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Show Novel Ophthalmic Pathology in an Autopsy Case of Autosomal Dominant Retinal Vasculopathy With Cerebral Leukodystrophy Aaron M. Gruver, MD, PhD, Lynn Schoenfield, MD, Joshua F. Coleman, MD, Rula Hajj-Ali, MD, E Rene Rodriguez, MD, Carmela D. Tan, MD Abstract: Autosomal dominant retinocerebral vasculop-athy with cerebral leukodystrophy (RVCL) is a rare neu-rovascular syndrome causing retinal and central nervous system vasculopathy often recognized as contrast-enhancing white matter changes or pseudotumors on imaging. Heterozygous frameshift mutations in the 3- prime repair exonuclease 1 gene have been identified in families affected by RVCL. Variable light microscopic findings and a characteristic ultrastructural appearance of the vasculature in the brain have been reported. De-scription of the ophthalmic histopathology is exceedingly rare. Here, we report previously undescribed bilateral eye findings in a patient diagnosed with RVCL. The ophthalmic pathology includes thickening and reduplication of the retinal capillary basal lamina demonstrated by electron microscopy. These findings expand what is known about this disease and help further delineate its phenotype. Journal of Neuro-Ophthalmology 2011;31:20-24 doi: 10.1097/WNO.0b013e3181f45dba 2011 by North American Neuro-Ophthalmology Society The retinocerebral vasculopathies are a group of small vessel diseases that involve the cerebral and retinal arteries and, in some disorders, the vessels of the inner ear (1). One such type is cerebral autosomal dominant arte-riopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1). Characteristic manifestations are recurrent strokes, dementia, and migraine in the fifth and sixth decades. CADASIL is related to mutations in the Notch homolog 3 (NOTCH3) gene that encodes a cell surface receptor expressed in the vascular smooth muscle cells. The most recently designated of the retinocerebral vasculo-pathies is the autosomal dominant retinocerebral vascul-opathy with cerebral leukodystrophy (RVCL) (2). It encompasses 3 previously described syndromes: cerebror-etinal vasculopathy; hereditary vascular retinopathy; and hereditary endotheliopathy, retinopathy, nephropathy, and stroke (2-5). These syndromes map to chromosome 3p21.1-p21.3, and heterozygous frameshift mutations of the gene encoding the 3-prime repair exonuclease 1 (TREX1) have been documented in 9 families to date (2,6). Affected individuals usually present in middle age with a progressive loss of vision due to retinal vasculopathy. The extent of neurological disease varies and includes dementia, stroke, and migraine. Some kindred display systemic in-volvement that includes Raynaud phenomenon, micronodular cirrhosis, and renal dysfunction. The typical length of survival from the onset of symptoms is between 5 and 10 years. We report the pathological findings in a patient with RVCL with particular attention to previously undescribed ocular histopathologic and retinovascular abnormalities. CASE REPORT A 55-year-old white man presented with a 1-year history of gradual bilateral visual loss that eventually worsened to the point that he was unable to work. His medical history in-cluded a 10-year history of elevated liver enzymes, pro-teinuria, and a possible stroke. He was receiving oral prednisone for presumed bilateral retinal vasculitis and re-ferred to rheumatology and neurology for further evaluation. An extensive workup failed to show evidence of systemic vasculitis. Neurological evaluation revealed mild cognitive impairment with thought-processing and word-finding difficulty. MRI of the brain demonstrated mildly progressive Departments of Anatomic Pathology (AMG, LS, JFC, ERR, CDT) and Rheumatic and Immunologic Disease (RH-A), Cleveland Clinic, Cleveland, OH. Funding: No funding received for this work. The authors report no conflicts of interest. Address correspondence to Carmela D. Tan, MD, Department of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Avenue/L25, Cleveland, Ohio 44195; E-mail: tanc@ccf.org 20 Gruver et al: J Neuro-Ophthalmol 2011; 31: 20-24 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. white