Rafael C. Caruso

Mutations of MYO6 Are Associated with Recessive Deafness, DFNB37

Cosegregation of profound, congenital deafness with markers on chromosome 6q13 in three Pakistani families defines a new recessive deafness locus, DFNB37. Haplotype analyses reveal a 6-cM linkage region, flanked by markers D6S1282 and D6S1031, that includes the gene encoding unconventional myosin VI. In families with recessively inherited deafness, DFNB37, our sequence analyses of MYO6 reveal a frameshift mutation (36-37insT), a nonsense mutation (R1166X), and a missense mutation (E216V). These mutations, along with a previously published missense allele linked to autosomal dominant progressive hearing loss (DFNA22), provide an allelic spectrum that probes the relationship between myosin VI dysfunction and the resulting phenotype.

AMPA/Kainate Antagonist LY293558 Reduces Capsaicin-evoked Hyperalgesia but Not Pain in Normal Skin in Humans

Background Animal studies suggest that [small alpha, Greek]‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid‐kainate (AMPA‐KA) receptors are involved in pain processing. The effects of the competitive AMPA‐KA antagonist LY293558 in two types of experimental pain in human volunteers, brief pain sensations in normal skin, and mechanical allodynia‐pinprick hyperalgesia were studied after the injection of intradermal capsaicin. Methods Brief intravenous infusions of the competitive AMPA‐KA antagonist LY293558 were given to 25 healthy volunteers to examine acute toxicity and analgesic effects. Fifteen volunteers then entered a double‐blinded, three‐period crossover study. In a Phase II study, LY293558 infusions (100% maximally tolerated dose vs. 33% maximally tolerated dose vs. placebo) began 10 min after intradermal injection of 250 [micro sign]g capsaicin in volar forearm. Spontaneous pain, areas of mechanical allodynia and pinprick hyperalgesia, and side effects were determined every 5 min for 60 min. Results The median maximally tolerated dose was 1.3 +/− 0.4 (range, 0.9‐2.0) mg/kg. Tests of cognitive and neurological function were unchanged. Dose‐limiting side effects were hazy vision in 95% of volunteers and sedation in 40%. There were no significant changes in electrical or warm‐cool detection and pain thresholds or heat pain thresholds. LY293558 had little effect on brief pain sensations in normal skin. Both high and low doses of LY293558 significantly reduced pain intensity, pain unpleasantness, and the area in which light brush evoked pain after intradermal capsaicin. There was a trend toward a dose‐response effect of LY293558 on the area in which pinprick evoked pain after intradermal capsaicin, which did not reach statistical significance. Conclusions The authors infer that AMPA‐KA receptor blockade reduces the spinal neuron sensitization that mediates capsaicin‐evoked pain and allodynia. The low incidence of side effects at effective doses of LY293558 suggests that this class of drugs may prove to be useful in clinical pain states.

Clinical Biochemical and Pathologic Correlations in Bietti's Crystalline Dystrophy

We examined three affected members of a Chinese-American family with Biettis crystalline retinopathy. The clinical characteristics of a 24-year-old proband are contrasted to the clinical findings of her grandmother, for whom we have 26 years of follow-up data. Lymphocytes and fibroblasts from a skin biopsy of the grandmother contained crystalline lysosomal material, which supports the diagnosis. Biochemical studies of the crystalline lysosomal material failed to identify the stored compounds but did not show them to be cholesterol or cholesterol ester. Finally, histopathologic studies performed for this condition demonstrated advanced panchorioretinal atrophy, with crystals and complex lipid inclusions seen in choroidal fibroblasts.

Retinal toxicity after high-dose cisplatin therapy.

Because of increasing complaints of visual dysfunction, 13 patients with refractory or recently diagnosed ovarian carcinoma were evaluated for possible cisplatin-induced ophthalmologic toxicity. All patients had received high-dose cisplatin (200 mg/m2 in five divided daily doses) over two to four cycles. Eight patients (62%) developed symptoms of blurred vision and three (23%) also developed altered color perception. Retinal toxicity in the form of cone dysfunction was documented by electroretinography and color vision testing in 11 patients. Three patients were studied prospectively. Two patients who developed cone dysfunction had normal ophthalmologic exams before the initiation of chemotherapy or after one cycle of cisplatin, suggesting a causal relationship between cisplatin therapy and subsequent retinal abnormalities. Though visual acuity improved off therapy, color vision abnormalities persisted as long as 16 months beyond therapy.

