Lipofuscin Deposition Research Articles

Microglia in dementia with Lewy bodies

Microglial activation (neuroinflammation) is often cited as a pathogenic factor in the development of neurodegenerative diseases. However, there are significant caveats associated with the idea that inflammation directly causes either α-synuclein pathology or neurofibrillary degeneration (NFD). We have performed immunohistochemical studies on microglial cells in five cases of dementia with Lewy bodies (DLB), median age 87, and nine cases of non-demented (ND) controls, median age 74, using tissue samples from the temporal lobe and the superior frontal gyrus. Three different antibodies known to label microglia and macrophages were employed: iba1, anti-CD68, and anti-ferritin. All DLB cases showed both α-synuclein pathology (Lewy bodies and neurites) and NFD ranging from Braak stage II to IV. In contrast, all controls were devoid of α-synuclein pathology but did show NFD ranging from Braak stage I to III. Using iba1 labeling, our current results show a notable absence of activated microglia in all cases with the exception of two controls that showed small focal areas of microglial activation and macrophage formation. Both iba1 and ferritin antibodies revealed a mixture of ramified and dystrophic microglial cells throughout the regions examined, and there were no measurable differences in the prevalence of dystrophic microglial cells between DLB and controls. Double-labeling for α-synuclein and iba1-positive microglia showed that cortical Lewy bodies were surrounded by both ramified and dystrophic microglial cells. We found an increase in CD68 expression in DLB cases relative to controls. Since microglial dystrophy has been linked to NFD and since it did not appear to be worse in DLB cases over controls, our findings support the idea that the additional Lewy body pathology in DLB is not the result of intensified microglial dystrophy. CD68 is likely associated with lipofuscin deposits in microglial cells which may be increased in DLB cases because of impaired proteostasis. Overall, we conclude that neurodegenerative changes in DLB are unlikely to result directly from activated microglia but rather from dysfunctional ones.

El epitelio seminal en biopsia prostática puede semejar lesiones prostáticas malignas y premalignas

ObjectivesIn most prostate biopsies, the seminal epithelium is easily recognised because it meets characteristic histological criteria. However, some biopsies can mimic malignant or premalignant prostatic lesions. The aims of this study were to analyse the histological appearance of the biopsies that mimic adenocarcinomas or preneoplastic prostatic lesions, discuss the differential diagnosis and determine the frequency of seminal epithelia in prostate biopsies. MethodsWe consecutively reviewed 500 prostate puncture biopsies obtained using the sextant method and selected those cases in which we observed seminal vesicle or ejaculatory duct epithelium. In the biopsies in which the seminal epithelium resembled malignant or premalignant lesions, immunohistochemical studies were conducted that included prostate-specific antigen and MUC6. The most important clinical data were recorded. ResultsThirty-six (7.2%) biopsies showed seminal epithelium, and 7 of them (1.4%) resembled various prostate lesions, including high-grade prostatic intraepithelial neoplasia, atypical acinar proliferations, adenocarcinomas with papillary patterns and poorly differentiated carcinoma. The seminal epithelium resembled prostate lesions when the lipofuscin deposit, the perinuclear vacuoles or the nuclear pseudoinclusions were inconspicuous or missing. Five of the 7 biopsies showed mild to moderate cellular atypia with small and hyperchromatic nuclei, and only 2 showed cellular pleomorphism. The patients were alive and asymptomatic after an average of 6 years of progression. ConclusionsThe seminal epithelium resembles prostatic intraepithelial neoplasia, atypical acinar proliferations and various types of prostatic adenocarcinomas in approximately 1.4% of prostate biopsies.

Ultrastructural Changes in the White and Gray Matter of Mice at Chronic Time Points After Repeated Concussive Head Injury.