matter changes in the paramedian right precentral gyrus and subcortical white matter of the left superior frontal gyrus. Prominent hyperintensity was noted along the genu of the corpus callosum, body of the corpus callosum, and periatrial region (Fig. 1). These changes raised the question of demyelinating disease. A cerebral angiogram demonstrated a small anterior communicating artery aneurysm without evidence of vasculitis. Workup for an infectious process yielded no positive results. Ten months after initial presentation, systemic steroids were discontinued. After undergoing bilateral cataract sur-gery, the patient's vision was stable for approximately 2 years. Three years following initial presentation, he ex-perienced exacerbation of his visual disturbance. Fundus findings and fluorescein angiography during this time are shown (Fig. 2). An open brain biopsy of the right temporal lobe revealed no definitive abnormality. Superficial tem-poral artery biopsy showed intimal fibroplasia. Genetic testing for mutations of the NOTCH3 gene, implicated in CADASIL, was negative. The differential diagnosis in-cluded a central nervous system vasculitis or multiple sclerosis, and the patient was started on cyclophosphamide. Visual acuity stabilized at 20/100, right eye, and 20/60, left eye. However, musculoskeletal strength, gait, and memory did not improve. Additional family history re-vealed blindness and kidney failure in the patient's father and a history of ‘‘brain tumor'' in a cousin. This family history, poor response to cyclophosphamide, and lack of vasculitic changes on brain biopsy led to testing for RVCL. This proved positive for a mutation in the TREX1 gene (2). Several months later, his condition continued to decline, and the patient expired approximately 5 years after initial presentation. A complete autopsy, including examination of the eyes, was performed 12 hours after death. Tissues obtained were fixed in 10% buffered formalin and processed routinely for hematoxylin-eosin staining. The eyes were sectioned in the horizontal plane. Additional sections from brain and eye were fixed in a 3.75% glutaraldehyde solution, embedded in epoxy resin, cut into thin sections, and stained with uranyl acetate and lead citrate for examination with a Philips CM-12 transmission electron microscope. Gross examination of the brain showed a soft cavitary lesion (5.8 3 2.5 cm) in the right temporal lobe and an area of softening in the left lateral cerebellum (2.3 3 1.4 cm). Histologic examination of the brain demonstrated a mi-croscopic acute infarct of the left frontal cortex, dystrophic calcification of the pons and left parietal lobe, and multiple small foci of myelin loss in the frontal, temporal, parietal, and occipital lobes (Fig. 3). The small vessels showed vas-cular sclerosis. No senile plaques, neurofibrillary tangles, or amyloid deposition were identified. Intraocular lenses were present in both eyes. Microscopic examination demonstrated thickened retinal vessels and small telangiectasias. Some vessels contained fibrin thrombi (Fig. 4). Amyloid was not present, and no evidence of vasculitis was identified in either eye. Electron microscopy of the retina demonstrated thickening and reduplication of the capillary basal lamina, and similar findings were observed in the right temporal lobe (Fig. 5). No vascular pathology or demyelination was identified in the optic nerves. There were no specific pathologic changes noted in the microscopic study of the liver and kidneys. No re-duplication of the basal lamina in the kidneys or liver was identified by electron microscopy. No fibrin thrombi were identified in any of the other organs. DNA was extracted from frozen brain tissue for re-sequencing of TREX1 (NM_016381) to confirm the pre-viously reported mutation. Polymerase chain reaction was performed using published primers (2). Bidirectional se-quencing using a BigDye Terminator cycle sequencing kit v3.1 (Applied Biosystems, Foster City, CA) was carried on an ABI 3730 automated DNA sequencer. A heterozygous ‘‘GTCA'' duplication (r.907_910dupGTCA) in the coding region of TREX1 was reconfirmed by direct sequencing. This frameshift mutation changes