Journal of Pediatric Ophthalmology and Strabismus

Original Article 

Ocular and Histologic Findings in a Series of Children With Infantile Pompe Disease Treated With Enzyme Replacement Therapy

S. Grace Prakalapakorn, MD, MPH; Alan D. Proia, MD, PhD; Tammy L. Yanovitch, MD, MHSc; Stephanie DeArmey, MHS, PA-C; Nancy J. Mendelsohn, MD; Kyrieckos A. Aleck, MD; Priya S. Kishnani, MD

Abstract

Purpose:

To report the ophthalmologic and histologic findings in a series of children with infantile Pompe disease treated with enzyme replacement therapy (ERT).

Methods:

Records of children with infantile Pompe disease treated with ERT who had at least one complete ophthalmic examination and the ocular histopathology of children with infantile Pompe disease who were treated with ERT were reviewed. The patients’ clinical history, including external ocular examination, ocular alignment and motility, dilated fundus examination, and cycloplegic refraction, was evaluated. A literature review was performed for ophthalmologic findings in infantile Pompe disease using PubMed.

Results:

The clinical findings of 13 children were included and the ocular histopathology of 3 children with infantile Pompe disease who were treated with ERT were reviewed. Forty-six percent (6 of 13) had bilateral ptosis, 23% (3 of 13) had strabismus, 62% (8 of 13) had myopia, and 69% (9 of 13) had astigmatism. On histologic examination, there was vacuolar myopathy affecting the extraocular muscles, ciliary body, and iris smooth muscle and glycogen accumulation in corneal endothelial, lens epithelium, and retinal ganglion cells, and within lysosomes of scleral fibroblasts.

Conclusions:

It is important that ophthalmic providers are aware of the high prevalence of myopia, astigmatism, and ptosis in children with infantile Pompe disease treated with ERT because they are potentially amblyogenic but treatable factors.

[J Pediatr Ophthalmol Strabismus 2014;51(6):355–359.]

From Duke Eye Center, Durham, North Carolina (SGP); the Departments of Pathology (ADP) and Pediatrics (SD, PSK), Duke University, Durham, North Carolina; the Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma, Oklahoma City, Oklahoma (TLY); the Division of Medical Genetics, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota (NJM); and the Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, Arizona (KAA).

Supported by NIH EY016333 (SGP).

Drs. Kishnani and Mendelsohn received research grant support from Genzyme Corporation (Cambridge, MA). Dr. Kishnani is a member of the Pompe Disease Advisory Board and the Gaucher Registry Advisory Board for Genzyme Corporation, and has received honoraria from and served as a consultant to Genzyme Corporation. The remaining authors have no financial or proprietary interest in the materials presented herein.

The authors thank Deeksha Bali and Jennifer Goldstein for their help compiling genetic mutations.

Correspondence: S. Grace Prakalapakorn, MD, MPH, Duke Eye Center, 2351 Erwin Road, DUMC 3802, Durham, NC 27710. E-mail: grace. prakalapakorn@duke.edu

Received: April 14, 2014
Accepted: June 10, 2014
Posted Online: August 20, 2014

Abstract

Purpose:

To report the ophthalmologic and histologic findings in a series of children with infantile Pompe disease treated with enzyme replacement therapy (ERT).

Methods:

Records of children with infantile Pompe disease treated with ERT who had at least one complete ophthalmic examination and the ocular histopathology of children with infantile Pompe disease who were treated with ERT were reviewed. The patients’ clinical history, including external ocular examination, ocular alignment and motility, dilated fundus examination, and cycloplegic refraction, was evaluated. A literature review was performed for ophthalmologic findings in infantile Pompe disease using PubMed.

Results:

The clinical findings of 13 children were included and the ocular histopathology of 3 children with infantile Pompe disease who were treated with ERT were reviewed. Forty-six percent (6 of 13) had bilateral ptosis, 23% (3 of 13) had strabismus, 62% (8 of 13) had myopia, and 69% (9 of 13) had astigmatism. On histologic examination, there was vacuolar myopathy affecting the extraocular muscles, ciliary body, and iris smooth muscle and glycogen accumulation in corneal endothelial, lens epithelium, and retinal ganglion cells, and within lysosomes of scleral fibroblasts.

Conclusions:

It is important that ophthalmic providers are aware of the high prevalence of myopia, astigmatism, and ptosis in children with infantile Pompe disease treated with ERT because they are potentially amblyogenic but treatable factors.

[J Pediatr Ophthalmol Strabismus 2014;51(6):355–359.]

From Duke Eye Center, Durham, North Carolina (SGP); the Departments of Pathology (ADP) and Pediatrics (SD, PSK), Duke University, Durham, North Carolina; the Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma, Oklahoma City, Oklahoma (TLY); the Division of Medical Genetics, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota (NJM); and the Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, Arizona (KAA).