Mild traumatic brain injury is a risk factor for neurodegenerative disease. We recently developed a model of repetitive concussive injury in mice that we have extensively characterized from 24 hours to 24 months after injury. Animals show evidence of progressive spatial memory deficits, thinning of the corpus callosum, axonal injury, and neuroglial activation. Here, we extended our neuropathologic characterization to the ultrastructural level in both a qualitative and a quantitative study. We focused on chronic (3 and 6 months) postinjury time points when the earliest stages of degenerative secondary changes were previously observed. In both C57BL/6 and hTau mice, we found white matter damage typified by axonal degeneration, microglial phagocytosis, and increased neuroglial cell density. In the cerebral cortex, we observed evidence of synaptic degeneration, dark neurons, altered dendritic microfilaments, subtle changes to the microvasculature, a mild augmentation of age-related features such as lipofuscin deposition, and electron-dense inclusions in microglial and perivascular cells. The majority of these ultrastructural features seemed to be more prominent at 3 versus 6 months after injury. Similar patterns were observed in C57BL/6 and hTau mice. These findings further support the relevance of our concussive injury model to the consequences of repetitive mild traumatic brain injury in humans.

Mysterious Black Crystalline Pigment in the Duodenum

Introduction: Pigment deposit in small intestine is rare. Cases of melanosis-like or pseudomelanosis of the duodenum have been reported and usually associated with essential hypertension with patients taking antihypertensive medicines, chronic renal failure, or gastric bleeding. Melanin, lipofuscin, or hemosiderin deposits are pigments that may be contributing. We present a case of a rare black pigmentation of the duodenum. Case: 72 year-old African American female was seen in consultation for anemia and recent drop in hemoglobin. Although her INR was elevated at 4.5, she had no overt bleeding source. She has multiple co-morbidities including essential hypertension, chronic kidney disease, history of left colon cancer status post resection with no chemotherapy or radiation therapy, and previous metallic mitral and aortic valves replacements. Her medications included hydralazine, warfarin, insulin glargine, ergocalciferol, atorvastatin, isosorbide mononitrate, amlodipine, levothyroxine, minoxidil, clonidine, ferrous sulfate, montelukast, esomeprazole, and Colace (docusate). Physical exam was unremarkable. Specifically no skin rash or bruises were noted. Hemoglobin was 7.4 g/dl with a hematocrit of 21.9%. Iron was 13 mcg/dl, transferrin 87 mg/dl, iron saturation 12%, and ferritin 624 ng/ml. She had a recent unremarkable colonoscopy. Upper endoscopy was performed with no signs of active or recent bleeding. Blackish mucosa with intact villi was seen in the duodenal bulb and the second part of duodenum. Duodenal biopsies showed intact duodenal mucosa with slender villi and normal crypt to villous ratio. In the lamina propria, a black crystalline pigment was identified. There was no tissue reaction to this pigment with iron stain was negative and control adequate. Etiology of this pigment was deemed unknown. Discussion: While the clinical significance of pigment deposits in the duodenum is not known, observations suggest an association with chronic illnesses or the use of antihypertensive medications. Such association and the composition of those pigments are worth further exploration.

The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells

Accumulation and aggregation of misfolded proteins is a hallmark of several diseases collectively known as proteinopathies. Autophagy has a cytoprotective role in diseases associated with protein aggregates. Age-related macular degeneration (AMD) is the most common neurodegenerative eye disease that evokes blindness in elderly. AMD is characterized by degeneration of retinal pigment epithelial (RPE) cells and leads to loss of photoreceptor cells and central vision. The initial phase associates with accumulation of intracellular lipofuscin and extracellular deposits called drusen. Epidemiological studies have suggested an inverse correlation between dietary intake of marine n-3 polyunsaturated fatty acids (PUFAs) and the risk of developing neurodegenerative diseases, including AMD. However, the disease-preventive mechanism(s) mobilized by n-3 PUFAs is not completely understood. In human retinal pigment epithelial cells we find that physiologically relevant doses of the n-3 PUFA docosahexaenoic acid (DHA) induce a transient increase in cellular reactive oxygen species (ROS) levels that activates the oxidative stress response regulator NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2). Simultaneously, there is a transient increase in intracellular protein aggregates containing SQSTM1/p62 (sequestosome 1) and an increase in autophagy. Pretreatment with DHA rescues the cells from cell cycle arrest induced by misfolded proteins or oxidative stress. Cells with a downregulated oxidative stress response, or autophagy, respond with reduced cell growth and survival after DHA supplementation. These results suggest that DHA both induces endogenous antioxidants and mobilizes selective autophagy of misfolded proteins. Both mechanisms could be relevant to reduce the risk of developing aggregate-associate diseases such as AMD.

