Mcardle Disease Associated Maculopathy and the Role of Glycogen in the Retina

Home , Maculopathy

Marques JH and Beirão JM, J Ophthalmic Clin Res 2020, 7: 067 DOI: 10.24966/OCR-8887/100067 HSOA Journal of Ophthalmology & Clinical Research

Case Report

demanding tissues like the RPE depend on glycogen phosphoryla- McArdle Disease associated tion to produce energy and, on the other hand, glycogen erroneous accumulation may impair cellular functions. Probably due to higher Maculopathy and the Role of photoreceptor concentration and subsequent energy demand in the macula, this is the primary site for degeneration in our patient. The Glycogen in the Retina present report reinforces the role of the glycogen pathway as a pos- sible player in the pathophysiology of RPE pathologies, genetically and/or environmentally determined. Keywords: Age-related macular degeneration; Geographic atrophy; João Heitor Marques1* and João Melo Beirão1,2 Glycogen; McArdle; Retinal pigmented epithelium 1Serviço de Oftalmologia, Centro Hospitalar e Universitário do Porto, Portugal Introduction 2Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal Intracellular glycogen works as a buffer for glucose metabolism. Glycogen phosphorylase breaks down glycogen, making glucose available for aerobic and anaerobic energetic pathways. It can be rapidly metabolized without ATP requirement. A deficit in glycogen phosphorylation results, not only in energy shortage, but also in its Abstract intracellular accumulation, which may further interfere with other Purpose: To report a case of maculopathy with pattern dystrophy cellular functions. and geographic atrophy in a patient with McArdle disease and to review the glycogen pathway’s disorders as a source of energy but Glycogen Storage Disease type V (GSDV), also known as McAr- also cause of disease in the retina. dle disease [1], is a genetic myopathy caused by loss-of-function mu- tation in both alleles of the PYGM gene. It results in an inherited Setting/Venue: Centro Hospitalar Universitário do Porto, Portugal. deficit of myophosphorylase, the skeletal muscle isoform of glycogen Methods: Case report with multimodal imaging, including color fun- phosphorylase enzyme. This leads, not only to ATP depletion, but also dus photography, infrared fundus photography, fluorescein angiogra- to the accumulation of ADP, inhibiting calcium pump and sodium-po- phy and optical coherence tomography. tassium pumps, during energy demand [2]. Muscle histology shows Results: A 61-year-old man with McArdle disease, a rare deficit of negative chemical staining for myophosphorylase activity and subsa- glycogen phosphorylation, with genetic and phenotypic (muscle bi- rcolemmal deposits of glycogen on periodic acid-Schiff stain [3]. opsy) confirmation. He had history of muscle weakness and pain Its estimated prevalence is 1:100000 [4], making it the most com- sincechildhood and recently complained of progressive visual loss. Fundus examination observation and multimodal imaging revealed mon disorder of skeletal muscle carbohydrate metabolism. GSDV is macular reticular pattern dystrophy of both eyes, associated with not usually a lethal condition. Clinically, it manifests as exercise intol- geographic atrophy in left eye. erance and reversible acute episodes of contractures, associated with rhabdomyolysis and myoglobinuria. Conclusion: Previous cases of McArdle disease-associated retinopathy with reticular pattern dystrophy had been reported. More- In the eye, the Retinal Pigmented Epithelium (RPE) is a spe- over, this is the first reported case that presented with geographic cialized tissue responsible for keeping the photoreceptors operating atrophy of the Retinal Pigmented Epithelium (RPE). Such findings and, ultimately, maintaining visual function. RPE forms the outer suggest that these phenotypes are part of the same pathological blood-retinal barrier: on one side, its tight junctions protect the retina spectrum and similar to other acquired retinal pigmented epithelium from blood-borne toxins and provides ocular immune privilege. On diseases, such as age-related macular degeneration. Metabolic high the other side, it must deliver nutrients and disposes waste products. Moreover, the RPE absorbs non-transduced light, mitigates photo-ox- *Corresponding author: João Heitor Marques, Serviço de Oftalmologia, Centro idative stress, recycles retinoids and secrets essential growth factors Hospitalar Universitário do Porto, Hospital Santo António (HSA), Largo do Prof. [5,6]. Abel Salazar, 4099-001 Porto, Portugal, Tel: +351 913680726: E-mail: joao- [email protected] Glucose is the major energy substrate for retinal metabolism [7] Citation: Marques JH, Beirão JM (2020) McArdle Disease associated Macu- and its source to the outer retina is the RPE. The RPE also manages lopathy and the Role of Glycogen in the Retina. J Ophthalmic Clin Res 7: 067. the conversion of glucose to glycogen and back, as a buffer [8], be- Received: April 06, 2020; Accepted: April 13, 2020; Published: April 20, 2020 tween the choriocapillaris and the photoreceptors. This way, it is able to manage the demand of the photoreceptors. Copyright: © 2020 Marques JH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits un- The RPE is implicated in the pathogenesis of several retinal de- restricted use, distribution, and reproduction in any medium, provided the original generations, including Age-Related Macular Degeneration (AMD) author and source are credited. [9]. Citation: Marques JH, Beirão JM (2020) McArdle Disease associated Maculopathy and the Role of Glycogen in the Retina. J Ophthalmic Clin Res 7: 067.