Patients with Bardet-Biedl Syndrome Have Hyperleptinemia Suggestive of Leptin Resistance

OBJECTIVE Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls. DESIGN AND METHODS Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype. RESULTS Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations. CONCLUSIONS Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.

Evaluation of Visual Function Following Neodymium:YAG Laser Posterior Capsulotomy

PURPOSE Improvement in visual acuity is the primary endpoint for successful neodymium:YAG (Nd:YAG) laser posterior capsulotomy for posterior capsule opacification. There is limited information on related parameters of visual function that may also improve after laser treatment. The authors evaluate changes in contrast sensitivity and glare disability, aside from visual acuity, following Nd:YAG laser posterior capsulotomy. METHODS Measurements of visual acuity, contrast sensitivity (using the Pelli-Robson chart), and glare disability (using the Brightness Acuity Tester [Mentor O & O, Inc., Norwell, MA]) were obtained from 24 consecutive patients before and after Nd:YAG laser posterior capsulotomy. Glare testing was done with both the Pelli-Robson and Early Treatment Diabetic Retinopathy Study (ETDRS) charts. The degree of glare disability was indicated by the difference between visual function with glare (at medium and high settings) and without glare. Prelaser measurements were taken within 2 weeks prior to treatment, and postlaser measurements were obtained within 3 months after treatment. Only one eye per patient was evaluated. RESULTS Mean differences between prelaser and postlaser measurements were significantly different from zero: (1) Contrast sensitivity, mean difference = 0.24 log units (P < 0.0001); (2) High glare disability using Pelli-Robson chart, mean difference = 0.15 log units (P = 0.004); (3) Visual acuity using ETDRS chart, mean difference = 11 letters (P < 0.0001); 4) High glare disability using ETDRS chart, mean difference = 7 letters (P = 0.005). CONCLUSIONS Using the above methods for visual function testing, Nd:YAG laser capsulotomy is shown to significantly improve visual acuity, contrast sensitivity, and glare disability measurements as compared with prelaser values. The ophthalmologist may find it helpful to document the last two measurements prior to Nd:YAG laser capsulotomy, especially in patients who have good visual acuity but complain of glare sensitivity.

Electroretinographic Findings in the Mucopolysaccharidoses

The degree of retinal involvement of 20 patients (ages 3-21) with mucopolysaccharidosis (MPS) types I, II, and III was assessed using electroretinography (ERG) under standardized conditions. ERG evidence of retinal dysfunction ranged from none to severe in MPS I and II, and from moderate to severe in MPS III. The ERG abnormalities were common to all three types of MPS, and showed the pattern seen in rod-cone degenerations, where the rod-mediated responses are more severely affected than the cone-mediated responses. The ophthalmoscopic signs were less striking than the electrophysiologic findings, and were usually restricted to mild changes of the retinal pigment epithelium.

Phase I Clinical Trial of Alitretinoin and Tamoxifen in Breast Cancer Patients: Toxicity, Pharmacokinetic, and Biomarker Evaluations

