Electronegative electroretinogram in mucolipidosis IV.

OBJECTIVE: To demonstrate the progression of electroretinographic (ERG) findings in mucolipidosis IV. METHODS: Two patients with mucolipidosis IV were examined clinically and their condition was followed up for ophthalmic manifestations of the disease. Electroretinograms were performed on both patients, and conjunctival biopsy specimens were analyzed for characteristic ultrastructural inclusion bodies using light and electron microscopy. Genomic DNA isolated from peripheral blood was screened for 2 major founder mutations in the ML4 gene using polymerase chain reaction and restriction fragment length polymorphism analyses. Haplotypes were confirmed by automated sequencing of polymerase chain reaction products. RESULTS: In patient 1, an ERG obtained at 12 months of age showed mildly subnormal amplitude of rod-mediated and cone-mediated responses and significantly prolonged rod and cone b-wave implicit times. An ERG obtained when the patient was 6.6 years old disclosed marked progression with greater loss of b-wave than a-wave responses to rod-and-cone-mediated activity. Scotopic ERG at the highest intensity was electronegative in configuration. In patient 2, ERG showed minimal rod-mediated responses, severely subnormal cone-mediated responses, and prolonged cone b-wave implicit times. Again, electronegative configuration of the scotopic bright flash response indicated greater disturbance of b-wave generators. CONCLUSIONS: Novel ERG findings in 2 cases of mucolipidosis IV are reported with associated clinical courses, histopathologic abnormality, and genetic studies. In both cases ERGs demonstrate an electronegative configuration, suggesting that the primary retinal disturbance in mucolipidosis IV may occur at or proximal to the photoreceptor terminals.

Electroretinographic findings in patients with Stargardt disease and fundus flavimaculatus.

PURPOSE: To characterize the clinical and electroretinogram (ERG) features of our cohort of patients with Stargardt disease (STGD) exhibiting coding sequence variations in the ABCA4 gene. METHODS: Review of 76 patients with the clinical diagnosis of Stargardt disease/fundus flavimaculatus (STGD/FF) from the University of Iowa Department of Ophthalmology and Visual Sciences (41 patients) and the Casey Eye Institute (35 patients). Clinical examination, Goldmann perimetry, and electroretinography were performed on all 76 patients. Patients were divided into three groups on the basis of their funduscopic and electroretinographic features: (1) a normal ERG by the standards of the laboratory; (2) minimal rod or cone abnormalities; (3) severe ERG dysfunction. The latter category was further subdivided on the basis of a cone-dominated loss of function (C > R or "cone-rod dystrophy") or diffuse depression of rods and cones (C = R). Mutational analysis of the coding sequence of the ABCA4 gene was performed by single strand conformation polymorphism analysis followed by automated DNA sequencing. Each electroretinographic group was analyzed for the presence of disease causing changes using exact tests of binomial proportions corrected for multiple comparisons by Bonferroni method. Quantitative polymerase chain reaction (QPCR) was performed on patients who were homozygous for disease causing changes in the ABCA4 gene to rule out the possibility of deletions. RESULTS: Overall, 56 of 76 patients (and 77 of 152 alleles) exhibited coding sequence variations that were compatible with high-penetrance disease-causing mutations. The most common of these were His423Arg (9), frameshift mutations (7), Ala1038Val (7), and Pro1380Leu (6). Although no patients with His423Arg presented with normal ERGs, no significant correlation was observed between specific sequence variations and the electroretinographic characteristics or fundus appearance. However, a significantly greater fraction of patients with normal ERG studies failed to exhibit detectable disease-causing coding sequence variations in the ABCA4 gene identified on either allele (P = 0.0006). CONCLUSION: STGD/FF patients in our cohort exhibit a wide range of electroretinographic abnormalities, some of which are more prevalent than previously suspected. No direct correlation between clinical appearance, electrophysiologic characteristics and specific ABCA4 alleles could be identified, although a significantly lower number of our cohort with a normal ERG exhibited detectable coding sequence variations in the ABCA4 gene. However, four patients with ERG dysfunction were homozygous for a His423Arg change proven by QPCR not to be an artifact of a deletion. The presence of electrophysiologic dysfunction is not uncommon in our cohort of patients with STGD. Thus, the ERG provides clinically important information of retinal function for STGD/FF and, as such, is still indicated as part of the evaluation of these patients.

Clinical phenotype as a prognostic factor in Stargardt disease.

PURPOSE: To determine the prognostic significance of widespread flecks, described as fundus flavimaculatus, in patients with Stargardt disease. DESIGN: Historical cohort study. SUBJECTS AND METHODS: Patients with Stargardt disease were identified by searching preexisting databases at the University of Iowa and Oregon Health Sciences University. The medical records of these patients were evaluated for the validity of the diagnosis, initial and final visual acuity, length of follow-up, and initial and final phenotype. Phenotype was graded as I, II, or III on the basis of the distribution of flecks and the extent of atrophy. The relationship between final visual acuity and final clinical appearance (phenotype I versus II versus III) was evaluated controlling for length of follow-up and age using a Cochran-Mantel-Haenszel test. The clinical progression of visual acuity loss for each phenotype was analyzed using life tables and Kaplan-Meier survival analysis for age and length of follow-up effects. RESULTS: A total of 214 patients were confirmed to have Stargardt disease; 131 patients were seen at multiple visits. Eighty-two patients were identified with phenotype I, 62 with phenotype II, and 70 with phenotype III. The final visual outcome was significantly better for patients whose ophthalmoscopic abnormalities were limited to the macula (phenotype I): 80 of 82 patients with phenotype I (97.6%) maintained 20/200 or better visual acuity in at least one eye as compared to 40/62 (64.5%) patients with phenotype II and 13/70 (18.6%) patients with phenotype III (P < 0.0001). Survival analysis showed a similarly significant difference in the survival probabilities (likelihood of maintaining 20/200 or better vision) for the three phenotypes considered over age and over follow-up length (P < 0.0001), with phenotypes II and III demonstrating significantly more deterioration in vision over time. CONCLUSIONS: The presence of midperipheral flecks, especially early in life, carries a poorer visual prognosis for patients with Stargardt disease than when disease is limited to the macula. The development of midperipheral flecks is an indicator of more extensive fundus involvement and thus poorer long-term visual prognosis.