• Page 2 of 5 •

Therefore, our purpose is to report a case of GSDV associated with geographic atrophy of the RPE and to review the glycogen pathways’ as a source of energy but also degeneration in the retina. Methods 1. Case report with macular multimodal imaging, including color fundus photography, infrared fundus photography, fluorescein angiography and spectral-domain optical coherence tomography. 2. Systematic review of indexed articles on the glycogen role in Age-Related Macular Degeneration that were published until Feb- ruary 2020. Results We report a case of a man with exercise intolerance and pain during physical efforts since a young age. He had no relevant medical history except for controlled arterial hypertension and past history of smoking (he quit 15 years before). At the age of 61, on routine blood samples, repeated over-the-limit creatine kinase measurements motivated the referral to our center. GSDV diagnosis was made with suggestive muscle biopsy and genetic confirmation (compound het- erozygote PYGM gene with mutations C148T and T2392CA, both associated with loss of function of myophosphorylase). Figure 1: Infra-red fundus photograph (left) and corresponding OCT B-scan (right) of the right (upper) and left (bottom) eyes. Six months after diagnosis, the patient complained of progressive vision loss in both eyes. Given this, he was referred to our Ophthal- mology Department. His visual acuity was 0.7 on his right eye and 0.4 on his left eye (decimal scale). Intraocular pressure measured with Goldmann applanation tonometer was 16mmHg in both eyes. Ante- rior segment examination was unremarkable. Fundus observation revealed no typical drusen in the periphery or posterior pole. There was macular reticular-like pattern dystrophy in both eyes, associated with geographic atrophy in left eye. Color and infra-red fundus photography, fluorescein angiography (Figure 1) and spectral-domain macular optical coherence tomography (Figure 2) confirmed the findings: On the right eye, optical coherence tomography shown no sub-RPE deposits (drusen) and focal degeneration of RPE and external photoreceptor tips together with corresponding changes in the external nuclear layer. On the left eye, optical coherence tomography revealed no sub-RPE deposits (drusen), an area of complete atrophy of the RPE and external retinal lay- ers and changes similar to the previous described around the atrophic area. Discussion The present case-report confirms that degenerative geographic Figure 2: Fluorescein angiography at minute 2 (upper) and color fundus photo- atrophy is not a specific finding of classic AMD and is not always graph (bottom) of right and left eyes. accompanied by the presence of drusen. Moreover, pattern dystrophy and geographic atrophy may be part of the same pathological spectrum. Regarding our case, we had no ophthalmic records before the di- Although there is no direct causal relationship between GSDV and agnosis, but visual symptoms started just in the seventh decade of the development of RPE atrophy, this case suggests that a single defi- life. Thus, we may assume that macular RPE atrophy began at around cit in energetic pathways may be capable of causing RPE atrophy or, that time, even if other asymptomatic retinal changes were eventual- at least, accelerate it. ly present before. Given that the metabolic deficit is congenital, an additional factor should be involved to explain the late onset of the In another perspective, it favors the hypothesis that the current disease. If we consider age as the second factor, we may postulate that definition of AMD encompasses not a single disease, since different glycogen phosphorylation deficit leads to a slow RPE suffering and pathological paths may lead to the same manifestation. debris accumulation that, after decades, results in cellular death.