the amino acids starting at codon 304 and culminates in a stop codon resulting in a truncated protein (Fig. 6). DISCUSSION While RVCL has been recently classified based on the presence of mutations in TREX1, variations in its phenotype FIG. 1. Fluid attenuated inversion recovery (FLAIR) MRI of the brain shows periventricular white matter changes. Gruver et al: J Neuro-Ophthalmol 2011; 31: 20-24 21 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. resulted in the syndromes being viewed as separate entities in the past (2). Brain pathology previously reported in cases is variable and includes foci of coagulation necrosis, subacute cerebral infarction, spongiosis, and white matter astrocytic gliosis (7,8). Vascular changes include fibrinoid necrosis, variable thickening of the media in small to medium sized whitematter vessels, obliterative fibrosis of the vessel wall, and vascular proliferation and telangiectasia (3,7,8). A FIG 2. A. Fundus photograph of the right eye demonstrating pallor of the optic disc with overlying telangiectasias and an area of adjacent hemorrhage (arrow). B. Fluorescein angiogram of the right eye shows perivascular leakage of dye and vessel wall staining (arrows) as well as telangiectatic vascular changes (arrowheads) in the macula. FIG. 3. Representative section taken from the frontal lobe demonstrates small patches of absent blue staining of myelin in the white matter (Luxol fast blue, 3200). FIG. 4. A. Light microscopy of the retina shows that some of the vessels contain fibrin thrombi (arrow) (hematoxylin and eosin, 3400). B. Vascular telangiectasia (arrow) is evident in a longitudinally oriented vessel (periodic acid- Schiff, 3400). C. Vascular wall thickening (arrow) is demonstrated in a cross-section of a retinal vessel (periodic acid-Schiff, 3400). 22 Gruver et al: J Neuro-Ophthalmol 2011; 31: 20-24 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. characteristic thickening and reduplication of the capillary basement membranes in the brain has been reported in 3 studies to date (7-9). Jen et al (7) also described similar ultrastructural findings in reprocessed samples of kidney, stomach, appendix, omentum, and skin. Neuropathology observed in the present case, on both biopsy and autopsy samples, is concordant with published findings. Additionally, the scattered areas of white matter demyelination identified histologically correlate with neuroimaging findings. Retinal capillary obliteration and telangiectasia have been demonstrated by fluorescein angiography; however, docu-mentation of ophthalmic histopathology in RVCL is ex-ceedingly rare (3,7,10). In 1988, Grand et al (3) reported that cornea, trabecular meshwork, ciliary body, ciliary process, anterior chamber, and iris were found to be normal. Micro-infarctions and changes due to cytomegalovirus retinitis were identified. Although ultrastructural investigations revealed atrophy of ganglion cells and inner nuclear layer cells in areas of microinfarction, the vasculature was reportedly normal. The observation of significant vascular changes by light micros-copy, including telangiectasias and fibrin thrombi, is unique to the present case. Furthermore, thickening and reduplication of the retinal capillary basal lamina was demonstrated on electron microscopy. Fluorescein angiography in our study, and in reported cases, demonstrates findings consistent with retinal vasculitis (9,11). Despite this, no histological evidence of retinal vasculitis has been described. While patients with RVCL share a group of mutations resulting in carboxy-terminal truncations in TREX1, the pathogenesis of this disorder remains to be elucidated. Richards et al have shown that the mutations in TREX1 associated with RVCL do not alter the catalytic activity of the enzyme. Rather, the truncated protein loses its normal intracellular localization (2). This has led to the hypothesis that TREX1 in patients with RVCL does not participate in the repair of oxidative DNA damage because of its abnormal location within the cell. It has been proposed that the misplaced TREX1 may accumulate to cause a detrimental effect on endothelial cells (2). It remains to be determined how