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Case Reports Indian Pediatrics 2001; 38: 914-918 |
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Hyperornithinemia Associated with Gyrate Atrophy of the Choroid and Retina in a Child with Myopia |
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Hyperornithinemia associated with gyrate atrophy of the choroid and retina is a rare, autosomal recessive disorder resulting from a deficiency of the mitochondrial matrix enxyme, ornithine d-aminotransferase (OAT). This enzyme catalyses the pyridoxal phosphate-dependent transamination of orni-thine and a-ketoglutarate to D'-pyrroline 5-carboxylic acid and glutamic acid. Over 150 biochemically documented cases have been reported of which one-third are Finnish(1,2). There is paucity of cases reported from India(3,4). We report a case of this metabolic disorder in a child who was investigated for high myopia associated with degenerative changes in the fundus. Since this disorder can present in the pediatric age with myopia, children presenting with degenerative myopia need to be investigated for it. Case Report A 6-year-old female child of second degree consanguineous parents, presented with a 2-year history of deterioration in vision. The past medical history was unremarkable. She did not have night blindness or constriction of the visual fields. She had been prescribed glasses for myopia when she was 4 years of age. Her great grandmother had visual complaints at 60 years of age for which she was not investigated. General physical examination did not reveal any abnormality. There was no muscle weakness. Ophthalmic examination showed that she had myopia. Visual acuity at 4 years of age was 6/36 with a correction of –4Sp/–2cyl in both eyes. The visual acuity at 6 years was 6/36 with a correction of –4Sp/3cyl in right eye and –5.75Sp/–2.75cyl in left eye. No concentric constriction of visual fields was noted on perimetry. Color vision was normal. Fundoscopy revealed sharply demarcated depigmented lesions in the midperiphery of both retina characteristically described as gyrate atrophy. The routine blood chemistry including liver and renal function tests and muscle enzymes were within normal limits. The blood ammonia was 54 µg/dl (reference range 25-93 µg/dl). Quantitative analysis of plasma and urinary amino acids were carried out by gradient elution high-performance liquid chromato-graphy (HPLC) using a C18 octadecylsilyl (ODS), 5 µm particle column after pre-column derivatization with ophthalaldehyde. A massive increase in the concentration of ornithine in plasma and urine, 844 µmol/L (reference range 24-112 µmol/L) and 1345 µmol/g creatinine (reference range 0-168 µmol/g creatinine) respectively; mild hypo-lysinemia-57 µmol/L (reference range 107-244 µmol/L) and lysinuria-1795 µmol/g creatinine (reference range 180-350 µmol/g creatinine) was noted. The d-lactam of ornithine was detected in her urine. No other abnormal amino acids were detected. In view of the ophthalmo-logical findings associated with increased blood ornithine without hyperammonemia or homocitrullinuria, a diagnosis of hyperorni-thinemia associated with gyrate atrophy of the choroid and retina, was made. The patient was started on pyridoxine 20 mg/day orally and arginine restricted diet with plenty of gelatin which is a rich source of proline. She was advised to come for a follow up after three months to monitor her blood ornithine levels. Discussion The majority of cases of myopia in children are variants in the frequency curve of axial length and curvature. Pathological axial mayopia is a degenerative and progressive condition which is essentially a disturbance of growth on which are imposed degenerative phenomenon. The clinical manifestations of degenerative myopia are the same as those of simple myopia except that the visual acuity may not be corrected to normal with any lenses. Thus, myopia of a mild degree may show marked degenerative changes while high myopia may show no changes. An inborn error of ornithine metabolism resulting in hyper-ornithinemia, as in this case, leads to degenerative myopia. Hyperornithinemia occurs in two types of genetic disease. In gyrate atrophy of the choroid and retina associated with hyperor-nithinemia, plasma ornithine concentration is increased 10-20 fold and there is no hyperammonemia or homocitrullinuria(1). Hypolysinemia occurs due to increased renal clearance of lysine. Plasma glutamic acid concentrations are sometimes reduced. A deficiency in the activity of ornithine d-aminotransferase (OAT) can be demonstrated in cultured fibroblasts and phytohemagglutinin (PHA)-stimulated lymphocytes. In another disorder, the hyperornithinemia-hyperammo-nemia-homocitrullinuria syndrome (HHH syndrome), a defect in the transporter that mediates ornithine entry into the mitochondria results in increased plasma ammonium and glutamine concentrations particularly after ingestion of a protein load. Urinary excretion of orotic acid is increased in HHH individuals. Gyrate atrophy of the choroid and retina begins in childhood and leads to blindness in the fourth to seventh decade of life. The affected individuals develop axial myopia in early childhood and most have impaired peripheral and night vision by the first decade. Sharply demarcated, circular areas of chorio-retinal atrophy are observed in the periphery of the retina on fundoscopy. There is concentric reduction of the visual fields leading to tunnel vision and eventually blindness, Posterior capsular cataracts have been reported in nearly all patients. The standard tests of visual function become abnormal at an irregular rate, with periods of rapid progression interspersed with periods of relatively stable function. The