Expanding the phenotypic and genotypic spectrum of patients with HGSNAT-related retinopathy.

BACKGROUND: Variants in HGSNAT have historically been associated with syndromic mucopolysaccharidosis type IIIC (MPSIIIC) but more recent studies demonstrate cases of HGSNAT-related non-syndromic retinitis pigmentosa. We describe and expand the genotypic and phenotypic spectrum of this disease. MATERIALS AND METHODS: This is a retrospective, observational, case series of 11 patients with pericentral retinitis pigmentosa due to variants in HGSNAT gene without a syndromic diagnosis of MPSIIIC. We reviewed ophthalmologic data extracted from medical records, genetic testing, color fundus photos, fundus autofluorescence (FAF), and optical coherence tomography (OCT). RESULTS: Of the 11 patients, the mean age was 52 years (range: 26-78). The mean age of ophthalmologic symptoms onset was 45 years (range: 15-72). The visual acuity varied from 20/20 to 20/80 (mean 20/30 median 20/20). We described five novel variants in HGSNAT: c.715del (p.Arg239Alafs *37), c.118 G>A (p.Asp40Asn), c.1218_1220delinsTAT, c.1297A>G (p.Asn433Asp), and c.1726 G>T (p.Gly576*). CONCLUSIONS: HGSNAT has high phenotypic heterogeneity. Data from our cohort showed that all patients who had at least one variant of c.1843 G>A (p.Ala615Thr) presented with the onset of ocular symptoms after the fourth decade of life. The two patients with onset of ocular symptoms before the fourth decade did not carry this variant. This may suggest that c.1843 G>A variant is associated with a later onset of retinopathy.

Laser Therapy in the Treatment of Diabetic Retinopathy and Diabetic Macular Edema.

PURPOSE OF REVIEW: This review highlights indications and evidence on laser therapy in the management of diabetic retinopathy and diabetic macular edema. Particular focus is placed upon the benefits and limitations of conventional laser photocoagulation versus more modern laser photocoagulation techniques, as well as the role of laser photocoagulation in treatment of diabetic retinopathy and diabetic macular edema with the frequent utilization of pharmacologic, including anti-vascular endothelial growth factor (VEGF), therapy. RECENT FINDINGS: Laser photocoagulation remains the gold-standard therapy for the effective, definitive treatment of PDR, and also is highly effective in the management of DME. However, numerous recent studies have demonstrated the clinical efficacy and improved functional and anatomic outcomes of combination therapy with pharmacologic treatment. Continuing innovations in laser technology and improved understanding of laser-retinal interactions and pathophysiology demonstrate that laser therapy will continue to play a critical role in the treatment of diabetic retinopathy and diabetic macular edema for many years to come.

Retinal emboli after cervicopetrous junction internal carotid artery pseudoaneurysm stenting.

PURPOSE: To describe acute and chronic retinal ischemic changes following an internal carotid artery pseudoaneurysm stenting procedure, and to review current evidence for risk factors and management of post-procedural retinal ischemic events. OBSERVATION: A 50-year-old man presented with a 3-month history of pulsatile tinnitus, headache, and intermittent blurry vision. A CT angiogram of head and neck showed bilateral cervicopetrous internal carotid artery (ICA) pseudoaneurysms. The patient underwent successful repair with angioplasty and stenting of the flow-limiting high-grade (>95%) stenosis of his left high cervical ICA. On post-operative day 1, the patient reported monocular vision loss with a large central scotoma. He was found to have a central macular area of retinal whitening and multiple areas of perivascular retinal whitening on exam, concerning for retinal artery occlusions secondary to peri-procedural emboli. Dual antiplatelet therapy was started and a stroke evaluation was performed. Two months later, his visual acuity in the affected eye was counting fingers and his left eye fundus examination was notable for multiple areas of scattered hemorrhages, microaneurysms, and retinal exudates in the distribution of prior retinal ischemia. OCT imaging revealed atrophic changes in the left macula. Subsequently, the patient completed stage-2 repair of the left ICA pseudoaneurysm followed by uncomplicated repair of the right ICA. Four months later, his left eye visual acuity and retinal findings remained stable. CONCLUSIONS AND IMPORTANCE: Post-procedure retinal emboli and ischemia are important, vision threatening possible ocular complications for patients undergoing carotid vascular and endovascular procedures.

Altered phenotype in LMAN1-deficient mice with low levels of residual LMAN1 expression.

