Anti-γ-enolase autoimmune retinopathy manifesting in early childhood

Abstract

Objective: To describe the clinical, molecular, and serologic findings of a case in which autoimmune retinopathy and early-onset heritable retinal degeneration were both considered in the differential diagnosis.

Methods: A 3-year-old girl had clinical findings suggestive of a childhood-onset retinal degeneration. Samples of DNA and serum were collected. The coding regions of 11 genes associated with Leber congenital amaurosis were sequenced. The patient's serum reactivity to soluble and insoluble fractions of human retinal protein was compared with that of healthy control subjects (n = 32), patients with inflammatory eye disease (n = 80), and patients with molecularly confirmed retinal degenerations (n = 11). Two-dimensional gel electrophoresis and mass spectrometry were used to identify a protein that corresponded to a reactive band on Western blot.

Results: No plausible disease-causing mutations were identified in any of the retinal disease genes tested. However, the patient's serum showed reactivity to a single retinal antigen of approximately 47 kDa. Two-dimensional gel electrophoresis and mass spectrometry revealed the major reactive species to be neuron-specific enolase (NSE). Autoantibodies targeting NSE were not observed in any healthy control subjects or patients with inflammatory eye disease. However, anti-NSE activity was found in 1 child with molecularly confirmed Leber congenital amaurosis.

Conclusion: This patient's clinical and laboratory findings coupled with the recently discovered role of anti-NSE antibodies in canine autoimmune retinopathy suggest that autoantibodies targeting NSE are involved in the pathogenesis of her disease.

Clinical relevance: Infection or inflammation within the retina early in life may lead to an autoimmune phenocopy of early-onset inherited retinal degeneration.

Figure 1

Photographs of the right (A) and left (B) optic nerve heads of the patient showing crisp margins and a completely normal salmon color.

Figure 2

Montages of retinal photographs taken of the right (A) and left (B) eyes of the patient. The optic nerve heads appear much more pale in these images than those shown in figure 1 because of the exposure settings required to show retinal details in this darkly pigmented fundus. There is arteriolar narrowing in both eyes but it is much more pronounced in the right eye than the left. There is an oval area of yellowish discoloration centered on the macula of the right eye and a much smaller lesion in the left eye just inferior to the fovea. There is a granular appearance to the entire fundus in the right eye which is much less noticeable in the left. There is some perivenous hypopigmentation in both eyes, most noticeable in the left.

Figure 3

Higher magnification color photographs of the superotemporal (A) and inferotemporal (B) aspects of the left fundus showing marked perivenous hypopigmentation.

Figure 4

Goldmann visual field of the left eye showing a near normal V4e isopter (magenta) and I4e isopter (blue) and moderate symmetrical constriction of the I2e isopter (red).

Figure 5

Aqueous soluble (S) and detergent soluble (I) fractions of human retina probed with patient’s serum (left lanes) or with secondary antibody only (right lanes). Note the prominent gamma-enolase band at approximately 47 kDa.

Figure 6

Probing of a PVDF membrane containing retinal proteins separated by 2D gel electrophoresis with patient serum. Note the major reactive spot (arrow). The corresponding spot on a silver stained gel was identified as gamma enolase. The approximate positions of the molecular weight markers, based on the corresponding silver stained gel, are indicated on the right side of the panel, and the approximate pH gradient is indicated at the top of the blot.