A novel rhodopsin point mutation, proline-170-histidine, associated with sectoral retinitis pigmentosa.

Identification and classification of all retinitis pigmentosa (RP) causing mutations contribute to a better understanding of disease variants. In this report we describe a New Zealand family, of European heritage, affected by a sectoral type RP phenotype in association with a novel rhodopsin mutation (proline-170-histidine) in a highly conserved site.

Transient retinal effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA, ASA404), an antitumor vascular-disrupting agent in phase I clinical trials.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer vascular-disrupting agent, has induced transient visual symptoms in some patients. Exploratory investigations were undertaken to characterize the visual disturbances in two consecutive phase I trials. METHODS: Assessments were made in 21 patients before and immediately after a 20-minute IV infusion of DMXAA, including visual acuity, funduscopy, color discrimination, pattern electroretinography (PERG), pattern visual-evoked potentials (VEP), and full-field electroretinography (ERG). Evaluation of late effects was undertaken subsequently in 12 patients before and after 6 weeks of IV DMXAA at one dose per week. RESULTS: Frequency and intensity of transient visual disturbance increased with DMXAA dose, occurring in two thirds of patients at 3000 mg x m(-2). Symptoms included blurring, flickering, fragmentation, alteration of colors, and contrast and mild photosensitivity, starting during the infusion and resolving completely, usually within 60 minutes. Visual acuity was unchanged but color discrimination was perturbed. Dose-dependent increases in PERG P50 implicit time by up to 23 ms returned toward baseline values within 90 minutes. Prominent transient changes on ERG included prolonged scotopic rod and 30-Hz flicker implicit times and reduced 30-Hz flicker amplitude. In the second trial, no clinically significant sustained effects were detected, although an increase in bright flash a-wave implicit time (P = 0.022) was seen on whole-group analysis. In vitro studies showed nonspecific phosphodiesterase inhibition by DMXAA. CONCLUSIONS: DMXAA induced acute, transient disturbance of retinal activity consistent with phosphodiesterase inhibition. No clinically significant cumulative effects were noted and most effects occurred at doses higher than those used in ongoing clinical trials (ClinicalTrials.gov numbers, NCT00856336, NCT00863733, and NCT00003697).

Reversible optic neuropathy due to metronidazole.

Metronidazole is a little known cause of drug-induced optic neuropathy. We report a patient who developed progressive visual loss after an 8-month course of Metronidazole. Electrophysiology confirmed a bilateral optic neuropathy. Her vision improved dramatically with cessation of the drug.

Photodynamic therapy with verteporfin for choroidal neovascularization due to age-related macular degeneration and other causes: a New Zealand outcomes study.

PURPOSE: To assess the efficacy and safety of photodynamic therapy (PDT) for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and other conditions by analysing visual acuity changes. METHODS: A retrospective review of patients treated with PDT was conducted. CNV was confirmed on fluorescein angiography. Visual acuity outcomes were recorded at 3-monthly intervals to a maximum of 48 months. The primary outcome measure was the proportion of patients avoiding moderate visual loss (losing less than three lines of visual acuity relative to baseline) at 12 months. RESULTS: A total of 343 patients receiving PDT were followed up for a mean of 14.9 months. Two hundred and eighty-five (83%) patients presented with CNV due to AMD and 58 patients (17%) due to other causes. Seventy per cent of patients with CNV secondary to AMD avoided moderate visual loss at both 12 and 24 months. Secondary outcomes (including mean change in visual acuity, proportion of patients with stable or improved vision and proportion of patients with severe vision loss) also compared favourably with the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Investigation. Of patients with CNV secondary to causes other than AMD, 76% avoided moderate visual loss at both 12 and 24 months. The safety profile identified one severe adverse reaction, with development of a serous pigment epithelial detachment and subsequent rip. CONCLUSION: The results of this present retrospective, open-label, clinical practice study in New Zealand are consistent with the findings of multicentre randomized, placebo-controlled trials and confirm the treatment benefit of PDT in a clinical setting.

Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial.

OBJECTIVES: To assess the efficacy and cost effectiveness of a home safety programme and a home exercise programme to reduce falls and injuries in older people with low vision. DESIGN: Randomised controlled trial. SETTING: Dunedin and Auckland, New Zealand. PARTICIPANTS: 391 women and men aged > or =75 with visual acuity of 6/24 or worse who were living in the community; 92% (361 of 391) completed one year of follow-up. INTERVENTIONS: Participants received a home safety assessment and modification programme delivered by an occupational therapist (n = 100), an exercise programme prescribed at home by a physiotherapist plus vitamin D supplementation (n = 97), both interventions (n = 98), or social visits (n = 96). MAIN OUTCOME MEASURES: Numbers of falls and injuries resulting from falls, costs of implementing the home safety programme. RESULTS: Fewer falls occurred in the group randomised to the home safety programme but not in the exercise programme (incidence rate ratios 0.59 (95% confidence interval 0.42 to 0.83) and 1.15 (0.82 to 1.61), respectively). However, within the exercise programme, stricter adherence was associated with fewer falls (P = 0.001). A conservative analysis showed neither intervention was effective in reducing injuries from falls. Delivering the home safety programme cost NZ650 dollars (234 pounds sterling, 344 euros, US432 dollars) (at 2004 prices) per fall prevented. CONCLUSION: The home safety programme reduced falls and was more cost effective than an exercise programme in this group of elderly people with poor vision. The Otago exercise programme with vitamin D supplementation was not effective in reducing falls or injuries in this group, possibly due to low levels of adherence. Trial registration number ISRCTN15342873.

A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation.

Light stimuli produce graded hyperpolarizations of the photoreceptor plasma membrane and an associated decrease in a voltagegated calcium channel conductance that mediates release of glutamate neurotransmitter. The Ca(v)1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the poreforming subunit of the Ca(v)1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2). The molecular mechanism of the pathology underlying the CSNB2 phenotype remains to be established. Recent clinical investigations of a New Zealand family found a severe visual disorder that has some clinical similarities to, but is clearly distinct from, CSNB2. Here, we report investigations into the molecular mechanism of the pathology of this condition. Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745. The I745T CACNA1F allele produced a remarkable approximately -30-mV shift in the voltage dependence of Ca(v)1.4 channel activation and significantly slower inactivation kinetics in an expression system. These findings imply that substitution of this wild-type residue in transmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Ca(v)1.4 channel activity is likely to cause the unusual phenotype.

Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2.

PURPOSE: To describe the phenotype in a New Zealand family with an unusual severe X-linked retinal disorder with a novel I745T mutation in CACNA1F, the gene responsible for incomplete congenital stationary night blindness (CSNB2). METHODS: Members of the family tree were invited for clinical, psychophysical and electrodiagnostic evaluation. RESULTS: Male family members had severe non-progressive visual impairment, abnormal colour vision, congenital nystagmus, hyperopia and normal fundi. Some were intellectually disabled. Female family members had congenital nystagmus and decreased visual acuity frequently associated with high myopia. Electroretinograms (ERG) identified reduced rod and cone responses with negative waveform in male and female family members, with atypical features for CSNB2. CONCLUSIONS: Although there were similarities to CSNB2, distinctive features in male family members included severity of phenotype, and association of intellectual disability. Moreover, all female heterozygotes had clinical and ERG abnormalities. CACNA1F encodes the Ca(v)1.4 alpha1 subunit of a voltage-gated calcium channel, which may mediate neurotransmitter release from photoreceptors. Molecular analyses, reported separately, identified a novel I745T CACNA1F mutation that was associated in vitro with major alterations in gating and kinetics of the Ca(v)1.4 channel. It is speculated that the unique phenotype described in this family may reflect similarly altered function of Ca(v)1.4 channel activity in vivo.