electroretino-gram, which may be normal initially eventually diminishes in amplitude and usually is totally extinguished well before the chorioretinal atrophy becomes complete. A few patients have been reported to have mild proximal muscle weakness. Tubular aggregates in type 2 skeletal muscle fibres and ultrastructural abnormalities in the mitochondria of the skeletal muscle and liver have been described(5). The human OAT gene has been cloned and mapped (10q26), and more than 60 mutations causing the disease have been identified(1). Despite clinical, biochemical and mole-cular characterization of gyrate atrophy, the exact pathophysiologic mechanism of the progressive retinal degeneration is unknown and several hypotheses have been proposed. Sipila and coworkers(5) have proposed that deficiency of creatine and creatine phosphate may account for both the histologic abnormali-ties in muscle and chorioretinal degeneration. They have suggested that the high ornithine concentrations inhibit glycine transaminidase thereby reducing creatinine synthesis and causing a reduction in total body creatine and creatine phosphate. The well-documented sensitivity of glycine transaminidase to ornithine in vitro and the observations that fasting plasma guanido-acetate, creatine and creatinine are all reduced in patients with gyrate atrophy as compared to normals provide evidence for this hypothesis(6). Another hypothesis for the pathophysiology of gyrate atrophy involves the deficient synthesis of D1-pyrroline-5-carboxylate owing to the defi-ciency of OAT and to inhibitory effects of ornithine on D1-pyrroline-5-carboxylate syn-thase, the enzyme that catalyses the formation of D1-pyrroline-5-carboxylate from glutamate. The observation that D1-pyrroline-5-carboxy-late synthase is inhibited in vitro by near-physiological concentrations of L-ornithine and that ornithine is toxic to cells lacking OAT support this hypothesis(7). No form of therapy has been reported to be unequaivocally effective in patients with this rare disorder. Pyridoxine, the precursor of the cofactor, pyridoxal phosphate, has been administered in pharmacological doses in an attempt to stimulate any residual OAT activity. A signficant reduction in plasma ornithine has been reported in seven patients with this therapy(8-10). Fibroblast OAT in six of these patients responded in vitro to high concentrations of pyridoxal phosphate in the assay mixture. One patient described by Valle and co-workers had an in vivo response without an in vitro response while Kennaway et al.(11) described a patient with an in vitro response without an in vivo response. The B6-responsive patients of Weleber and co-workers showed a biochemical response as indicated by a decrease in blood ornithine levels, even to low doses of pryidoxine (18-30 mg/day). Clinical improvement was observed with high doses (600 mg/day) of this vitamin. However, the two pyridoxine-responsive patients of Hayasaka and co-workers had some progression of their chorioretinal degeneration over two years despite lowering of their blood ornithine levels while on 120 mg and 600 mg of this vitamin. Hence the possibility remains that pyriodoxine therapy may not produce clinical improvement even if it produces a biochemical response. However, the rate of progression of the disease may be slowed by this therapy. Lowering of plasma ornithine has also been achieved by dietary restriction of arginine by lowering protein intake to 0.2 g/kg/day. Dietary arginine restriction limites the source of ornithine. The long-term reduction of orni-thine accumulation by an arginine-restricted diet has slowed the progression of the chorioretinal atrophy(12). Promotion of the renal excretion of ornithine by administration of pharmacological doses of lysine and a-aminoisobutyric acid have been attempted. Although these compounds increase ornithine excretion, the long-term efficacy of this therapy is not known. Creatine supplementation has been tried for therapy by some workers(13) because of the hypothesis that gyrate atrophy may be due to a deficiency of creatine and creatine phosphate. Although creatine supplementation has resulted in improvement in histologic abnormalities in the skeletal muscle there was a continued progress of the chorioretinal lesions in 13 patients at a 5-years follow-up(14). These results however indicate that creatine depletion does play a role in muscle abnormalities. Based on a hypothesis that a deficiency of proline in the retina and choroid may produce atrophies in the affected patients despite normal serum proline levels, supple-mental proline has been administered. Proline therapy has been reported to minimize the progression of the disease in one patient and halt the progression in two of the four patients of Hayasaka and coworkers(15). Thus, the outcome of this therapy is mixed. In conclusion, no single therapy has been shown to halt the progression of this disease in all affected patients. Genetic counseling of the family members and evaluation of their blood ornithine levels which are elevated even in the presymptomatic stage when all other standard visual function tests may be normal, forms an important part of management of these cases. Recently, a microradiographic method for assay of OAT has been reported indicating a potential for prenatal diagnosis by the first trimester chorionic villus sampling(16). Contributors: AS referred the child for a detailed work-up at NIMHANS and helped in drafting the paper. NL analyzed the blood and urine samples. RC co-ordinated the work-up of the case, and drafted the paper; she will act as the guarantor for the paper. Funding: None. Competing interests: None stated.
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