better understand how the retina functions in boys with Duchenne muscular dystrophy. We recorded the electroretinograms of 11 boys with Duchenne muscular dystrophy and found abnormal signal transmission at the level of the photoreceptor and ON-bipolar cell in both the rod and cone generated responses. The OFF-bipolar cell that responds to the offset of the stimulus continues to function normally. The results support our hypothesis that retinal dystrophin plays a role in receptor function or controlling ion channels at the level of the photoreceptor and depolarizing bipolar cell.

A DELETION POLYMORPHISM DUE TO ALU-ALU RECOMBINATION IN INTRON 2 OF THE RETINOBLASTOMA GENE : ASSOCIATION WITH HUMAN GLIOMAS

The retinoblastoma gene (RB) encodes a tumor suppressor that is inactivated in a number of different types of cancer. We searched for gross alterations of this gene in tumors of the central nervous system by using Southern blot hybridization. A common alteration was found in several tumors and was mapped to the region around exon 2. Nucleotide sequencing showed that the alteration was caused by a 799‐bp deletion in intron 2 of the RB gene and was probably due to homologous recombination between two Alu repeats. Deletions of this type have not been found previously in the RB gene. The deletion turned out to be a polymorphism with an allele frequency estimated at 2.2% in 185 patients without cancer. The deletion was foud in five of 48 patients with brain tumors (allele frequency of 5.2%). This difference is not statistically significant (P = 0.149, Fishers exact test). Confining the analysis only to glioma brain tumors revealed a statistically significant difference compared with the cancer‐free patient controls (P = 0.027, Fishers exact test). Further study is needed to determine if the deletion is a weak brain cancer–predisposing mutation or a harmless polymorphism. Finding this mutation in a tumor and the germline DNA of a retinoblastoma patient could lead to incorrect estimation of the heritability of a tumor. Mol. Carcinog. 19:69–73, 1997.

Electroretinography is necessary for spasmus nutans diagnosis

The purpose of the present study was to determine whether that which clinically appeared to be spasmus nutans could actually represent retinal sensory deficits diagnosable by electroretinography. Eight patients clinically thought to have spasmus nutans underwent electroretinography according to international standards. Five had normal electroretinograms and represented cases of true spasmus nutans. Three patients had abnormal electroretinograms, indicating that they did not have spasmus nutans. The clinical findings used to diagnose spasmus nutans can be simulated by retinal dystrophies. A normal electroretinogram is needed to confirm the diagnosis of spasmus nutans.

ERG phenotype of a dystrophin mutation in heterozygous female carriers of Duchenne muscular dystrophy

PURPOSE Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD). DMD is associated with an abnormal electroretinogram (ERG) if the mutation disrupts the translation of retinal dystrophin (Dp260). Our aim was to determine if incomplete ERG abnormalities would be associated with heterozygous carriers of dystrophin gene mutations. METHODS Ganzfeld ERGs were obtained under scotopic and photopic testing conditions from a family which includes the heterozygous maternal grandmother, the heterozygous mother, and her children, two affected boys and dizygotic twin sibs, an unaffected male and heterozygous female. Southern blot analyses were done to characterise the dystrophin mutation. RESULTS The dystrophin gene was found to contain a deletion encompassing exon 50. The ERGs in the two affected boys were abnormal, consistent with the DMD ERG phenotype. Serial ERGs of the heterozygous females were abnormal; however, they were less severely affected than the DMD boys. The ERG of the female sib showed a greater abnormality than her mother and maternal grandmother. The unaffected twin had a normal ERG. CONCLUSIONS The ERG shows abnormalities associated with carrier status in this family with a single exon deletion. A large study of confirmed obligate carriers is planned to clarify further the value of the ERG in detecting female heterozygous carriers of dystrophin gene mutations.

The Value of Flash Visual Evoked Potentials in Albinism

In albinism, the majority of temporal retinal fibers serving the nasal visual field cross at the chiasm and project to the contralateral hemisphere. This misrouting is seen in hemispheric asymmetries present in the visual evoked potential (VEP). Misrouting of retinal fibers was also thought to occur in dissociated vertical deviation, Prader-Willi syndrome, and perhaps carrier states of albinism. However, recent literature is reaching the conclusion we have drawn in our laboratory: only albinism shows VEP hemispheric asymmetries that reverse when the other eye is stimulated. Use of different stimuli, recording conditions, and response criteria among investigators has created some confusion in differentiating what constitutes asymmetry. We conclude that use of a diffuse flash stimulus and a bipolar electrode derivation that compares differences between the left and right occipital hemispheres will clearly differentiate albinism from all other conditions, making it especially useful in a pediatric population.

