Showing papers by "Byron L. Lam published in 2011"

Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa

Abstract: Increasingly, mutations in genes causing Mendelian disease will be supported by individual and small families only; however, exome sequencing studies have thus far focused on syndromic phenotypes characterized by low locus heterogeneity. In contrast, retinitis pigmentosa (RP) is caused by >50 known genes, which still explain only half of the clinical cases. In a single, one-generation, nonsyndromic RP family, we have identified a gene, dehydrodolichol diphosphate synthase (DHDDS), demonstrating the power of combining whole-exome sequencing with rapid in vivo studies. DHDDS is a highly conserved essential enzyme for dolichol synthesis, permitting global N-linked glycosylation. Zebrafish studies showed virtually identical photoreceptor defects as observed with N-linked glycosylation-interfering mutations in the light-sensing protein rhodopsin. The identified Lys42Glu variant likely arose from an ancestral founder, because eight of the nine identified alleles in 27,174 control chromosomes were of confirmed Ashkenazi Jewish ethnicity. These findings demonstrate the power of exome sequencing linked to functional studies when faced with challenging study designs and, importantly, link RP to the pathways of N-linked glycosylation, which promise new avenues for therapeutic interventions.

Impact of rituximab on relapse rate and disability in neuromyelitis optica

Abstract: Background: Neuromyelitis optica (NMO) is a severe demyelinating disease often leading to serious disability. Accumulating evidence now implicates humoral mechanisms in its pathogenesis. In the absence of an approved therapy, anti-inflammatory/immunosuppressant drugs have been used empirically for more than three decades. Recent evidence for a role of antibody to aquaporin-4 in the pathogenesis of NMO has led to the use of rituximab, a monoclonal antibody targeting the CD20 epitope on the entire B cell lineage.Objectives: To evaluate the impact of rituximab on the relapse rate and disability in NMO.Methods: This is an IRB approved retrospective longitudinal study of NMO patients treated with rituximab.Results: We identified 53 patients with NMO, 23 of whom had been treated with rituximab. These patients (2 males, 21 females) had a mean age of 37.1 ± 14.6 years at the time of diagnosis. Eight of the 23 treated with rituximab were treatment naive. All 23 were scheduled to receive infusions every six or 12 m...

Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients.

Abstract: Purpose:To report 11 cases of autosomal recessive vitelliform macular dystrophy and to compare their molecular findings and phenotypic characteristics with those of patients with the more common and well-described dominant form of the disease.Methods:Blood samples were obtained from 435 unrelated in

Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome.

Abstract: Objective To investigate whether mutations in NPHP5 can cause Leber congenital amaurosis (LCA) without early-onset renal disease. Methods DNA samples from 276 individuals with nonsyndromic LCA were screened for variations in the NPHP5 gene. Each had been previously screened for mutations in 8 known LCA genes without identifying a disease-causing genotype. Results Nine of the 276 LCA probands (3.2%) harbored 2 plausible disease-causing mutations (7 different alleles) in NPHP5 . Four of these have been previously reported in patients with Senior-Loken syndrome (F141del, R461X, H506del, and R489X) and 3 are novel (A111del, E346X, and R455X). All 9 patients had severe visual loss from early childhood but none had overt renal disease in the first decade of life. Two patients were diagnosed with nephronophthisis in the second decade. Retinal imaging studies showed retained photoreceptor nuclei and retinal pigment epithelium integrity mainly in the cone-rich central retina, a phenotype with strong similarities to that of NPHP6 disease. Conclusions Mutations in NPHP5 can cause LCA without early-onset renal disease. Abnormalities observed in the photoreceptor outer segments (a cilial structure) may explain the severe visual loss in NPHP5 -associated LCA. Clinical Relevance The persistence of central photoreceptor nuclei despite severe visual loss in NPHP5 disease is encouraging for future therapeutic interventions.