Supported by NIH EY016333 (SGP).

Drs. Kishnani and Mendelsohn received research grant support from Genzyme Corporation (Cambridge, MA). Dr. Kishnani is a member of the Pompe Disease Advisory Board and the Gaucher Registry Advisory Board for Genzyme Corporation, and has received honoraria from and served as a consultant to Genzyme Corporation. The remaining authors have no financial or proprietary interest in the materials presented herein.

The authors thank Deeksha Bali and Jennifer Goldstein for their help compiling genetic mutations.

Correspondence: S. Grace Prakalapakorn, MD, MPH, Duke Eye Center, 2351 Erwin Road, DUMC 3802, Durham, NC 27710. E-mail: grace. prakalapakorn@duke.edu

Received: April 14, 2014
Accepted: June 10, 2014
Posted Online: August 20, 2014

Introduction

Pompe disease is an inherited (autosomal recessive) lysosomal storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), which results in glycogen accumulation in various body tissues.1 Based on age of onset, organ involvement, and degree of myopathy, Pompe disease is broadly classified into two forms: infantile and late-onset.2

The infantile form includes those whose symptoms begin before they are 1 year old, and can be divided into two subtypes (classic and atypical), based on the severity and presence or absence of cardiomyopathy.3 Prior to the advent of enzyme replacement therapy (ERT) with alglucosidase alfa, most patients with infantile Pompe disease, in particular those with the classic form (severe cardiomyopathy and respiratory failure), did not survive past their first birthday.4 The introduction of ERT has dramatically improved their survival.5

To our knowledge, we are the first to report the ophthalmologic and histologic findings in a series of children with infantile Pompe disease treated with ERT.

Patients and Methods

This study was approved by the Duke Health System Institutional Review Board and was compliant with the requirements of the United States Health Insurance Portability and Accountability Act. Written informed consent was obtained for each patient from the legal guardian. Verbal assent was obtained from all patients at least 6 and younger than 12 years. We reviewed the records of 13 children and the post-mortem specimens of 3 children (one of whom was included in the clinical portion of this study) with infantile Pompe disease treated with ERT who had at least one complete ophthalmic examination. Patients were recruited from cases seen at Duke University Medical Center or from their participation in research studies on Pompe disease at Duke University. All patients had both a clinical (hypotonia and developmental delay in the first year of life) and genetic (GAA enzyme activity less than 1% in skin fibroblasts and two severe mutations in the GAA gene [Table A, available in the online version of this article]) diagnosis of infantile Pompe disease.

We reviewed the patients’ clinical history, including external ocular examination, ocular alignment and motility, dilated fundus examination, and cycloplegic refraction. For refractive errors, hyperopia, myopia, and high myopia were defined as a spherical equivalent of +0.50 diopters (D) or greater, −0.50 D or greater, and −6.00 D or less.

We also performed a literature search in PubMed for English-language–only articles (1946 to 2013), using combinations of the following search terms: “acid maltase deficiency,” “eye,” “glycogen-storage disease type II,” “glycogenosis type II,” “infantile,” “ocular,” and “Pompe.”

Results

Clinical Ophthalmologic Findings

Our series of children included 9 (69%) males and 4 (31%) females (Tables AB, available in the online version of this article). Eleven had classic and 2 had atypical disease. Average age at first eye examination was 3.2 years (range: 1.3 to 5.5 years) (Table C, available in the online version of this article). Eighty-five percent (11 of 13) had more than one eye examination.

Of those with classic disease, 45% (5 of 11) had bilateral ptosis and 27% (3 of 11) had strabismus (Table B). Of those with strabismus, all had intermittent exotropia. Eighteen percent (4 of 22) of eyes had hyperopia, 68% (15 of 22) had myopia, and 18% (4 of 22) had high myopia (Table C). Astigmatism of 1.00 D or greater, 2.00 D or greater, and 3.00 D or greater was detected in 68% (15 of 22), 59% (13 of 22), and 41% (9 of 22) of eyes, respectively. All astigmatism of 1.00 D or greater was with-the-rule.

Of the 2 patients with atypical disease, 1 had bilateral ptosis and neither had strabismus or myopia (Table B). One hundred percent (4 of 4) of eyes had hyperopia and 25% (1 of 4) of eyes had astigmatism (of 1.00 D or greater) (Table C).

All patients were initially given an intravenous infusion of 20 mg/kg of alglucosidase alfa every other week according to the Myozyme (Genzyme Corporation, Cambridge, MA) package insert instructions.6 Eighty-two percent (9 of 11) of those with classic and 50% (1 of 2) of those with atypical disease were titrated up to 40 mg/kg or more every other week in an attempt to improve their cardiomyopathy and muscle weakness (Table B).

Histologic Findings

We performed histologic examinations of eyes from a 7-month-old boy treated with ERT for 2 months, a 1-year-old girl treated with ERT for 4 months,7 and a 21-month-old girl treated with ERT for 15 months (case 11). In all cases, there was vacuolar myopathy affecting the extraocular muscle fibers, ciliary body, and iris smooth muscle; moderate accumulation of glycogen in corneal endothelial and retinal ganglion cells; and marked accumulation of glycogen in the lens epithelium (Figures 1A–1C). In our previously reported case,7 we also noted glycogen accumulation within lysosomes of scleral fibroblasts (Figure 1D).

(A) Inferior oblique muscle from a 21-month-old girl (case 11) treated with enzyme replacement therapy (ERT) for 15 months shows vacuolar myopathy affecting many, but not all, of the extraocular muscle fibers (hematoxylin–eosin, magnification bar = 50 µm). (B) The lens epithelium from the same child had marked accumulation of glycogen (periodic acid–Schiff reagent, magnification bar = 50 µm). (C) Ciliary body smooth muscle from this child had marked vacuolar myopathy affecting most of the cells (hematoxylin–eosin, magnification bar = 50 µm). (D) Transmission electron microscopy of a scleral fibroblast from a 1-year-old girl treated with ERT for 4 months shows glycogen accumulation within lysosomes (original magnification ×7,100).

Figure 1.

(A) Inferior oblique muscle from a 21-month-old girl (case 11) treated with enzyme replacement therapy (ERT) for 15 months shows vacuolar myopathy affecting many, but not all, of the extraocular muscle fibers (hematoxylin–eosin, magnification bar = 50 µm). (B) The lens epithelium from the same child had marked accumulation of glycogen (periodic acid–Schiff reagent, magnification bar = 50 µm). (C) Ciliary body smooth muscle from this child had marked vacuolar myopathy affecting most of the cells (hematoxylin–eosin, magnification bar = 50 µm). (D) Transmission electron microscopy of a scleral fibroblast from a 1-year-old girl treated with ERT for 4 months shows glycogen accumulation within lysosomes (original magnification ×7,100).

Discussion

Although ophthalmologic findings in patients with infantile Pompe disease have been reported in isolated case reports,7–12 we are the first to report ophthalmologic findings in a series of children with infantile Pompe disease treated with ERT. Prior to the availability of ERT, two cases of strabismus in a 9-month-old8 and 3-year-old10 boy with Pompe disease had been described. Since the advent of ERT, the presence of not only strabismus,9 but also ptosis9,12 and myopia,9 have been reported in patients with infantile Pompe disease who received ERT (Table 1). In addition to the previously reported ophthalmologic findings, we also found a high prevalence of astigmatism in our population of patients.

Previously Reported Eye Findings in Children With Infantile Pompe Disease

Table 1:

Previously Reported Eye Findings in Children With Infantile Pompe Disease

In our series of children with infantile Pompe disease receiving ERT, ptosis, strabismus, myopia, and astigmatism were present. Approximately half of our patients had ptosis. Although a previous study reported that a child with atypical infantile Pompe disease had partial resolution of ptosis within 6 months of increasing Myozyme from 20 to 40 mg/kg every other week, despite receiving the increased dose of Myozyme, one of our patients with severe ptosis and significant chin-up head positioning ultimately required surgical repair (case 2). The low prevalence of strabismus (n = 3, all with classic disease) in our study was surprising considering the significant degree of muscle weakness.

Clinically significant refractive errors, which we defined as those for which the ophthalmologist prescribed spectacles, were only seen in those with classic disease due to myopia and astigmatism. Approximately two-thirds of those with classic disease had myopia, of which approximately one-third had high myopia. A family history of myopia was not associated with myopia in those with classic disease (P = .44).

Based on our histological observations, we hypothesize that myopia may be due to one or more of the following: (1) elongation of the globe caused by compression from enlarged and possibly stiffened extraocular muscles due to glycogen accumulation; (2) induced myopia caused by accumulation of glycogen in the lens that may cause osmotic lens swelling in a fashion similar to that in diabetics13; (3) induced myopia caused by glycogen accumulation in ciliary smooth muscle, reducing tension on zonules and allowing the lens to become more spherical; and (4) scleral elongation caused by altered visco-elastic properties of the sclera due to the disruption of the normal synthesis of collagen, proteoglycans, and/or non-collagenous glycoproteins due to the accumulation of glycogen within scleral fibroblasts.14 Although biometry and keratometry measurements would help clarify if myopia was due to an increase in axial length or changes in the refractive power of the cornea or lens, these measurements were not routinely obtained, which is a limitation of our study. Another study limitation is our small sample size, but we hope our findings will help elucidate the etiologies of ophthalmic findings seen in these patients and help focus future treatment strategies.

Most children with classic disease had astigmatism, and more than half had astigmatism of 2.00 D or greater. All astigmatism of 1.00 D or greater was with-the-rule. Although ptosis can cause with-the-rule astigmatism, astigmatism was not more common in those with ptosis (P = .64). Interestingly, our patient who underwent unilateral ptosis repair had a shift in astigmatism from 4.00 to 2.50 D after ptosis surgery (case 2). Thus, although ptosis may have some role in the etiology of with-the rule astigmatism seen in these patients, ptosis is likely not the sole cause of the astigmatism.

Our findings suggest that patients with infantile Pompe disease receiving ERT (particularly classic infantile-onset disease) have a high prevalence of clinically significant ophthalmic findings that are potentially amblyogenic but treatable and merit annual comprehensive ophthalmologic evaluation. Further longitudinal studies are needed to further define the spectrum of ocular abnormalities that may arise as survival rates improve.

References

  1. Hirshhorn R, Reuser AJJ. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill; 2001:3389–3420.
  2. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267–288. doi:10.1097/01.gim.0000218152.87434.f3 [CrossRef]
  3. Slonim AE, Bulone L, Ritz S, Goldberg T, Chen A, Martiniuk F. Identification of two subtypes of infantile acid maltase deficiency. J Pediatr. 2000;137:283–285. doi:10.1067/mpd.2000.107112 [CrossRef]
  4. Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148:671–676. doi:10.1016/j.jpeds.2005.11.033 [CrossRef]
  5. Kishnani PS, Corzo D, Leslie ND, et al. Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease. Pediatr Res. 2009;66:329–335. doi:10.1203/PDR.0b013e3181b24e94 [CrossRef]
  6. Myozyme [package insert]. Cambridge, MA: Genzyme Corporation; 2012.
  7. Yanovitch TL, Banugaria SG, Proia AD, Kishnani PS. Clinical and histologic ocular findings in Pompe disease. J Pediatr Ophthalmol Strabismus. 2010;47:34–40. doi:10.3928/01913913-20100106-08 [CrossRef]
  8. Goebel HH, Kohlschutter A, Pilz H. Ultrastructural observations on the retina in type II glycogenosis (Pompe’s disease). Ophthalmologica. 1978;176:61–68. doi:10.1159/000308694 [CrossRef]
  9. Slingerland NW, Polling JR, van Gelder CM, van der Ploeg AT, Bleyen I. Ptosis, extraocular motility disorder, and myopia as features of Pompe disease. Orbit. 2011;30:111–113. doi:10.3109/01676830.2010.546932 [CrossRef]
  10. Smith RS, Reinecke RD. Electron microscopy of ocular muscle in type II glycogenosis (Pompe’s disease). Am J Ophthalmol. 1972;73:965–970. doi:10.1016/0002-9394(72)90468-0 [CrossRef]
  11. Toussaint D, Danis P. Eye Histopathology study of a case of generalized glycogenosis (Pompe disease) [article in French]. Bull Soc Belge Ophtalmol. 1964;137:313–325.
  12. Yanovitch TL, Casey R, Banugaria SG, Kishnani PS. Improvement of bilateral ptosis on higher dose enzyme replacement therapy in Pompe disease. J Neuroophthalmol. 2010;30:165–166.
  13. Bron AJ, Sparrow J, Brown NA, Harding JJ, Blakytny R. The lens in diabetes. Eye. 1993;7:260–275. doi:10.1038/eye.1993.60 [CrossRef]
  14. Rada JA, Shelton S, Norton TT. The sclera and myopia. Exp Eye Res. 2006;82:185–200. doi:10.1016/j.exer.2005.08.009 [CrossRef]



Previously Reported Eye Findings in Children With Infantile Pompe Disease

Reference Sex Age Type RE Ptosis Strabismus ERT
Toussaint & Danis,11 1964 F 5 months Classic NS NS NS No
Goebel et al.,8 1978 M 9 months Classic NS NS ET No
Yanovitch et al.,7 2010 F 1 year NS No No No Yes
Smith & Reinecke,10 1972 M 3 years NS NS NS V-pattern ET No
Slingerland et al.,9 2011 M 4.5 years Classic High myopia Yes NS, had “restricted” extraocular movements Yesa
Yanovitch et al.,12 2010 M 17 years Atypical No Yes No Yesb

10.3928/01913913-20140813-01

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