Retinal pathology in idiopathic moyamoya angiopathy detected by optical coherence tomography.

To investigate whether patients with moyamoya angiopathy without obvious retinal pathologies such as retinal infarctions or the congenital morning glory anomaly may have subtle subclinical retinal changes. In this cross-sectional study, spectral domain optical coherence tomography was used to analyze the retinal morphology of 25 patients with idiopathic moyamoya angiopathy and 25 age- and sex-matched healthy controls. We analyzed the retinal vasculature with blue laser autofluorescence, lipofuscin deposits with MultiColor confocal scanning laser ophthalmoscopy, and the optic nerve head (ONH) volume with a custom postprocessing algorithm. In addition to the total retinal thickness, semiautomated segmentation was used for segmentation of retinal layers in macular cross scans, macular volume scans, and peripapillary ring scans. The main finding was a pronounced reduction of the ONH volume in moyamoya angiopathy compared with controls (0.76 ± 0.45 mm(3) and 1.47 ± 0.50 mm(3), respectively; p < 0.0001), which was associated with a less pronounced reduction of the retinal nerve fiber layer in macular volume scans (0.97 ± 0.11 mm(3) and 1.10 ± 0.10 mm(3), respectively; p < 0.001). Autofluorescence and MultiColor confocal scanning laser ophthalmoscopy images revealed no pathologies except for one branch retinal artery occlusion. Our results indicate that even patients with moyamoya angiopathy who do not have obvious retinal abnormalities have retinal abnormalities. These can be detected by spectral domain optical coherence tomography, and the association of ONH abnormalities with the vascular changes may suggest that idiopathic moyamoya angiography is a systemic disease involving abnormalities of the early mesodermal development.

Subducted and melanotic cells in advanced age-related macular degeneration are derived from retinal pigment epithelium.

To describe, illustrate, and account for two cell types plausibly derived from RPE in geographic atrophy (GA) and choroidal neovascularization (CNV) of AMD, using melanosomes, lipofuscin, and basal laminar deposit (BLamD) as anatomical markers. Human donor eyes with GA (n = 13) or CNV (n = 39) were histologically processed, photodocumented, and analyzed for frequencies of occurrence. We defined RPE as cells containing spindle-shaped melanosomes and RPE lipofuscin, internal to basal lamina or BLamD, if present, or Bruch's membrane if not, and RPE-derived cells as those plausibly derived from RPE and not attached to basal lamina or BLamD. 'Subducted' cells contain RPE melanosomes and localize to the sub-RPE space, on Bruch's membrane. Credible transitional forms from RPE cells were seen. Grades of RPE overlying 'Subducted' cells were 'Atrophic with BLamD' (32.2% vs. 37.0% of 'Subducted,' for GA and CNV eyes, respectively), 'Dissociated' (22.0% vs. 21.7%), 'Nonuniform' (22.0% vs. 23.9%), and 'Sloughed' RPE (10.2% vs. 4.3%). Found exclusively in CNV scars, 'Melanotic' cells containing spherical melanosomes were adjacent to 'Entombed' RPE with spindle-shaped and spherical melanosomes. Of subretinal 'Melanotic' cells, 40.0% associated with 'Atrophy with BLamD,' 36.8% with 'Atrophy without BLamD,' and 20.6% with 'Entombed.' 'Dissociated' RPE within atrophic areas may be the source of 'Subducted' cells. 'Entombed' RPE within fibrovascular and fibrocellular scars may be the source of 'Melanotic' cells. An imaging correlate for 'Subducted' cells awaits discovery; 'Melanotic' cells appear gray-black in the CNV fundus. Results provide a basis for future molecular phenotyping studies.