Volume 7 • Issue 1 • 100067 J Ophthalmic Clin Res ISSN: 2378-8887, Open Access Journal DOI: 10.24966/OCR-8887/100067 Citation: Marques JH, Beirão JM (2020) McArdle Disease associated Maculopathy and the Role of Glycogen in the Retina. J Ophthalmic Clin Res 7: 067.

• Page 3 of 5 •

One limitation of this report is that our patient was not screened for We postulate that AMD, as we know it, may be a manifestation of other genetic loci associated with macular pattern dystrophies, such different forms of progressive energy deficiency, caused by lipid and as PRPH2, ABCA4, BEST1, CDH3, EFEMP1, ELOVL4, IMPG1, also carbohydrate metabolism impairment. IMPG2, PROM1, PRPH2 and TIMP3. Nonetheless, previous cases Conclusion of McArdle disease have been associated with pattern dystrophy of the RPE [10-13]. In these previous reports, ophthalmic manifestations Geographic atrophy can be caused by a glycogen phosphorylation were also detected in middle-age individuals. One of these reports ex- deficit in the RPE. To consider the eye part of central nervous sys- cluded other genetic loci as cause of the retinopathy. Ours is the first tem, may contribute to mutually understand neurological and retinal reported case that presented concomitantly with geographic atrophy. degenerative diseases. Finally, knowledge about molecular pathways that control retinal metabolism may provide important clues about Hernández et al., [14] showed that, in RPE from human donors, retinal degenerative pathology, such as AMD, and enlighten future the present glycogen phosphorylase enzyme was the muscle isoform therapies. (myophosphorylase) and the brain isoform, but not the liver one. This reinforces the retinopathy pathogenesis in our case. Financial Disclosure: None The relation between RPE suffering and vision loss is of great References interest and it has mainly been studied in AMD. 1. McArdle B (1951) Myopathy due to a defect in muscle glycogen break- Hypoxia in RPE seams to deeply alter its metabolism. In mice down. Clin Sci 10: 13-35. model, hypoxiainduced RPE cells revealed under expression of the 2. Lewis SF, Haller RG (1986) The pathophysiology of McArdle’s disease: PYGM gene and intracellular accumulation of glycogen. These Clues to regulation in exercise and fatigue. J Appl Physiol 61: 391-401. changes impact nutrient availability for the sensory retina and pro- 3. Bartram C, Edwards RHT, Beynon RJ (1995) McArdle’s disease-muscle mote photoreceptor degeneration [15]. glycogen phosphorylase deficiency. Biochim Biophys Acta 1272: 1-13. Probably due to higher photoreceptor concentration and subse- 4. Haller RG (2000) Treatment of McArdle disease. Arch Neurol 57: 923- quent energy demand in the macula, this is the primary site for degen- 924. eration in our patient. 5. Simó R, Villarroel M, Corraliza L, Hernández C, Garcia-Ramírez M, et AMD is the leading cause of blindness in developed countries al. (2010) The retinal pigment epithelium: Something more than a con- stituent of the blood-retinal barrier-implications for the pathogenesis of [16]. It is a multifactorial disease modified by environmental (e.g., diabetic retinopathy. J Biomed Biotechnol 2010: 190724. smoking) and genetic factors, not fully understood. Extracellular li- 6. Strauss O (2005) The retinal pigment epithelium in