Determination of cranio‐spinal canal compliance distribution by MRI: Methodology and early application in idiopathic intracranial hypertension

Abstract: Purpose: To develop a method for derivation of the cranial-spinal compliance distribution, assess its reliability, and apply to obese female patients with a diagnosis of idiopathic intracranial hypertension (IIH). Materials and Methods: Phase contrast-based measurements of blood and cerebrospinal fluid (CSF) flows to, from, and between the cranial and spinal canal compartments were used with lumped-parameter modeling to estimate systolic volume and pressure changes from which cranial and spinal compliance indices are obtained. The proposed MRI indices are analogous to pressure volume indices (PVI) currently being measured invasively with infusion-based techniques. The consistency of the proposed method was assessed using MRI data from seven aged healthy subjects. Measurement reproducibility was assessed using five repeated MR scans from one subject. The method was then applied to compare spinal canal compliance contribution in seven IIH patients and six matched healthy controls. Results: In the healthy subjects, as expected, spinal canal contribution was consistently larger than the cranial contribution (average value of 69%). Measurement variability was 8%. In IIH, the spinal canal contribution is significantly smaller than normal controls (60 versus 78%, P < 0.03). Conclusion: An MRI-based method for derivation of compliance indices analogous to PVI has been implemented and applied to healthy subjects. The application of the method to obese IIH patients suggests a spinal canal involvement in the pathophysiology of IIH. J. Magn. Reson. Imaging 2011;. © 2011 Wiley Periodicals, Inc.

Automatic montage of SD-OCT data sets.

Abstract: This paper proposes an automatic algorithm for the montage of OCT data sets, which produces a composite 3D OCT image over a large field of view out of several separate, partially overlapping OCT data sets. First the OCT fundus images (OFIs) are registered, using blood vessel ridges as the feature of interest and a two step iterative procedure to minimize the distance between all matching point pairs over the set of OFIs. Then the OCT data sets are merged to form a full 3D montage using cross-correlation. The algorithm was tested using an imaging protocol consisting of 8 OCT images for each eye, overlapping to cover a total retinal region of approximately 50x35 degrees. The results for 3 normal eyes and 3 eyes with retinal degeneration are analyzed, showing registration errors of 1.5±0.3 and 2.0±0.8 pixels respectively.

Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.

Abstract: A homozygous Alu insertion in exon 9 of the MAK (male germ cell–associated kinase) gene was recently identified as the cause of disease in an isolated patient with retinitis pigmentosa (RP). Twenty additional probands were then found to be homozygous for this insertion.1 Another recent study involving other populations identified a further eight patients with RP and other MAK mutations.2 MAK encodes a kinase involved in the regulation of photoreceptor connecting cilium length.3 In human retina, MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors.1 We asked whether genotype was the only distinguishing feature of this type of autosomal recessive (ar) RP, of which there are many other molecular forms.4,5 Noninvasive techniques were used to study the phenotype of patients with MAK mutations; many of the patients had been followed for years to decades. There was a specific visual field pattern in early stages and longitudinal data provided a preliminary view of the natural history of rod and cone visual loss. All but one of the patients had Ashkenazi Jewish (AJ) heritage, an association caused by specific mutations in CLRN1,6 PCDH15,7 and DHDDS8,9 that has also been observed in RP. The phenotypic features that we noted in RP patients with MAK mutations may permit a more directed gene search in simplex or multiplex RP patients and lead to identification of an increased number of arRP patients with this molecular diagnosis. An available murine model, the Mak-knockout mouse,3 enhances the opportunity to perform proof-of-concept research and make progress toward human therapy.

Trends in glaucoma medication expenditure: Medical Expenditure Panel Survey 2001-2006.

Abstract: Objective To study trends of glaucoma medication expenditure from 2001 to 2006 using a nationally representative sample of US adults. Methods We analyzed glaucoma medication expenditure trends among participants of the 2001-2006 Medical Expenditure Panel Survey, a subsample of the National Health Interview Survey, which is a continuous multipurpose, multistage area probability survey of the US civilian noninstitutionalized population. After adjusting for survey design and inflation using the 2009 inflation index, data from 1404 participants 18 years and older using glaucoma medication were analyzed. Results Mean annual glaucoma medication expenditure per subject increased from $445 in 2001 to $557 in 2006 (slope = 20.8; P Conclusions Factors associated with increasing glaucoma medication expenditure trends include the increasing use of prostaglandin analogs, changes in insurance coverage, and possibly more aggressive glaucoma treatment. The findings are pertinent to the development of cost-effective strategies that optimize treatment and reduce expenditures.

Age-Related Macular Degeneration and Smoking Cessation Advice by Eye Care Providers: A Pilot Study

Abstract: Smoking is a modifiable risk factor for age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the United States. We conducted a pilot study among eye care providers and AMD patients to assess smoking cessation preferences and cessation services offered at a large academic medical center. Most patients who smoke reported never being advised to quit smoking, although most eye care providers reported that they had advised smokers to quit. Two-thirds of providers expressed a desire for additional training and resources to support patient quit attempts, indicating the need for the integration of smoking cessation opportunities in the clinic setting.

Proteomic analyses of corneal tissue subjected to alkali exposure.

Abstract: Purpose. To determine whether exposure to alkaline chemicals results in predictable changes in corneal protein profile. To determine whether protein profile changes are indicative of severity and duration of alkali exposure.

Ridge-based retinal image registration algorithm involving OCT fundus images

Abstract: This paper proposes an algorithm for retinal image registration involving OCT fundus images (OFIs). The first application of the algorithm is to register OFIs with color fundus photographs; such registration between multimodal retinal images can help correlate features across imaging modalities, which is important for both clinical and research purposes. The second application is to perform the montage of several OFIs, which allows us to construct 3D OCT images over a large field of view out of separate OCT datasets. We use blood vessel ridges as registration features. The brute force search and an Iterative Closest Point (ICP) algorithm are employed for image pair registration. Global alignment to minimize the distance between matching pixel pairs is used to obtain the montage of OFIs. Quality of OFIs is the big limitation factor of the registration algorithm. In the first experiment, the effect of manual OFI enhancement on registration was evaluated for the affine model on 11 image pairs from diseased eyes. The average root mean square error (RMSE) decreases from 58 μm to 40 μm. This indicates that the registration algorithm is robust to manual enhancement. In the second experiment for the montage of OFIs, the algorithm was tested on 6 sets from healthy eyes and 6 sets from diseased eyes, each set having 8 partially overlapping SD-OCT images. Visual evaluation showed that the montage performance was acceptable for normal cases, and not good for abnormal cases due to low visibility of blood vessels. The average RMSE for a typical montage case from a healthy eye is 2.3 pixels (69 μm).

Peer Reviewed: Age-Related Macular Degeneration and Smoking Cessation Advice by Eye Care Providers: A Pilot Study

Abstract: Smoking is a modifiable risk factor for age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the United States. We conducted a pilot study among eye care providers and AMD patients to assess smoking cessation preferences and cessation services offered at a large academic medical center. Most patients who smoke reported never being advised to quit smoking, although most eye care providers reported that they had advised smokers to quit. Two-thirds of providers expressed a desire for additional training and resources to support patient quit attempts, indicating the need for the integration of smoking cessation opportunities in the clinic setting.

Electrophysiology testing in unexplained visual loss for the neuro-ophthalmologist

Abstract: Visual electrophysiologic tests are objecti ve clinical tests that are helpful or essenti al in a variety of reti nal and visual disorders. This presentati on will provide an overview of clinical electrophysiologic tests and focus on the applicati on of electroreti nogram (ERG) in unexplained visual loss in neuro-ophthalmology. A variety of clinical cases will be presented to illustrate the appropriateness and uti lity of visual electrophysiology testi ng. At the conclusion of this presentati on, the att endee will understand the basic principles and clinical applicati ons of full-fi eld ERG, multi focal ERG, and patt ern VEP, enabling the att endee to incorporate these tests eff ecti vely in clinical practi ce.