Combined deficiency of coagulation factors V and VIII (F5F8D) is an autosomal recessive bleeding disorder caused by loss-of-function mutations in either LMAN1 or MCFD2. The latter genes encode 2 components of a mammalian cargo receptor that facilitates secretion of coagulation factor V (FV) and factor VIII (FVIII) from the endoplasmic reticulum (ER) to the Golgi via coat protein complex II vesicles. F5F8D patients exhibit FV and FVIII levels that are ∼10% to 15% of normal. We report herein a comparative analysis for a series of murine Lman1 alleles. Consistent with previous reports, mice completely deficient in LMAN1 (Lman1-/-) exhibit ∼50% FV and FVIII levels. In contrast, mice carrying a hypomorphic Lman1 allele (Lman1cgt/cgt) that expresses ∼6% to 8% of wild-type Lman1 mRNA levels exhibit intermediate plasma FV and FVIII reductions (∼70% of wild-type levels). Lman1-/- mice exhibit ER accumulation of another LMAN1 cargo, alpha-1 antitrypsin (A1AT), with an intermediate level of A1AT ER retention observed in Lman1cgt/cgt mice. Finally, the previously reported strain-specific, partially penetrant, perinatal lethality of LMAN1-deficient mice (Lman1gt1/gt1) was confirmed in Lman1-/- mice, although it was not observed in Lman1cgt/cgt mice. Taken together, these results show a dose-dependent effect of residual LMAN1 on the secretion of its cargo proteins. The results also suggest that human subjects with hypomorphic LMAN1 mutations might present with mild bleeding phenotypes resulting from more modest reductions in FV and FVIII, which could be missed by routine clinical evaluation. Finally, these findings suggest that therapeutic targeting of LMAN1 to reduce FV and FVIII as an anticoagulant strategy may only require partial inhibition of LMAN1 function.

A Case of Lacrimal Gland Ductal Carcinoma With Regional Lymph Node Metastasis.

Ductal carcinoma of the lacrimal gland is a very rare and aggressive neoplasm, with clinical and histopathologic similarities to salivary ductal carcinoma. Of the 25 previously reported cases, 2 patients had metastases to local lymph nodes confirmed on pathologic examination. The authors now report the clinical presentation, histopathologic and immunohistochemical features, and the treatment of a third patient with lacrimal gland ductal carcinoma with spread to local lymph nodes. In contrast to ductal carcinoma, lymph node involvement has not been reported in the largest series of adenoid cystic carcinoma, a much more common lacrimal gland malignancy. This case highlights the need for possible lymph node surveillance in patients with lacrimal gland ductal carcinoma.

Murine coagulation factor VIII is synthesized in endothelial cells.

The primary cellular source of factor VIII (FVIII) biosynthesis is controversial, with contradictory evidence supporting an endothelial or hepatocyte origin. LMAN1 is a cargo receptor in the early secretory pathway that is responsible for the efficient secretion of factor V (FV) and FVIII to the plasma. Lman1 mutations result in combined deficiency of FV and FVIII, with levels of both factors reduced to ~10% to 15% of normal in human patients. We generated Lman1 conditional knockout mice to characterize the FVIII secretion profiles of endothelial cells and hepatocytes. We demonstrate that endothelial cells are the primary biosynthetic source of murine FVIII and that hepatocytes make no significant contribution to the plasma FVIII pool. Utilizing RiboTag mice and polyribosome immunoprecipitation, we performed endothelial cell-specific messenger RNA isolation and quantitative polymerase chain reaction analyses to confirm that endothelial cells highly express F8 and to explore the heterogeneity of F8 expression in different vascular beds. We demonstrate that endothelial cells from multiple, but not all, tissues contribute to the plasma FVIII pool in the mouse.

Attitudes of Ghanaian women toward genetic testing for sickle cell trait.

OBJECTIVE: To explore the attitudes of Ghanaian women toward genetic testing for the sickle cell trait and to investigate key factors that promote or impede the decision to pursue knowledge of the carrier status. METHODS: A survey, administered in person to Ghanaian women, collected demographic information and information on the participants' knowledge about their carrier status, their attitudes toward genetic testing, and their perceptions of the implications of being a carrier. The results for women who had previously undergone testing and those who had not were compared. RESULTS: Of 124 participants, 75 had been tested for the sickle cell trait and 49 had not. Some 53% of the women who had been tested did not know their carrier status. Most women agreed that getting a prenatal genetic test was important. However, nontested women were more likely to lack the financial resources to undergo testing, to think that testing is futile because sickle cell disease is not curable, and to believe that the outcome of their child's health is determined by God. CONCLUSION: The women tended to have favorable attitudes toward genetic testing, but numerous barriers remained that precluded knowledge of their carrier status or the pursuit of this knowledge.