visual function. poprotein deposits beneath the RPE (drusen) are the hallmark of the Physiol Rev 85: 845-881. early stages of the disease. RPE atrophy (geographic atrophy) further results in photoreceptor degeneration and, consequently, vision loss. 7. Zeitschrift HK-B (1927) undefined. On the metabolism of the retina. There is currently no treatment for atrophic AMD. 8. Senanayake Pd, Calabro A, Hu JG, Bonilha VL, Darr A, et al. (2006) Glucose utilization by the retinal pigment epithelium: Evidence for rapid Cultured RPE from AMD patients revealed accumulation of lipid uptake and storage in glycogen, followed by glycogen utilization. Exp droplets and glycogen granules, disintegration of mitochondria and Eye Res 83: 235-246. increased number of autophagosomes [17]. The group of Zhang et 9. Ao J, Wood JPM, Chidlow G, Gillies MC, Casson RJ, et al. (2018) al., has recently shared evidence for the involvement of an overac- Retinal pigment epithelium in the pathogenesis of age-related macular tive mTOR pathway in AMD [18], which, in turn, promotes glyco- degeneration and photobiomodulation as a potential therapy?. Clin Exp Ophthalmol 46: 670-686. gen accumulation [19]. Other study showed that, in animal models of stress-induced RPE, pharmacological inhibition of the mTOR path- 10. Leonardy NJ, Harbin RL, Sternberg P (1988) Pattern dystrophy of the way preserves photoreceptor function [20]. retinal pigment epithelium in a patient with McArdle’s disease. Am J Ophthalmol 106: 741-742. Inês Laíns et al., focused on the metabolomics in AMD and their 11. Casalino G, Chan W, McAvoy C, Coppola M, Bandello F, et al. (2018) findings implicate glycerophospholipid, taurine, purines pathways Multimodal imaging of posterior ocular involvement in McArdle’s dis- [21]. The same pathways have also been implicated in degenerative ease. Clin Exp Optom 101: 412-415. neurological disorders like Alzheimer’s disease [22,23]. 12. Alsberge JB, Chen JJ, Zaidi AA, Fu AD (2018) Retinal Dystrophy in a Patient with McArdle Disease. Retin Cases Brief Rep. If we look at the retina as an elongation of the central nervous system and at the RPE cells as analogous to astrocytes, the metabolic 13. Mahroo OA, Khan KN, Wright G, Ockrim Z, Scalco RS, et al. (2019) similarities are evident: in the brain, glycogen is found almost exclu- Retinopathy Associated with Biallelic Mutations in PYGM (McArdle sively in astrocytes and it composes the largest energy reserve [24]. Disease). Ophthalmology 126: 320-322. Some studies have also implicated the glycogen pathways in memory 14. Hernández C, Garcia-Ramírez M, García-Rocha M, Saez-López C, consolidation [25] and possibly in Alzheimer’s disease [26]. Valverde ÁM, et al. (2014) Glycogen storage in the human retinal pigment epithelium: A comparative study of diabetic and non-diabetic do- Genetic risk factors for AMD are under investigation and they nors. Acta Diabetol 51: 543-552. mostly relate to lipid metabolism [27]. It would be interesting to look 15. Kurihara T, Westenskow PD, Gantner ML, Usui Y, Schultz A, et al. for changes in carbohydrate metabolism as risk factors for conversa- (2016) Hypoxia-induced metabolic stress in retinal pigment epithelial tion of drusen to geographic atrophy. cells is sufficient to induce photoreceptor degeneration. Elife: 5.

• Page 4 of 5 •

16. Wong WL, Su X, Li X, Cheung CM, Klein R, et al. (2014) Global preva- 22. Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, et al. lence of age-related macular degeneration and disease burden projection (2014) Plasma phospholipids identify antecedent memory impairment in for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob older adults. Nat Med 20: 415-418. Heal 2: 106-116. 23. Jové M, Portero-Otín M, Naudí A, Ferrer I, Pamplona R (201) Metabolo- 17. Golestaneh N, Chu Y, Xiao YY, Stoleru GL, Theos AC, et al. (2017) mics of human brain aging and age-related neurodegenerative diseases. J Dysfunctional autophagy in RPE, a contributing factor in age-related Neuropathol Exp Neurol 73: 640-657. macular degeneration. Cell Death Dis 8: 2537. 24. Brown AM (2004) Brain glycogen re-awakened. J Neurochem 89: 537- 18. Zhang M, Jiang N, Chu Y, Postnikova O, Varghese R, et al. (2020) Dys- 552. regulated metabolic pathways in age-related macular degeneration. Sci Rep 10: 2464. 25. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, et al. (2011) Astrocyte-neuron lactate transport is required for long-term memory for- 19. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and mation. Cell 144: 810-823. disease. Cell 149: 274-293. 26. Bass B, Upson S, Roy K, Montgomery EL, Jalonen TO, et al. (2015) 20. Zhao C, Yasumura D, Li X, Matthes M, Lloyd M, et al. (2011) Glycogen and amyloid-beta: Key players in the shift from neuronal hy- mTOR-mediated dedifferentiation of the retinal pigment epithelium ini- peractivity to hypoactivity observed in Alzheimer’s disease. Neural Re- tiates photoreceptor degeneration in mice. J Clin Invest 121: 369-383. gen Res 10: 1023-1025. 21. Laíns I, Chung W, Kelly RS, Gil J, Marques M, et al. (2019) Human 27. DeAngelis MM, Owen LA, Morrison MA, Morgan DJ, Li M, et al. plasma metabolomics in age-related macular degeneration: Meta-analy- (2017) Genetics of age-related macular degeneration (AMD). Hum Mol sis of two cohorts. Metabolites: 9. Genet 26: 45-50.

Volume 7 • Issue 1 • 100067 J Ophthalmic Clin Res ISSN: 2378-8887, Open Access Journal DOI: 10.24966/OCR-8887/100067

Advances In Industrial Biotechnology | ISSN: 2639-5665 Journal Of Genetics & Genomic Sciences | ISSN: 2574-2485

Advances In Microbiology Research | ISSN: 2689-694X Journal Of Gerontology & Geriatric Medicine | ISSN: 2381-8662

Archives Of Surgery And Surgical Education | ISSN: 2689-3126 Journal Of Hematology Blood Transfusion & Disorders | ISSN: 2572-2999

Archives Of Urology Journal Of Hospice & Palliative Medical Care

Archives Of Zoological Studies | ISSN: 2640-7779 Journal Of Human Endocrinology | ISSN: 2572-9640

Current Trends Medical And Biological Engineering Journal Of Infectious & Non Infectious Diseases | ISSN: 2381-8654

International Journal Of Case Reports And Therapeutic Studies | ISSN: 2689-310X Journal Of Internal Medicine & Primary Healthcare | ISSN: 2574-2493

Journal Of Addiction & Addictive Disorders | ISSN: 2578-7276 Journal Of Light & Laser Current Trends

Journal Of Agronomy & Agricultural Science | ISSN: 2689-8292 Journal Of Medicine Study & Research | ISSN: 2639-5657 Journal Of AIDS Clinical Research & STDs | ISSN: 2572-7370 Journal Of Modern Chemical Sciences Journal Of Alcoholism Drug Abuse & Substance Dependence | ISSN: 2572-9594 Journal Of Nanotechnology Nanomedicine & Nanobiotechnology | ISSN: 2381-2044 Journal Of Allergy Disorders & Therapy | ISSN: 2470-749X Journal Of Neonatology & Clinical Pediatrics | ISSN: 2378-878X Journal Of Alternative Complementary & Integrative Medicine | ISSN: 2470-7562 Journal Of Nephrology & Renal Therapy | ISSN: 2473-7313 Journal Of Alzheimers & Neurodegenerative Diseases | ISSN: 2572-9608 Journal Of Non Invasive Vascular Investigation | ISSN: 2572-7400 Journal Of Anesthesia & Clinical Care | ISSN: 2378-8879 Journal Of Nuclear Medicine Radiology & Radiation Therapy | ISSN: 2572-7419 Journal Of Angiology & Vascular Surgery | ISSN: 2572-7397 Journal Of Obesity & Weight Loss | ISSN: 2473-7372 Journal Of Animal Research & Veterinary Science | ISSN: 2639-3751 Journal Of Ophthalmology & Clinical Research | ISSN: 2378-8887 Journal Of Aquaculture & Fisheries | ISSN: 2576-5523 Journal Of Orthopedic Research & Physiotherapy | ISSN: 2381-2052 Journal Of Atmospheric & Earth Sciences | ISSN: 2689-8780 Journal Of Otolaryngology Head & Neck Surgery | ISSN: 2573-010X Journal Of Biotech Research & Biochemistry Journal Of Pathology Clinical & Medical Research Journal Of Brain & Neuroscience Research Journal Of Pharmacology Pharmaceutics & Pharmacovigilance | ISSN: 2639-5649 Journal Of Cancer Biology & Treatment | ISSN: 2470-7546 Journal Of Physical Medicine Rehabilitation & Disabilities | ISSN: 2381-8670 Journal Of Cardiology Study & Research | ISSN: 2640-768X Journal Of Plant Science Current Research | ISSN: 2639-3743 Journal Of Cell Biology & Cell Metabolism | ISSN: 2381-1943 Journal Of Practical & Professional Nursing | ISSN: 2639-5681 Journal Of Clinical Dermatology & Therapy | ISSN: 2378-8771 Journal Of Protein Research & Bioinformatics Journal Of Clinical Immunology & Immunotherapy | ISSN: 2378-8844 Journal Of Psychiatry Depression & Anxiety | ISSN: 2573-0150 Journal Of Clinical Studies & Medical Case Reports | ISSN: 2378-8801 Journal Of Pulmonary Medicine & Respiratory Research | ISSN: 2573-0177 Journal Of Community Medicine & Public Health Care | ISSN: 2381-1978

Journal Of Cytology & Tissue Biology | ISSN: 2378-9107 Journal Of Reproductive Medicine Gynaecology & Obstetrics | ISSN: 2574-2574

Journal Of Dairy Research & Technology | ISSN: 2688-9315 Journal Of Stem Cells Research Development & Therapy | ISSN: 2381-2060

Journal Of Dentistry Oral Health & Cosmesis | ISSN: 2473-6783 Journal Of Surgery Current Trends & Innovations | ISSN: 2578-7284

Journal Of Diabetes & Metabolic Disorders | ISSN: 2381-201X Journal Of Toxicology Current Research | ISSN: 2639-3735

Journal Of Emergency Medicine Trauma & Surgical Care | ISSN: 2378-8798 Journal Of Translational Science And Research

Journal Of Environmental Science Current Research | ISSN: 2643-5020 Journal Of Vaccines Research & Vaccination | ISSN: 2573-0193

Journal Of Food Science & Nutrition | ISSN: 2470-1076 Journal Of Virology & Antivirals

Journal Of Forensic Legal & Investigative Sciences | ISSN: 2473-733X Sports Medicine And Injury Care Journal | ISSN: 2689-8829

Journal Of Gastroenterology & Hepatology Research | ISSN: 2574-2566 Trends In Anatomy & Physiology | ISSN: 2640-7752

Submit Your Manuscript: https://www.heraldopenaccess.us/submit-manuscript

Herald Scholarly Open Access, 2561 Cornelia Rd, #205, Herndon, VA 20171, USA. Tel: +1 202-499-9679; E-mail: [email protected] http://www.heraldopenaccess.us/