Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.

Truncating mutations were generally found to cause a more severe phenotype but this correlation was not absolute. Three dimensional facial imaging demonstrated the potential for classifying facial features. Behavioural problems were highly correlated with the level of adaptive functioning, and also included autism. No correlation of behaviour with the type of mutation was found.

Tooth development is under strict genetic control. Oligodontia is defined as the congenital absence of 6 or more permanent teeth, excluding the third molar. The occurrence of non-syndromic oligodontia is poorly understood, but in recent years several cases have been described where a single gene mutation is associated with oligodontia. Several studies have shown that MSX1 and PAX9 play a role in early tooth development. We screened one family with non-syndromic oligodontia for mutations in MSX1 and PAX9. The pedigree showed an autosomal-dominant pattern of inheritance. Direct sequencing and restriction enzyme analysis revealed a novel heterozygous A to G transition mutation in the AUG initiation codon of PAX9 in exon 1 in the affected members of the family. This is the first mutation found in the initiation codon of PAX9, and we suggest that it causes haploinsufficiency.

To determine whether the Diagnosys full-field stimulus threshold (D-FST) is a valid, sensitive and repeatable psychophysical method of measuring and following visual function in low-vision subjects. Fifty-three affected eyes of 42 subjects with severe retinal degenerative diseases (RDDs) were tested with achromatic stimuli on the D-FST. Included were subjects who were either unable to perform a static perimetric field or had non-detectable or sub-microvolt electroretinograms (ERGs). A subset of 21 eyes of 17 subjects was tested on both the D-FST and the FST2, a previous established full-field threshold test. Seven eyes of 7 normal control subjects were tested on both the D-FST and the FST2. Results for the two methods were compared with the Bland–Altman test. On the D-FST, a threshold could successfully be determined for 13 of 14 eyes with light perception (LP) only (median 0.9 ± 1.4 log cd/m2), and all eyes determined to be counting fingers (CF; median 0.3 ± 1.8 log cd/m2). The median full-field threshold for the normal controls was −4.3 ± 0.6 log cd/m2 on the D-FST and −4.8 ± 0.9 log cd/m2 on the FST2. The D-FST offers a commercially available method with a robust psychophysical algorithm and is a useful tool for following visual function in low vision subjects.

IMPORTANCE X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100 000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome.OBJECTIVE To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTSA 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non-X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27).INTERVENTIONS All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURESThe primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence.RESULTS Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log μV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found.CONCLUSIONS AND RELEVANCE Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00100230

During the preparation of the manuscript, the mice in Figure 2 were incorrectly identified as having been infected with S. mansoni. The correct legend for Figure The JCI regrets the error.

No abstract

Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets.