Corneal vesicles accumulate collagen VI associated with tissue remodeling in apolipoprotein a-I deficiency: a case report

In 2012, a 61-year-old woman with blurred vision presented with corneal opacity of the left eye. Her visual acuity was 20/40 OS and 20/20 OD. She had been diagnosed with HDL deficiency at the age of 46 years, 1997. but she had been off treatment for about 10 years. She had undergone PKP of the right eye for the same symptoms when she was 58 years old, 2009.

The patient was the fourth of 8 siblings. A brother died in an accident and a sister died in childhood. None of her family members had been diagnosed with HDL deficiency, and there was no family history of consanguineous marriage. On physical examination, she had bilateral xanthomas of the eyelids and focal yellow skin discolorations in the cubital fossae of both forearms, but there was no tonsillar hypertrophy or Achilles tendon xanthoma.

Blood tests showed an extremely low HDL-cholesterol level (6 mg/dL) with undetectable Apo A-I (<5 mg/dL). Levels of Apo B and Apo E were slightly elevated (109 mg/dL and 5.8 mg/dL, respectively). Serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, and lecithin-cholesterol acyltransferase levels were within the normal limits. A genetic evaluation was performed as previously described [4], and showed that she was homozygous for the Apo A-I_Tsukuba mutation, which is a single-nucleotide insertion of cytosine that alters the reading frame from codon 5 and produces a premature stop codon at codon 34 (Fig. 1). Thus, this patient was diagnosed with genetic Apo A-I deficiency. Electrocardiogram, echocardiogram, and myocardial scintigraphy showed significant ischemic heart failure and angiography showed severe stenosis of the coronary arteries. Consequently, she underwent percutaneous coronary intervention and coronary artery bypass grafting.

On slit-lamp examination, there was a diffuse corneal stromal opacity with a lucid zone in the left eye. Confocal microscopy (Heidelberg Retinal Tomograph Rostock Cornea Module, Heidelberg Engineering, Heidelberg, Germany) revealed high-intensity vesicles (10–100 μm in diameter) in the corneal stroma (Fig. 2). In 2013, PKP was performed for the left eye, and the corneal button tissues were examined histopathologically and immunohistochemically.

Our patient demonstrated clinical findings typical to Apo A-I deficiency. Histopathologically, vesicles in the corneal stroma were significantly larger (10–100 μm in diameter) than those described in the report by Osakabe and colleagues (200 nm–2 μm in diameter) [5]. Apo A-I mutations, including Apo A-I_Iowa, are known to induce amyloidosis [6]. However, our patient did not have any accumulation of amyloid in the corneal stroma. It is possible that we failed to detect cholesterol ester in the vesicles by Sudan black staining because we embedded the corneal button in paraffin. It was also regretful that the right cornea had not been examined immunohistochemically.

Collagen VI is a major extracellular matrix protein, bridging cells to the surrounding connective tissue and organizing the three-dimensional tissue architecture. The mutations in the genes encoding Collagen VI chains result in several forms of inherited myopathies, decrease of stiffness in cartilage [7]. It is also distributed in corneal stroma, and reported the change of its expression level during wound healing period [8‐10].

To our knowledge, ours is the first report of a patient with confirmed mucoid degeneration and accumulations of collagen VI in the stromal vesicles. Our results suggest that structural changes in corneal collagen fibrils contribute to the formation of stromal vesicles.