Gyrate Atrophy Of Choroid And Retina

A number sign (#) is used with this entry because gyrate atrophy of the choroid and retina is caused by homozygous or compound heterozygous mutation in the OAT gene (613349) on chromosome 10q26.

Description

Gyrate atrophy of the choroid and retina due to deficiency of ornithine aminotransferase is clinically characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. Characteristic chorioretinal atrophy with progressive constriction of the visual fields leads to blindness at the latest during the sixth decade of life. Patients generally have normal intelligence (summary by Peltola et al., 2002).

See 238970 for another hyperornithinemia syndrome.

Clinical Features

Hyperornithinemia presumably due to deficiency of ornithine ketoacid aminotransferase was found in 9 patients with gyrate atrophy of the choroid and retina (Simell and Takki, 1973). The clinical history of gyrate atrophy is usually night blindness that begins in late childhood, accompanied by sharply demarcated circular areas of chorioretinal atrophy. During the second and third decades the areas of atrophy enlarge. Ornithine levels were 10 to 20 times higher than normal in plasma, urine, spinal fluid, and aqueous humor. No consistent clinical abnormality other than the ocular one was found. Hyperammonemia was not found in the fasting state or after meals or stress testing. All the patients' parents were from the same geographic area of Finland.

Most patients with gyrate atrophy have posterior subcapsular cataracts by the end of the second decade (Kaiser-Kupfer et al., 1983).

Sipila et al. (1979) studied 21 patients with gyrate atrophy with hyperornithinemia and found that type II muscle fibers were almost universally atrophic and had tubular aggregates. Despite the changes in type II fibers, the patients usually had no muscle symptoms, although some showed impaired performance when speed or acute strength was required. The disease progresses to almost complete loss of type II fibers, but the progression of muscle changes is slower than that of ocular pathology. Valtonen et al. (1996) found type II muscle fiber atrophy in all 7 patients with gyrate atrophy studied by muscle biopsy and found tubular aggregates in 6 of the 7 patients. CT and MRI studies showed changes in the thigh muscles in all patients.

It has been suggested that changes in skeletal muscle, as well as the ocular changes, may be mediated by hyperornithinemia-induced deficiency of high-energy creatine phosphate. Abnormal brain MRI and EEG studies are found in another disorder of creatine metabolism, guanidinoacetate methyltransferase deficiency (612736); for this reason, Valtonen et al. (1999) investigated CNS involvement in gyrate atrophy, which seems to be associated with a milder degree of phosphocreatine deficiency. They compared 23 untreated gyrate atrophy patients with age-matched healthy controls, and with 9 patients who had received creatine or creatine precursor supplementation daily for several years. The MRI or EEG findings of the patients on creatine supplementation did not differ from those of the untreated group. Brain MRI revealed degenerative lesions in the white matter in 50% of the gyrate atrophy patients, and 70% of the patients had premature atrophic changes, with a striking increase in the number of Virchow spaces. Of the patients whose EEG was recorded, 58% had abnormal slow background activity, focal lesions, or high-amplitude beta rhythm. The EEG findings were not associated with the MRI changes or with the age or sex of the patients. Valtonen et al. (1999) concluded that early degenerative and atrophic brain changes and abnormal EEG are features of gyrate atrophy, in addition to the well-characterized eye and muscle manifestations.

Stoppoloni et al. (1978) reported a patient with gyrate atrophy at age 3 years and 9 months who also had mild mental retardation, delayed language development, and speech defects.

Valle et al. (1977) demonstrated deficiency of ornithine-delta-aminotransferase, a pyridoxal-dependent enzyme, in transformed lymphocytes.

Some cases of OAT deficiency are B6-responsive. Wirtz et al. (1985) found no complementation when fibroblasts from four B6-responsive and three B6-nonresponsive patients were fused. This suggests that the 2 forms are allelic. B6-responsive patients had higher activity of OAT in cell homogenates and greater incorporation of radioactivity from (14)C-ornithine into protein in cultured cells in situ than did B6-unresponsive patients.

Shih et al. (1988) studied fibroblasts from heterozygotes for the pyridoxine-responsive variant and from heterozygotes for the pyridoxine-nonresponsive variant. Both contain intermediate levels of OAT activity. The 2 variants could be distinguished, however, by the in vitro responsiveness of OAT activity to pyridoxal phosphate (PLP) stimulation. The ratios of OAT with no PLP added were lowest for controls, intermediate for pyridoxine-nonresponsive heterozygotes, and highest for pyridoxine-responsive heterozygotes. Kennaway et al. (1989) studied the mutant enzyme in 9 patients with gyrate atrophy of the choroid and retina by use of a radiochemical assay to measure the Km for PLP in fibroblast mitochondria and the heat stability of OAT at 45 degrees in the presence and absence of PLP. The apparent Km for PLP was lower in nonresponsive patients than in patients responsive to pyridoxine. In 7 patients studied, the apparent Km for ornithine was normal. The patient with the mildest clinical disease, responsive to pyridoxine, had the most stable enzyme, but also the highest Km for PLP. OAT protein was clearly detectable by Western blot analysis of mitochondrial proteins in the pyridoxine-responsive patients and in 2 of 5 nonresponders, but was low or undetectable in the 3 other patients.

