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Editor,—Primary oxalosis is a rare autosomal recessive inborn error of glyoxylate metabolism in which two different enzyme defects lead to increased serum oxalate levels resulting in calcium oxalate crystal deposition in various tissues including the eyes, kidney, myocardium, brain, synovia, skin, and peripheral vessels.1 2 This contributes to urolithiasis and end stage renal failure.
Ocular features of oxalosis have characteristically included the crystalline retinopathy (flecked retina), black geographic maculopathy, and optic atrophy.1 3-8 We report two additional cases of primary oxalosis who underwent combined liver/renal transplantation at 1 year of age, but who initially did not manifest crystalline retinopathy or optic atrophy but developed poor vision despite successful transplantation.
An 18 month old female was initially evaluated before her simultaneous kidney/liver transplant. She was undergoing peritoneal dialysis for her end stage renal disease secondary to biopsy confirmed primary oxalosis, diagnosed at age 6 months.
Visual acuity was CSM in each eye. She had no pupillary abnormalities. Extraocular motility was normal and she was orthophoric. Her anterior segment was entirely unremarkable without any evidence of conjunctival, corneal, or lenticular opacities (Figs 1, 2, 3).
Funduscopically she demonstrated striking pigmentary changes symmetrically throughout both eyes. Her optic nerves appeared healthy without optic atrophy. Her vessels were not attenuated. Her foveal area had increased pigment clumping but without exudate or discrete crystals. She had diffuse RPE changes throughout her periphery.
She underwent combined renal/liver transplantation at 18 months of age and subsequently had annual ophthalmological examinations. On her most recent evaluation at age 6, visual acuity was 5/140 in each eye with a cycloplegic refraction of −4.00 sphere in each eye. Her anterior segments remained unremarkable without any lenticular opacities. Funduscopically she remained without any evidence of optic atrophy. She demonstrated profound retinal pigment epithelium (RPE) changes diffusely with extensive bilateral symmetrical submacular fibrosis. She did not have any peripheral crystalline retinopathy. There was no significant arteriolar attenuation.
This young male was the product of a second pregnancy to a non-consanguineous 22 year old mother and 44 year old father. It was a full term uncomplicated pregnancy with a birth weight of 9 lb. He did well until 4 months of age when he presented with presumed viral gastroenteritis which subsequently proved to be primary oxalosis (PH 1) after a confirmatory renal biopsy. He was maintained on peritoneal dialysis for end stage renal disease. He underwent a simultaneous kidney/liver transplant at 15 months of age. He has done well systemically for three subsequent years without any signs of rejection.
At 4½ years of age he was noted to have decreased vision in the left eye on a school screening. Neither the child nor parent had noted any ocular problems. He had not previously undergone patching, spectacle correction, or ocular surgery. At age 4½ years his visual acuity was 20/30 right eye and 20/100 left eye at distance. Near vision was 20/20 and 20/80 respectively. He had no altered head position. Ocular movements and motility were normal and he was orthophoric. He had no nystagmus. Pupillary testing was normal without evidence of a pupillary defect. Anterior segment evaluation was unremarkable, specifically without any conjunctival, corneal, or lenticular opacities. Cycloplegic refraction: +1.00 sphere right eye and +1.50 sphere left eye.
Funduscopically he had no evidence of optic atrophy. He had evidence of bilateral symmetrical subretinal fibrous changes within both macula with surrounding RPE pigmentation (Fig 4). He had marked pigmentary changes with pigment clumping in the periphery decreasing with increased distance from the macula. There were no crystals evident in either eye. There was no significant arteriolar attenuation. After intensive patching of his right eye, follow up visual acuity at age 6 was 20/20 right eye and 20/100 left eye.
Two children underwent combined liver/kidney transplantation at 15 and 18 months of age for primary oxalosis (PH 1). Profound alteration of the retinal pigment epithelium was evident before transplantation. There was no progression of retinopathy after transplantation. The most recent visual acuity was 5/140 in each eye of the first patient and 20/20 and 20/100 in the second patient. No strabismus was noted. The prominent feature in both children was the bilateral symmetrical submacular RPE changes with extensive fibrosis (“white geographic maculopathy”). Neither child demonstrated any peripheral crystalline retinopathy or optic atrophy.
Primary hyperoxaluria type 1 (PH 1) is caused by a deficiency of the hepatic peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT).9 This enzyme is encoded by the AGXT gene on chromosome 2q37.3.10 In the absence of AGT glyoxylate is not adequately converted to less toxic metabolites and instead is metabolised to oxalate and glycolate. AGT has pyridoxal phosphate as its cofactor. In the majority of patients the disease results from the lack of a functional gene product but in one third of the patients there is a misrouting of the enzyme to the mitochondria instead of the peroxisomes.
Primary hyperoxaluria type 2 (PH 2) is due to the deficiency of the enzyme d-glycerate dehydrogenase/glyoxylate reductase. The biochemical criteria for diagnosis include hyperoxaluria andl-glyceric aciduria.
Oxalosis has classically been included in the differential diagnosis of crystalline retinopathy. This differential includes Bietti's crystalline dystrophy and cystinosis, though both of these also manifest corneal crystals. Additionally, talc and canthazanthine retinopathy should be included as well as methoxyflurane toxicity and tamoxifen retinopathy. Intraretinal crystals have also been described in advanced stages of hyperornithaemia, gyrate atrophy, and Sjogren–Larsson syndrome.
These children represent the product of treatment of the underlying metabolic problems by liver/kidney transplantation for the most severe form of infantile primary hyperoxalosis. Despite early intervention, these children still developed white geographic maculopathy and poor vision. Previously, 15 ocular cases have been reported in the English literature citing the typical funduscopic picture of crystalline retinopathy, black geographic ringlet maculopathy, and optic atrophy.3 5-8 Those previous reports indicated the maculopathy caused only mild, if any, visual impairment, whereas the worst vision was in those patients with optic atrophy.6Unlike the previous reports, in our children their maculopathy was associated with poor vision in all but one eye, despite combined liver/kidney transplantation at an early age. It may be that our patients were younger and with a more severe disease. We postulate that the visual decrement is a result of subfoveal fibrosis. The one eye with good vision shows less subretinal fibrosis than the fellow eye with poor vision.
Successful hepatorenal transplantation has been followed by progressive and ultimately complete mobilisation of the oxalate deposits with resolution of the manifestations of systemic oxalosis including cardiomyopathy, cardiac dysrhythmias, and osteodystrophy. It may be that if there was not significant foveal involvement or optic nerve damage before transplantation these children could have an excellent visual outcome. Given that these two patients underwent liver/renal transplantation by age 18 months old and yet have poor vision, it is imperative that treatment be initiated at the earliest possible stage.
The patients described above represent early involvement of retinal oxalosis with infantile PH 1, yet neither child demonstrated any crystals. It is important for the ophthalmologist to be cognizant of the “non-crystalline” retinopathy which is the result of calcium oxalate deposition and subsequent RPE reaction.
As more children will be diagnosed appropriately with newer molecular testing and with the increased success of combined liver and kidney transplantation, the ophthalmologist will be more involved with these patients and must be aware of the wide spectrum of ocular manifestations of oxalosis.