PURPOSE To determine the overall and dose-limiting toxicities (DLTs) of alitretinoin (9-cis-retinoic acid) in combination with tamoxifen and the pharmacokinetics of alitretinoin alone and when combined with tamoxifen in patients with metastatic breast cancer. The effect of tamoxifen and alitretinoin on MIB-1, a marker of proliferation, in unaffected breast tissue was explored. PATIENTS AND METHODS Eligible patients had metastatic breast cancer. Previous tamoxifen therapy was allowed. Planned dose levels for alitretinoin ranged from 50 to 140 mg/m2/d with 20 mg/d tamoxifen in all patients after 4 weeks of alitretinoin as a single agent. Plasma concentrations of alitretinoin and retinol were measured at baseline and after 1, 2, and 3 months. Breast core biopsies were obtained at baseline and after 2 months of therapy. RESULTS Twelve patients with metastatic breast cancer received a total of 86 cycles of therapy. At 90 mg/m2/d, three of five patients experienced a DLT: grade 3 headache, grade 3 hypercalcemia, and grade 3 noncardiogenic pulmonary edema. At 70 mg/m2/d, one of six patients experienced a DLT (headache), and this level was considered the maximal tolerated dose in this study. Three toxicities occurred that had not been reported previously with alitretinoin: an asymptomatic delay in dark adaptation, a marked decrease in high-density lipoprotein cholesterol, and the occurrence of enthesopathy. Two of the nine assessable patients had a durable clinical response: one partial response and stable disease for 18 months and one complete response in continuous remission for 48+ months. Both responding patients were estrogen receptor-positive and had had previous tamoxifen therapy. There was a high degree of interpatient variability of plasma alitretinoin concentrations, although a significant decline in alitretinoin plasma levels over time was observed. MIB-1 scores declined in four of the eight paired breast specimens obtained. CONCLUSION The combination of tamoxifen and alitretinoin is well tolerated and has antitumor activity in metastatic breast cancer. The recommended phase II dose is 70 mg/m2/d with 20 mg/d tamoxifen.

Centrifugal Expansion of Fundus Autofluorescence Patterns in Stargardt Disease Over Time

OBJECTIVE To study the longitudinal changes in autofluorescence in Stargardt disease to reveal aspects of disease progression not previously evident. Changes in autofluorescence reflect changing fluorophore compositions of lipofuscin and melanin in retinal pigment epithelial cells, which has been hypothesized to contribute to Stargardt disease pathogenesis. METHODS We examined the temporospatial patterns of fundus autofluorescence with excitation at both 488 nm (standard fundus autofluorescence) and 795 nm (near-infrared autofluorescence) in a longitudinal case series involving 8 eyes of 4 patients (range of follow-up, 11-57 months; mean, 39 months). Image processing was performed to analyze spatial and temporal cross-modality associations. RESULTS Longitudinal fundus autofluorescence imaging of fleck lesions revealed hyperautofluorescent lesions that extended in a centrifugal direction from the fovea with time. Patterns of spread were nonrandom and followed a radial path that left behind a trail of diminishing autofluorescence. Longitudinal near-infrared autofluorescence imaging also demonstrated centrifugal lesion spread but with fewer hyperautofluorescent lesions, suggestive of more transient hyperautofluorescence and more rapid decay at longer wavelengths. Fundus autofluorescence and near-infrared autofluorescence abnormalities were spatially correlated with each other, and together they reflect systematic progressions in fleck distribution and fluorophore composition occurring during the natural history of the disease. CONCLUSIONS Stargardt disease fleck lesions do not evolve randomly in location but instead follow consistent patterns of radial expansion and a systematic decay of autofluorescence that reflect changing lipofuscin and melanin compositions in retinal pigment epithelial cells. These progressive foveal-to-peripheral changes are helpful in elucidating molecular and cellular mechanisms underlying Stargardt disease and may constitute potential outcome measures in clinical trials.

Triple-A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: a case report.

BackgroundTriple-A syndrome (Allgrove syndrome) is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and – occasionally – autonomic instability. Mutations have been found in the AAAS gene on 12q13.Case presentationWe present the case of a 12 year-old boy with classic systemic features of triple-A syndrome and several prominent ophthalmic features, including: accommodative spasm, dry eye, superficial punctate keratopathy, and pupillary hypersensitivity to dilute pilocarpine. MRI showed small lacrimal glands bilaterally. DNA sequencing of PCR-amplified fragments from the 16 exons of the AAAS gene revealed compound heterozygosity for a new, out-of-frame 5-bp deletion in exon 15, c1368-1372delGCTCA, and a previously-described nonsense mutation in exon 9, c938C>T, R286X.ConclusionsIn addition to known ophthalmic manifestations, triple-A syndrome can present with accommodative dysregulation and ocular signs of autonomic dysfunction.