Case of the Month

Edited by Robert N. Johnson, MD

Case History

A 29-year-old woman presented for evaluation of yellow spots in both eyes.

On examination, visual acuity was 20/16 in the right eye and 20/20 in the left eye. The anterior segment examination was unremarkable. Dilated examination revealed pigmented yellow spots involving the macula and nasal mid-periphery of both eyes (Figures 1 and 2). Fundus autofluorescence showed focal areas of subtle hypoautofluorescence centrally with surrounding haloes of hyperautoflourescence (Figures 3 and 4). Optical coherence tomography revealed changes at the level of the retinal pigment epithelium (RPE) in both eyes (Figures 5 and 6).

Differential Diagnosis

Isolated pattern dystrophy (PRPH2/RDS), pattern dystrophy associated with systemic disease (e.g., pseudoxanthoma elasticum, myotonic dystrophy, maternally inherited diabetes and deafness, hereditary spastic paraplegia, McArdle disease), Stargart’s disease, central serous chorioretinopathy.

Additional History and Diagnosis

The patient reported a several year history of exercise intolerance due to fatigue and muscle cramping. A muscle biopsy had been performed and revealed a deficiency of glycogen phosphorylase, consistent with McArdle disease, a glycogen storage disease. She had no family history of retinal dystrophy. Given the medical history and clinical findings, the diagnosis of pattern dystrophy associated with McArdle disease was made.

Discussion

McArdle disease (glycogen storage disease type V) is a rare genetic condition that is characterized by a deficiency of skeletal muscle glycogen phosphorylase, an enzyme that is responsible for breaking down muscle glycogen.¹ This deficiency results in inability to mobilize muscle glycogen during exercise when anaerobic metabolism is required. Pattern dystrophy-type retinal findings have been reported in multiple patients with McArdle disease.^2-5

McArdle disease is autosomal recessive and is associated with mutations in the PYGM gene on chromosome 11, which encodes skeletal muscle glycogen phosphorylase.¹ Symptoms of the disease include fatigue and muscle cramping induced by exercise and relieved with rest. Intense exercise may lead to rhabdomyolysis. Laboratory studies may show elevated serum creatine kinase and myoblobinuria. Diagnosis of the disease requires a high index of suspicion and is based on a forearm exercise test showing inability to produce lactate, the absence of muscle glycogen phosphorylase on muscle biopsy, or DNA analysis of the PYGM gene.

Pattern dystrophy refers to a group of diseases that is characterized by patterned deposits of yellow, orange, or gray pigment in the macula and mid periphery. Isolated pattern dystrophies are most frequently associated with mutations in PRPH2 located on chromosome 6, and inherited in an autosomal dominant fashion.⁶ These dystrophies have been categorized into 5 principle groups based on their characteristic distribution of findings: adult-onset foveomacular vitelliform dystrophy, butterfly-shaped pigment dystrophy, reticular dystrophy of the RPE, multifocal pattern dystrophy simulating fundus flavimaculatus, and fundus pulverulentus.⁶ Retinal changes typical of isolated pattern dystrophy have also been associated with a number of systemic diseases including pseudoxanthoma elasticum,⁷ myotonic dystrophy, maternally inherited diabetes and deafness, and hereditary spastic paraplegia.⁶

The first case of pattern dystrophy in a patient with McArdle disease was reported in 1998 by Leonardy et al.,² and several others have followed since.^3-5 These cases describe bilateral, pigmented, yellow, reticular lesions at the level of the RPE involving the macula and periphery, very similar in appearance to the case we have shown here. Importantly, in recent series by Mahroo et al., patients with confirmed McArdle disease and pattern dystrophy lacked PRPH2 mutations.⁵ This suggests that though PRPH2-associated isolated pattern dystrophy and McArdle-associated pattern dystrophy share similar phenotypes, they are distinct entities.

The potential causative mechanism of pattern dystrophy in McArdle disease is unknown. As mentioned previously, McArdle disease results from a mutation in the PYGM gene on chromosome 11, leading to deficiency of skeletal muscle glycogen phosphorylase. Intriguingly, muscle glycogen phosphorylase isoforms have been detected in human RPE,⁸ so perhaps the McArdle’s-associated PYGM gene mutation has the potential to lead to RPE dysfunction. Alternatively, it is possible that the PYGM mutation could lead to dysregulation of another nearby genetic locus on chromosome 11 involved in RPE function.^2,3

This Case of the Month was adapted from the article “Retinal Dystrophy in a Patient with McArdle Disease” by Joseph Alsberge, Judy Chen, Ali Zaidi, and Arthur Fu, published online in Retinal Cases & Brief Reports on August 1, 2018.⁴

References

1. Quinlivan R, Buckley J, James M, et al. McArdle disease: a clinical review. J Neurol Neurosurg Psychiatry 2010;81:1182–1188.
2. Leonardy NJ, Harbin RL, Sternberg P. Pattern dystrophy of the retinal pigment epithelium in a patient with McArdle’s disease. Am J Ophthalmol 1988;106:741–742.
3. Casalino G, Chan W, McAvoy C. Multimodal imaging of posterior ocular involvement in McArdle’s disease. Clin Exp Optom 2017;101:412–415.
4. Alsberge JB, Chen JJ, Zaidi AA, Fu AD. Retinal dystrophy in a patient with McArdle disease. Retin Cases Brief Rep 2018 Aug 1; DOI: 10.1097/ICB.0000000000000790 [Epub ahead of print].
5. Mahroo OA, Khan KN, Wright G, et al. Retinopathy Associated with Biallelic Mutations in PYGM (McArdle Disease). Ophthalmology 2018 Oct 10; DOI: 10.1016/j.ophtha.2018.09.013. [Epub ahead of print]
6. Agarwal A. Heredodystrophic Disorders Affecting the Pigment Epithelium and Retina. In: Agarwal, A. Gass’ Atlas of Macular Diseases. Fifth ed. Elsevier:239-436.
7. McDonald HR, Schatz H, Aaberg TM. Reticular-like pigmentary patterns in pseudoxanthoma elasticum. Ophthalmology 1988;95:306-11.
8. Hernandez C, Garcia-Ramirez M, Garcia-Rocha M, et al. Glycogen storage in the human retinal pigment epithelium: a comparative study of diabetic and non-diabetic donors. Acta Diabetol 2014;51:543–552.