Genetic aspects in gyrate atrophy of the choroid and retina with hyperornithinaemia.

Abstract

The relative importance of genetic degenerative eye lesions as causes of blindness or impaired vision has increased because of the lack of effective treatment for such conditions as compared with other diseases. Related to the large and not very well-defined group of degenerative eye lesions termed tapeto-retinal degenerations, is a choroidal form known as gyrate atrophy of the choroid and retina.Night blindness is the most important subjective symptom in hereditary tapeto-retinal degeneration. Sharply-defined chorio-retinal atrophic areas of the fundus are typical of gyrate atrophy. In addition to constriction of the fields of vision, myopia, and complicated cataract, abnormalities in the electroretinogram, electro-oculogram, and fluorescein angiograms of the fundus form the basis for diagnosis.A constant relationship between gyrate atrophy of the choroid and retina and massively increased plasma ornithine concentration was found in our earlier studies (Simell and Takki, 1973; Takki, I974), in which it was suggested that the clinical symptoms and signs of the disease were due to large concentrations of ornithine in the plasma, aqueous humour, and cerebrospinal fluid or directly to the causative enzyme defect.Though gyrate atrophy of the choroid and retina is a relatively rare ophthalmological disease and the published series of patients are small, inheritance has been suggested. Con Kurstjens, I965;Rieger, 1972;Botermans, 1972), but autosomal inheritance now seems to be a probable cause (Kurstjens, I965; Botermans, I972). The combination ofclinical symptoms with inborn errors of metabolism was not understood until some relatives of the propositi were found to have the metabolic abnormality without the clinical disease (Ghadimi, Partington, and Hunter, I 96 I; Woody, Hutzler, and Dancis, I 966; Auerbach, DiGeorge, and Carpenter, I967). The aim of this work was to confirm the regular combination of massively increased plasma ornithine concentration with the ophthalmological symptoms and signs by studying the eyes and plasma and/or urinary amino-acids of relatives of the patients, to test the autosomal recessive mode of inheritance in this group of families, and to find a clinical method for heterozygote detection in hyperornithinaemia by studying ornithine metabolism in probable heterozygotes of the disease and in controls.

A mouse model of gyrate atrophy of the choroid and retina. Early retinal pigment epithelium damage and progressive retinal degeneration.

“…In human GA patients, the ERG amplitude decreases gradually and is usually undetectable by the end of the second decade of life, at a time when there is still normal-appearing retina in the posterior pole (5,30). The mean ERG amplitude in the Oat Ϫ/Ϫ mice is normal at 2 mo of age but declines slowly to ‫ف‬ 40% of normal by the end of 1 yr.…”

“…Complete loss of vision is associated with involvement of the macula. Electroretinography (ERG) abnormalities are present at an early stage of the disease, with impaired rod and cone responses ultimately progressing to a completely extinguished response (5)(6)(7). The biochemical and metabolic characteristics of GA have been studied extensively.…”

Gyrate Atrophy of Choroid and Retina With Myopia, Cataract and Systemic Proximal Myopathy

“…2,3 In addition to ocular findings, patients may present with delayed language development and speech defects. Other systemic abnormalities include low intellectual activity, mild proximal muscle weakness, peculiar, sparse scalp hair with areas of alopecia, and bizarre elongated segmented mitochondria in liver biopsies.…”

“…Simell and Takki (1973) established the presence of a large increase in plasma ornithine levels with gyrate atrophy. 2,3 Kupfer, Valle and Valle (1978) identified an absence of ornithine aminotransferase (OAT) as the specific enzyme abnormality associated with gyrate atrophy. 8 OAT is expressed in most tissues, including kidney, small intestine, liver, and retina.…”

“…1 It is transmitted as an autosomal recessive trait, which shows deficiency of pyridoxal phosphate-dependent mitochondrial matrix enzyme ornithine aminotransferase (OAT) 2 and results in a 10 to 20…”