Bovine generalized lipofuscinosis and sarcoplasmic inclusions: histopathological and histochemical features in three cases

Three adult Holstein-Friesian dairy cows (4 to 6 years old) which had been raised at three different farms were culled with a long history of locomotor dysfunction attributed to dislocation or subluxation of the hip joint (two cows) or foot rot (one cow). They revealed dark brown discoloration of multiple sites of the carcasses at postmortem examination. On histopathological and histochemical investigations, lipofuscin pigments showing autofluorescence, sudanophilia, argyrophilia, periodic acid-Schiff (PAS) positiveness, and acid fastness were stored within otherwise normal cells of various sites in the body, including many thoracic and abdominal viscera, skeletal muscle, diaphragm, and tongue. In the central nervous system, some neurons with massive lipofuscin deposition were prominently shrunken but associated with neither necrotic changes nor glial reaction. Such a generalized pigmentary condition was distinguished from neuronal ceroid lipofuscinosis and thus was diagnosed as generalized lipofuscinosis. Furthermore, distinct proteinaceous eosinophilic inclusions were simultaneously observed to a varying degree within myofibers of the diaphragm, heart, rumen, or small intestine. These inclusions stained weakly positive with PAS and negative with Nile blue, Sudan black B, periodic acid-methenamine silver (PAM), and acid-fast stains. Autofluorescence was not seen. Staining properties demonstrated by phosphotungstic acid-hematoxylin (purple blue) and Masson’s trichrome (bright red) stains were compatible with those of myofibrils, presumably suggesting that the inclusions have chemical composition similar or identical to that of myofibrils. It remains to be elucidated whether the occurrence of such sarcoplasmic inclusions was related to lipofuscinogenesis or a nonspecific phenomenon indicating an incidental finding.

Enhanced depth imaging optical coherence tomography of circumscribed choroidal hemangioma in 10 consecutive cases.

Purpose:The purpose was to evaluate the features of circumscribed choroidal hemangioma using spectral-domain enhanced depth imaging optical coherence tomography (EDI-OCT).Design:Retrospective observational case series.Participants:Ten patients with newly diagnosed circumscribed choroidal hemangioma.Methods:Spectral-domain EDI-OCT was performed with a Heidelberg Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany).Main Outcome Measures:Tumor thickness and EDI-OCT features.Results:The mean tumor diameter for all eyes was 5.4 mm and mean tumor thickness was 1187 μm by EDI-OCT compared to 2400 μm by ultrasonography. EDI-OCT imaged all tumors as smooth with a gently sloping anterior contour, gradual choroidal expansion, expansion of medium and large size choroidal vessels without compression of choriocapillaris, and intact Bruch's membrane (n = 10, 100%). The height of the medium and large choroidal vessels within the tumor compared to normal medium and large vessels was comparatively increased by a mean of 265% (medium vessels) and 576% (large vessels). Outer retinal abnormalities included subretinal fluid (n = 7, 70%), lipofuscin deposition (n = 1, 10%), irregularity and thinning of retinal pigment epithelium and absence or irregularity of the ellipsoid layer (n = 4, 40%), absent external limiting membrane (n = 2, 20%), and disruption of the outer nuclear layer and outer plexiform layer (n = 3, 30%). The inner retinal abnormalities included irregularity of inner nuclear layer and structural loss or edema of inner plexiform layer (n = 3, 30%). The ganglion cell layer and nerve fiber layer were intact (n = 10, 100%).Conclusion:EDI-OCT of circumscribed choroidal hemangiomas depicts a smooth, gently sloping choroidal mass with expansion of medium and large size choroidal vessels without compression of the choriocapillaris. Structural abnormalities of outer and inner retinal layers were noted.

Pompe disease: Shared and unshared features of lysosomal storage disorders.