Surgical Removal of Congenital Pupillary-lris-Lens Membrane

A pupillary membrane in a case of congenital pupillary-iris-lens membrane with goniodysgenesis was surgically peeled from the lens without causing cataract formation. Histopathology revealed ectopic iris. The ectopic iris found in this condition differentiates congenital pupillary-iris-lens membrane with goniodysgenesis as an entity from persistent pupillary membrane, hereditary goniodysgenesis, and Riegers anomaly. We suggest that congenital pupillary-iris-lens membrane with goniodysgenesis is a neurocristopathy. The finding of ectopic iris muscle is consistent with avian chimera experiments that have suggested that iris sphincter muscle is derived from the neural crest, not neural ectoderm. Membranes in this condition can be successfully removed when they cause vision loss and amblyopia.

Bilateral Choroidal Neonatal Neuroblastoma

We treated a bilateral, well-differentiated neuroblastoma of the choroid in a patient who had congenital abdominal neuroblastoma. Although orbital metastasis of neuroblastoma is common, intraocular metastasis is not. In our patient, there was no amplification of the N-myc oncogene in the tumor of either eye. This is consistent with early-stage primary neuroblastoma. Histologically, the tumors were identical in each eye and well differentiated with Homer Wright rosettes; most neuroblastoma metastases have few rosettes and are composed of more undifferentiated, anaplastic cells. We believe that our patient had bilateral primary tumors and not metastatic tumors.

Autosomal dominant inheritance of a negative electroretinogram phenotype in three generations.

PURPOSE We report an abnormal electroretinogram with a negative configuration in a child who presented with moderate myopia, nystagmus, and visual developmental delay. We investigated the electroretinogram and explored the possibility of a metabotropic glutamate receptor subtype 6 mutation in six family members spanning four generations. METHODS Case report and family study: Complete eye examinations and Ganzfeld electroretinograms were recorded from the maternal great-grandmother, maternal grandmother, mother, uncle, and sibling of the 7-month-old female proband. The electroretinogram was repeated in the proband at 17 months of age. Dark adaptometry was performed in all adult subjects. Fundus photographs and visual field examinations were administered to the grandmother and mother. The metabotropic glutamate receptor subtype 6 gene was amplified and sequenced in all affected subjects. RESULTS The proband had a negative electroretinogram and a normal fundus. The maternal grandmother, uncle, and mother had an abnormal electroretinogram identical to the proband yet had no visual complaints. The ophthalmology examinations in the adult subjects were normal, and subsequent examination of the proband at 17 months, 5 years, and 6.5 years of age showed no changes in the fundus or refractive error. Her nystagmus resolved by 5 years of age. Rod threshold and visual fields were normal in the affected adult subjects. No mutation in the metabotropic glutamate receptor subtype 6 gene was found. CONCLUSIONS In this family, a negative electroretinogram was not associated with decreased rod threshold, visual acuity loss, visual field loss, muscle disease, or metabotropic glutamate receptor subtype 6 mutation. Additional study will be required to understand the nature of the negative electroretinogram phenotype in this family.

Amblyopia in unilateral congenital ptosis: early detection by sweep visual evoked potential

Abstract•Background: Fixation preference assessment is a clinical tool widely used to determine amblyopia in young infants and children. It is our clinical experience that this tool underestimates amblyopia. The purpose of this study was to compare the results of sweep visual evoked potentials to fixation preference assessment in cases of unilateral ptosis. • Methods: Sweep visual evoked potentials were performed in 17 children with unilateral ptosis thought to have equal acuity by fixation preference asessment. Binocular and monocular sweep visual evoked potentials were recorded to square-wave gratings of 80% contrast counterphase modulated at 6 Hz. A range of spatial frequencies from 1 to 30 cycles per degree were presented over a 10-s period. Resolution acuity was determined as the zero-microvolt intercept of linear regression analysis on the visual evoked potential amplitude versus spatial frequency. • Results: Nine of the 17 children had interocular resolution acuity differences ranging from 0.8 to 2 octaves by sweep visual evoked potential testing. This correlates to a Snellen equivalent interocular difference of 2 to 7 lines and clinical amblyopia. • Conclusion: This study confirms our clinical impression that children who are unable to preform recognition acuity tasks and are thought to have equal vision by fixation preference assessment often have 2 or more lines of Snellen acuity difference (amblyopia) when they are finally old enough to be tested by Snellen methods. It also implies that amblyopia precedes refractive errors and strabismus in unilateral ptosis cases. Clinical methods to determine amblyopia other than fixation preference assessment need to be explored with a view to earlier detection, better definition and treatment of amblyopia.

Familial Total Ophthalmoplegia With Iris Transillumination (a Neurocristopathy)

A family with total (internal and external) ophthalmoplegia had associated iris transillumination. No abnormal visual-evoked response brain lateralization indicative of albinism was found. On the basis of avian chimera experiments showing iris muscles to be derived from neural crest cells, we proposed a neurocristopathic theory to explain all clinical findings in this family.