the manifestations of disease show a predilection for vessels of the brain and eye. Further study of RVCL may allow for subclassification based on precise mutations in TREX1 producing specific histopathologic and clinical findings. This could partially account for the observed phenotypic variation. The severity of disease present at autopsy may simply reflect the extent of accumulated endothelial damage present in target organs. The findings presented here provide further insight into a newly designated and rare neuro-ophthalmic syn-drome. Additional studies of RVCL will provide a better understanding of the molecular basis of small vessel diseases FIG. 5. A. Electron micrograph reveals thickening and reduplication (white arrowheads) of the capillary basal lamina within the eye (35000). B. Similar changes (white arrowheads) are noted in the vessels of the right temporal lobe (33000). FIG. 6. A. Electropherogram demonstrates the presence of a heterozygous GTCA duplication of base pairs 907- 910 as indicated by the arrows in the coding region of the TREX1 gene. B. The amino acid sequence is shown with the frameshift mutation in bold letters eventually result-ing in a carboxy-terminal truncation of the TREX1 protein. Gruver et al: J Neuro-Ophthalmol 2011; 31: 20-24 23 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. affecting the brain and eye leading to improvements in diagnostic studies and therapeutic options. ACKNOWLEDGMENTS The authors wish to thank Dr John P. Atkinson and Gloria Xiaotong Zhang for assistance with resequencing of the TREX1 gene. REFERENCES 1. Ringelstein EB, Nabavi DG. Cerebral small vessel diseases: cerebral microangiopathies. Curr Opin Neurol. 2005;18: 179-188. 2. Richards A, van den Maagdenberg AM, Jen JC, Kavanagh D, Bertram P, Spitzer D, Liszewski MK, Barilla-LaBarca M, Terwindt GM, Kasai Y, McLellan M, Grand MG, Vanmolkot KR, de Vries B, Wan J, Kane MJ, Mamsa H, Schafer R, Stam AH, Hann J, de Jong P, Storimans CW, van Schooneveld MJ, Oosterhuis JA, Gschwendter A, Dichgans M, Kotschet KE, Hodgkinson S, Hardy TA, Delatycki MB, Hajj-Ali RA, Kothari PH, Nelson SF, Frants RR, Baloh RW, Ferrari MD, Atkinson JP. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet. 2007;39:1068-1070. 3. Grand MG, Kaine J, Fulling K, Atkinson J, Dowton B, Farber M, Craver J, Rice K. Cerebroretinal vasculopathy. A new hereditary syndrome. Ophthalmology. 1988;95:649-659. 4. Storimans CW, Van Schooneveld MJ, Oosterhuis JA, Bos PJ. A new autosomal dominant vascular retinopathy syndrome. Eur J Ophthalmol. 1991;1:73-78. 5. Terwindt GM, Haan J, Ophoff RA, Groenen SM, Storimans CW, Lanser JB, Roos RA, Bleeker-Wagemakers EM, Frants RR, Ferrari MD. Clinical and genetic analysis of a large dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Brain. 1998;121: 303-316. 6. Ophoff RA, DeYoung J, Service SK, Joosse M, Caffo NA, Sandkuijl LA, Terwindt GM, Hann J, van den Maagdenberg AM, Jen J, Baloh RW, Barilla-LaBarca M, Saccone NL, Atkinson JP, Ferrari MD, Freimer NB, Frants RR. Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1- p21.3. Am J Hum Genet. 2001;69:447-453. 7. Jen J, Cohen AH, Yue Q, Stout JT, Vinters HV, Nelson S, Baloh RW. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology. 1997;49: 1322-1330. 8. Niedermayer I, Reiche W, Graf N, Mestres P, Feiden W. Cerebroretinal vasculopathy and leukoencephalopathy mimicking a brain tumor. report of two early-onset cases with Fanconi's anemia-like phenotypes suggesting an autosomal-recessive inheritance pattern. Clin Neuropathol. 2000;19:285-295. 9. Cohn AC, Kotschet K, Veitch A, Delatycki MB, McCombe MF. Novel ophthalmological features in hereditary endotheliopathy with retinopathy, nephropathy and stroke syndrome. Clin Experiment Ophthalmol. 2005;33: 181-183. 10. Qian Y, Kosmorsky G, Kaiser PK. Retinal manifestations of cerebroretinal vasculopathy. Semin Ophthalmol. 2007;22: 163-165. 11. Weil S, Reifenberger G, Dudel C, Yousry TA, Schriever S, Noachtar S. Cerebroretinal vasculopathy mimicking a brain tumor: a case of a rare hereditary syndrome. Neurology. 1999;53:629-631. 24 Gruver et al: J Neuro-Ophthalmol 2011; 31: 20-24 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