Pompe disease, an inherited deficiency of lysosomal acid α-glucosidase (GAA), is a severe metabolic myopathy with a wide range of clinical manifestations. It is the first recognized lysosomal storage disorder and the first neuromuscular disorder for which a therapy (enzyme replacement) has been approved. As GAA is the only enzyme that hydrolyses glycogen to glucose in the acidic environment of the lysosome, its deficiency leads to glycogen accumulation within and concomitant enlargement of this organelle. Since the introduction of the therapy, the overall understanding of the disease has progressed significantly, but the pathophysiology of muscle damage is still not fully understood. The emerging complex picture of the pathological cascade involves disturbance of calcium homeostasis, mitochondrial abnormalities, dysfunctional autophagy, accumulation of toxic undegradable materials, and accelerated production of lipofuscin deposits that are unrelated to aging. The relationship of Pompe disease to other lysosomal storage disorders and potential therapeutic interventions for Pompe disease are discussed.

A neuronal aging pattern unique to humans and common chimpanzees

Lipofuscin pigment accumulation is among the most prominent markers of cellular aging in postmitotic cells. The formation of lipofuscin is related to oxidative enzymatic activity and free radical-induced lipid peroxidation. In various mammals such as rat, dog, macaque as well as in cheirogaleid primates, most of the large neurons, such as cerebellar Purkinje cells and neocortical pyramidal cells, show heavy lipofuscin accumulation in adulthood. In contrast, a well-known yet poorly studied feature of the aging human brain is that although lipofuscin accumulation is most marked in large neurons of the cerebral cortex, the large neurons of the cerebellar cortex-the Purkinje cells-appear to remain free of lipofuscin accumulation. It is however, not known whether this characteristic of human Purkinje cells is shared with other primates or other mammals. This study reports results from histological observation of Purkinje cells in humans, non-human primates, and other mammals. Procedures include histochemistry, immunocytochemistry, and fluorescence microscopy. Abundant lipofuscin deposition was observed in Purkinje cells of all the species we examined except Homo sapiens (including Alzheimer's disease cases) and Pan troglodytes. In contrast, lipofuscin deposition was observed in neurons of the dentate nucleus. Our findings suggest that when compared with other primates, Purkinje cells in chimpanzees and humans might share a common aging pattern that involves mechanisms for neuroprotection. This observation is important when considering animal models of aging.

Neuroprotective effects of Bacopa monniera whole-plant extract against aluminum-induced hippocampus damage in rats: evidence from electron microscopic images.

Impaired antioxidant system and structural changes in hippocampus are considered as key instigators of neurodegenerative diseases. The present study aimed to investigate the antioxidant and tissue protective properties of Bacopa monniera whole-plant extract (BME) against aluminum (Al)- induced oxidative stress and hippocampus damage in rats. Male Wistar rats were evenly divided into four groups, nine in each and labeled as control, Al treated (10 mg/kg), BME administered (40 mg/kg) and combination of both Al plus BME (Al+BME) treated groups. After one month of treatment by oral administration, antioxidant status was determined, and structural changes in the hippocampus were evaluated by electron microscopy. Al-induced increased oxidative damage in the hippocampus was revealed by elevated thiobarbituric acid reactive substances (TBARS). This increased lipid peroxidation was associated with significantly decreased antioxidant enzyme activities, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). However, aluminum intoxicated rats treated with BME for 30 days showed significantly restored antioxidant enzyme activities along with decreased TBARS (P < 0.01). Further evidences from electron micrographs clearly indicated that Al-induced vacuolation, lipofuscin deposition and pyramidal cell degeneration in the hippocampus was attenuated with co-administration of the whole-plant extract. Our results demonstrate that structural derangement in hippocampus by aluminum is directly proportionate with increased lipid peroxidation. Nevertheless, B. monniera treatment potentiates the antioxidant status and suppressed the tissue damage induced by Al-intoxication. These findings suggest that B. monniera whole-plant extracts can be considered as a possible remedy to counteract aluminum-associated neurological disorders.