Inheritance

Barrett et al. (1987) reviewed 80 reported cases of gyrate atrophy and concluded that the pattern of inheritance was always consistent with the autosomal recessive hypothesis. Forty-four, or 55%, were female. No significant quantitative differences in OAT deficiency had been found in cultured fibroblasts and lymphocytes from male and female patients.

Clinical Management

The main source of ornithine is arginine in dietary protein, and restriction of arginine in the diet appears to have therapeutic value (Kaiser-Kupfer et al., 1980; Valle et al., 1980).

Kaiser-Kupfer et al. (2002) reported the results of 16 to 17 years of arginine-restricted diet on 2 sib pairs. In both families, the younger sib in each pair, who was prescribed the diet at an earlier age, demonstrated a slower progression of lesions compared with the older sib. They concluded that, if started at an early age, long-term substantial reduction of plasma ornithine levels might appreciably slow the progression of the chorioretinal lesions and, to a lesser extent, the progressive loss of retinal function in patients with gyrate atrophy.

Gene Therapy

Caruso et al. (2001) examined the course of change in visual function outcome variables in 5 patients with gyrate atrophy in anticipation of a gene replacement therapy clinical trial. In the 4 to 6 years during which each patient was followed, median visual field half-lives were 17.0 years (static perimetry) and 11.4 years (kinetic perimetry). Median electroretinogram half-lives were 16.0 years (maximal response) and 10.7 years (flicker response). The authors concluded that the decline in visual function outcome variables was frequently slow. Thus, a long-term clinical trial would be required to assess the efficacy of the intervention in the preservation of visual function in gyrate atrophy patients.

Population Genetics

Valle and Simell (2001) stated that approximately 200 biochemically confirmed cases of GACR are known. The incidence is highest in Finland, with an estimated frequency of about 1 in 50,000 individuals and an estimated frequency for heterozygotes of 1 in 110 individuals.

Mapping

Ramesh et al. (1988) demonstrated that the OAT locus segregated concordantly with gyrate atrophy in 1 pedigree and showed significant disequilibrium with gyrate atrophy, thus providing genetic evidence that a defect in the OAT structural gene on chromosome 10 is the cause of the disorder.

Molecular Genetics

In patients with gyrate atrophy of the choroid and retina, Mitchell et al. (1988) identified a mutation in the OAT gene (613349.0001).

Brody et al. (1992) discovered and characterized the molecular defect in 21 newly recognized OAT alleles. They determined the consequences of these and 3 previously described mutations on OAT mRNA, antigen, and enzyme activity in cultured fibroblasts. In 20 of the 24 alleles, normal amounts of normal-sized OAT mRNA were produced. By contrast, only 2 of the 24 had normal amounts of OAT antigen.

Animal Model

Wang et al. (1995) found that Oat-deficient mice produced by gene targeting exhibit neonatal hypoornithinemia and lethality, rescuable by short-term arginine supplementation. Postweaning, these mice developed hyperornithinemia similar to human gyrate atrophy patients. Studies in 1 human gyrate atrophy infant also showed transient hypoornithinemia. Thus, the authors concluded that the OAT reaction plays opposite roles in neonatal and adult mammals. Over several months, Oat-deficient mice develop a retinal degeneration with involvement of photoreceptors and pigment epithelium. Oat-deficient mice appear to be an authentic model of human gyrate atrophy.

To determine whether chronic, systemic reduction of ornithine can prevent gyrate atrophy, Wang et al. (2000) used an arginine-restricted diet to maintain long-term reduction of ornithine in the mouse model of Oat deficiency produced by gene targeting. They evaluated the mice over a 12-month period by measurement of plasma amino acids, electroretinograms, and retinal histology and ultrastructural studies. They found that an arginine-restricted diet substantially reduced plasma ornithine levels and completely prevented retinal degeneration in Oat -/- mice. This result indicated that ornithine accumulation is a necessary factor in the pathophysiology of the retinal degeneration in gyrate atrophy and that restoration of OAT activity in retina is not required for effective treatment of gyrate atrophy.

History

Fuchs atrophia gyrata chorioideae et retinae is a rare disorder characterized by slowly progressive atrophy of the choroid, pigment epithelium, and retina. Francois et al. (1960) described a patient in which leukocyte inclusions were present not only in the patient but also in both parents, who were consanguineous, and in other members of the family through 4 generations. The authors originally suggested that the leukocyte anomaly was a heterozygous expression of the gene which in the homozygous state produces Fuchs atrophy. In a later publication, however, Francois et al. (1966) reported failure to find the Alder anomaly in 9 patients with the eye anomaly. The authors concluded that there is no true gyrate atrophy independent of ornithinemia. Presumed cases may represent simulating conditions.