The Retina in Lafora Disease: Light and Electron Microscopy

Berard-Badier, M; Pellissier, Jean‐François; Gambarelli, D.; Barsy, Thierry de; Roger, J; Toga, M

doi:10.1007/978-3-642-81445-7_14

Cited by 6 publications

(14 citation statements)

References 14 publications

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“…We did not detect any structural alterations in the macula on spectral-domain optical coherence tomography (in vivo imaging that provides ;5 μm axial resolution); a prior histologic report observed LB deposition in inner retinal layers of macula. 2 Our study revealed abnormal retinal function on ERG testing in all patients. Generalized rod bipolar cell dysfunction as evidenced by reduced b/a ratio of scotopic ERG was present in 3, and generalized cone system dysfunction with cone inner retinal (bipolar) involvement was observed in all 4 patients.…”

Section: Discussionsupporting

confidence: 47%

“…The bipolar cell dysfunction observed on ERG is in keeping with the histologic bipolar cell atrophy described in LD. 2 The ERG also demonstrated generalized reduction in rod photoreceptor function (decreased rod a-wave amplitude) in both EPM2B patients. Although no abnormality was noted in photoreceptor layers in postmortem eyes (genes unknown), the observed rod a-wave changes in EPM2B patients may indicate functional changes to precede structural changes in specific disease stages or may be unique to EPM2B.…”

Section: Discussionmentioning

confidence: 80%

“…Although no abnormality was noted in photoreceptor layers in postmortem eyes (genes unknown), the observed rod a-wave changes in EPM2B patients may indicate functional changes to precede structural changes in specific disease stages or may be unique to EPM2B. 2 Reports using early ERG techniques (1978 or earlier) suggested normal responses or transiently subnormal bipolar cell activity in LD 3,7 ; the current techniques are superior, and can better delineate the locus of abnormality. ERG may be a valuable tool to monitor LD progression, and potentially serve as a useful biomarker to investigate intervention efficacy in gene replacement or other therapeutic clinical trials.…”

Section: Discussionmentioning

confidence: 87%

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Ocular phenotype and electroretinogram abnormalities in Lafora disease

et al. 2018

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Lafora disease (LD) is a teenage-onset progressive neurologic disorder caused by biallelic mutations in EPM2A (laforin) or EPM2B (malin) encoding laforin phosphatase and malin ubiquitin E3 ligase, respectively, both involved in glycogen structural integrity. Defective laforin or malin results in neuronal accumulation of malformed insoluble glycogen termed Lafora bodies (LBs). 1 Histologic reports indicate LB accumulation in the inner retinal layers with evidence of bipolar cell atrophy. 2 Funduscopic retinal examination has been reported unremarkable except in one patient with unilateral optic atrophy that may have been unrelated to LD. 3,4 Recently, retinitis pigmentosa was reported in a 21-year-old patient diagnosed only on skin biopsy, and was highlighted on the journal cover. 5 A subsequent letter to the editor suggested that this may represent an instance of false-positive interpretation of skin biopsy, but the debate remains unsettled. 1,5,6 We aimed to address this issue by performing multimodal imaging and electrophysiology (e-Methods in links.lww.com/WNL/A580) to characterize the eye phenotype in 4 patients with genetically confirmed LD, concurrently setting the stage to identify potentially useful ophthalmologic biomarkers in LD. e-Methods and tables e-1 and e-2, links.lww.com/WNL/A578, summarize the genetic results and clinical phenotype of the patients.

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Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 87%

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Ocular phenotype and electroretinogram abnormalities in Lafora disease

et al. 2018

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“…Glycogen storage in the diabetic retina has not been previously associated with primary neuronal dysfunction or cell loss in diabetic retinopathy, and although the retina represents a target in classical glycogen storage diseases, notably Lafora disease 41,42 and Pompe disease, 43 the pathologic features of these conditions differ greatly from diabetes. The glycogen stores observed in diabetic amacrine cells in the present study occurred as aggregates of normal beta-particles lying free within the cytoplasm, while in Lafora disease, discrete membrane-bound bodies contain filamentous aggregates of abnormal polyglucosans.…”