Hermansky’s Hypoxia: A Brain Teaser

Hermansky-Pudlak syndrome (HPS) is a rare heterogeneously inherited autosomal recessive group of disorders presenting with oculocutaneous albinism, bleeding diathesis and pulmonary disease. HPS is thought to occur as a consequence of disturbed formation of intracellular vesicles, most importantly, melanosomes, platelet dense granules and lysosomes. These abnormalities contribute to the morbidity associated with the disease, as ceroid lipofuscin deposits in lysosomes affect many organ systems. This is especially evident in the lungs where it is often associated with severe pulmonary fibrosis and premature death. Clinical recognition of HPS is critical as it facilitates genetic counseling, aids in prognostication and directs medical management as in our patient who presented with end stage fibrosis and severe hypoxia. J Med Cases. 2014;5(10):522-524 doi: http://dx.doi.org/10.14740/jmc1920w

Pompe disease: from pathophysiology to therapy and back again.

Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase (GAA) is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle myopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy (ERT) proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pompe skeletal muscle is affected at the termination stage—impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits—a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic manipulation of autophagy.

Antioxidant activity and delayed aging effects of hot water extract from Chamaecyparis obtusa var. formosana leaves.

The antioxidant activity and delayed aging effects of hot water extracts from leaves of Chamaecyparis obtusa var. formosana were investigated. Free radical, superoxide radical scavenging, and total phenolic content assays were employed to evaluate the in vitro activities of the extracts. In addition, in vivo assays using the nematode Caenorhabditis elegans were also performed in this study. The results showed that among all soluble fractions obtained from the extracts, the ethyl acetate-soluble fraction has the best in vitro and in vivo antioxidant activities. Moreover, it decreased significantly the deposition of lipofuscin (aging pigment) and extended the lifespan of C. elegans. Bioactivity-guided fractionation yielded six potent antioxidant constituents from the ethyl acetate-soluble fraction, namely, catechin, quercetin, quercetin-3-O-α-rhamnoyranoside, myricetin-3-O-α-rhamnoyranoside, vanillic acid, and 4-hydroxybenzoic acid. Quercetin-3-O-α-rhamnoyranoside pretreatment showed the highest survival of C. elegans upon juglone exposure. Taken together, the results revealed that hot water extracts from C. obtusa var. formosana leaves have the potential to be used as a source for antioxidant or delayed aging health food.

Normal black kidney.

A black kidney has 3 major differential diagnoses: hemosiderosis, lipofuscin pigment and melanotic renal cell carcinoma. Excluding lipofuscin, the other 2 are accompanied by an abnormal renal function. We report on a 25-year-old man who intended to donate a kidney to his cousin. On the operating room table when we incised the left flank region and exposed the kidney, we found a firm and black kidney so the operation was cancelled due to potential vascular injuries. Days after the incomplete procedure, we reviewed the donor's biochemistry and imaging to reassess his renal function, but the results showed quite normal renal function again. The result of Ham test was also negative. Two weeks later, we began the operation, removed the same left kidney and found that it was in the same conditions as it was before. We took the opportunity to send needle biopsies of the kidney for histopathologic analysis. The analysis showed a melanotic kidney without pathological changes in glomeruli and interstitium and vessels. A black kidney may result in hemosiderin, lipofuscin or melanin deposits in the kidney, which can confirm the diagnosis; however, special tests for underlying disease and renal function should be considered. Some causes of black kidney lead to abnormal function, but our patients's kidney returned to normal.

Whole exome sequencing detects homozygosity for ABCA4 p.Arg602Trp missense mutation in a pediatric patient with rapidly progressive retinal dystrophy

BackgroundA pediatric patient presented with rapidly progressive vision loss, nyctalopia and retinal dystrophy. This is the first report of homozygosity for the p.Arg602Trp mutation in the ABCA4 gene. The child became legally blind within a period of 2 years.Case presentationAn eight year-old Hispanic female presented with bilateral decreased vision following a febrile gastrointestinal illness with nausea and vomiting. Extensive workup involved pediatric infectious disease and rheumatology consultations.Initial visual acuity was 20/60 at distance and 20/30 at near in both eyes. Rapidly progressive vision loss occurred during a 2-year period resulting in visual acuities of 20/200 at distance in both eyes. Fundus exam disclosed attenuated vessels and multiple subretinal blister-like elevations. Optical coherence tomography showed far more lesions than were clinically evident with different levels of elevation. Autofluorescence imagery showed dramatic and widespread geographic areas of atrophy. The deposits that appeared drusen-like on clinical exam were hyperfluorescent, consistent with lipofuscin deposits containing A2e (N-retinylidene-N-retinylethanolamine) indicative of RPE cell dysfunction. Electroretinography was consistent with cone dystrophy, with relative preservation of rod function. Blood analysis and rheumatology evaluation found no evidence of a diffuse post-infectious/inflammatory process. The unique and rapid progression of her subretinal blister-like lesions was documented by fluorescein angiography, optical coherence tomography, autofluorescence imagery, and fundus photography. Family pedigree history disclosed consanguinity, her parents being first cousins. DNA analysis by whole exomic sequencing revealed homozygosity of p.Arg602Trp in the ABCA4 gene.ConclusionThe pediatric patient presented with a striking clinical appearance and dramatic rate of progression that was clinically more characteristic of an infectious or inflammatory process. This case expands the diverse range of phenotypes attributed to ABCA4 mutations and further supports the role of whole exome sequencing as a powerful new tool available to aid clinicians in establishing diagnosis for challenging cases.

Hermansky’s Hypoxia: A Brain Teaser

Hermansky-Pudlak syndrome (HPS) is a rare heterogeneously inherited autosomal recessive group of disorders presenting with oculocutaneous albinism, bleeding diathesis and pulmonary disease. HPS is thought to occur as a consequence of disturbed formation of intracellular vesicles, most importantly, melanosomes, platelet dense granules and lysosomes. These abnormalities contribute to the morbidity associated with the disease, as ceroid lipofuscin deposits in lysosomes affect many organ systems. This is especially evident in the lungs where it is often associated with severe pulmonary fibrosis and premature death. Clinical recognition of HPS is critical as it facilitates genetic counseling, aids in prognostication and directs medical management as in our patient who presented with end stage fibrosis and severe hypoxia. J Med Cases. 2014;5(10):522-524 doi: http://dx.doi.org/10.14740/jmc1920w

Pathophysiological Defects and Transcriptional Profiling in the RBM20-/- Rat Model

Our recent study indicated that RNA binding motif 20 (Rbm20) alters splicing of titin and other genes. The current goals were to understand how the Rbm20-/- rat is related to physiological, structural, and molecular changes leading to heart failure. We quantitatively and qualitatively compared the expression of titin isoforms between Rbm20-/- and wild type rats by real time RT-PCR and SDS agarose electrophoresis. Isoform changes were linked to alterations in transcription as opposed to translation of titin messages. Reduced time to exhaustion with running in knockout rats also suggested a lower maximal cardiac output or decreased skeletal muscle performance. Electron microscopic observations of the left ventricle from knockout animals showed abnormal myofibril arrangement, Z line streaming, and lipofuscin deposits. Mutant skeletal muscle ultrastructure appeared normal. The results suggest that splicing alterations in Rbm20-/- rats resulted in pathogenic changes in physiology and cardiac ultrastructure. Secondary changes were observed in message levels for many genes whose splicing was not directly affected. Gene and protein expression data indicated the activation of pathophysiological and muscle stress-activated pathways. These data provide new insights on Rbm20 function and how its malfunction leads to cardiomyopathy.

Differentiating retinal from optic nerve syndromes

Differentiate between optic nerve and retinal disease that share common characteristics utilizing clinical history, examination, and ancillary testing. Autofluorescence is a quick and noninvasive test that is helpful in detecting macular edema and deposition of lipofuscin. Optical coherence tomography (OCT) is becoming an indispensable tool in detecting subtle macular abnormalities that can be missed on funduscopic examination. Multifocal electroretinogram can also help in early screening of focal macular dystrophy. Many patients present to the ophthalmology clinic with decreased vision, and occasionally it can be difficult to find a clear cause to the vision loss. Such situations, not infrequently, require the ophthalmologist to differentiate between optic nerve and retinal diseases that can share some common characteristics. The ability to use the clinical history and examination along with additional ancillary testing including OCT, electrophysiology, and fluorescein angiography to differentiate optic nerve from retinal disease can be very helpful in formulating a differential and ultimately establishing a diagnosis.