Section: Glycogen Storage In Retinal Neurons: Pathologic Implicationsmentioning

confidence: 99%

Abnormal Glycogen Storage by Retinal Neurons in Diabetes

Gardiner

Canning

Tipping

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. It is widely held that neurons of the central nervous system do not store glycogen and that accumulation of the polysaccharide may cause neurodegeneration. Since primary neural injury occurs in diabetic retinopathy, we examined neuronal glycogen status in the retina of streptozotocin-induced diabetic and control rats.METHODS. Glycogen was localized in eyes of streptozotocin-induced diabetic and control rats using light microscopic histochemistry and electron microscopy, and correlated with immunohistochemical staining for glycogen phosphorylase and phosphorylated glycogen synthase (pGS).RESULTS. Electron microscopy of 2-month-old diabetic rats (n ¼ 6) showed massive accumulations of glycogen in the perinuclear cytoplasm of many amacrine neurons. In 4-month-old diabetic rats (n ¼ 11), quantification of glycogen-engorged amacrine cells showed a mean of 26 cells/mm of central retina (SD 6 5), compared to 0.5 (SD 6 0.2) in controls (n ¼ 8). Immunohistochemical staining for glycogen phosphorylase revealed strong expression in amacrine and ganglion cells of control retina, and increased staining in cell processes of the inner plexiform layer in diabetic retina. In control retina, the inactive pGS was consistently sequestered within the cell nuclei of all retinal neurons and the retinal pigment epithelium (RPE), but in diabetics nuclear pGS was reduced or lost in all classes of retinal cell except the ganglion cells and cone photoreceptors.CONCLUSIONS. The present study identifies a large population of retinal neurons that normally utilize glycogen metabolism but show pathologic storage of the polysaccharide during uncontrolled diabetes.

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“…The malstructured insoluble glycogen (polyglucosans) gradually precipitates over the months and accumulates into Lafora bodies (LB), which cannot be digested by the normal glycogen-digesting enzymes. LB accumulate in the somatodendritic compartments of neurons and clog dendrites [ 1 , 5 , 22 ] leading to severe and rapid neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Nationwide genetic testing towards eliminating Lafora disease from Miniature Wirehaired Dachshunds in the United Kingdom

Ahonen

Seath

Rusbridge

et al. 2018

Canine Genet Epidemiol

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BackgroundCanine DNA-testing has become an important tool in purebred dog breeding and many breeders use genetic testing results when planning their breeding strategies. In addition, information obtained from testing of hundreds dogs in one breed gives valuable information about the breed-wide genotype frequency of disease associated allele. Lafora disease is a late onset, recessively inherited genetic disease which is diagnosed in Miniature Wirehaired Dachshunds (MWHD). It is one of the most severe forms of canine epilepsy leading to neurodegeneration and, frequently euthanasia within a few years of diagnosis. Canine Lafora disease is caused by a dodecamer repeat expansion mutation in the NHLRC1 gene and a DNA test is available to identify homozygous dogs at risk, carriers and dogs free of the mutation.ResultsBlood samples were collected from 733 MWHDs worldwide, mostly of UK origin, for canine Lafora disease testing. Among the tested MWHD population 7.0% were homozygous for the mutation and at risk for Lafora disease. In addition, 234 dogs were heterozygous, indicating a carrier frequency of 31.9% in the tested population. Among the tested MWHDs, the mutant allele frequency was 0.2. In addition, data from the tested dogs over 6 years (2012–2017) indicated that the frequency of the homozygous and carrier dogs has decreased from 10.4% to 2.7% and 41.5% to 25.7%, respectively among MWHDs tested. As a consequence, the frequency of dogs free of the mutation has increased from 48.1% to 71.6%.ConclusionsThis study provides valuable data for the MWHD community and shows that the DNA test is a useful tool for the breeders to prevent occurrence of Lafora disease in MWHDs. DNA testing has, over 6 years, helped to decrease the frequency of carriers and dogs at risk. Additionally, the DNA test can continue to be used to slowly eradicate the disease-causing mutation in the breed. However, this should be done carefully, over time, to avoid further compromising the genetic diversity of the breed. The DNA test also provides a diagnostic tool for veterinarians if they are presented with a dog that shows clinical signs associated with canine Lafora disease.

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The Retina in Lafora Disease: Light and Electron Microscopy

Cited by 6 publications

References 14 publications

Ocular phenotype and electroretinogram abnormalities in Lafora disease

Ocular phenotype and electroretinogram abnormalities in Lafora disease

Abnormal Glycogen Storage by Retinal Neurons in Diabetes

Nationwide genetic testing towards eliminating Lafora disease from Miniature Wirehaired Dachshunds in the United Kingdom

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