History of the disease

Gyrate atrophy of the choroid and retina is one of scores of genetic dystrophies allied to retinitis pigmentosa. Although it was first described by Cutler in 1895⁸ and Fuchs in 1896,¹¹ interest in gyrate atrophy was sparked by the reports by Simmel and Takki in 1973⁴⁹ and Takki in 1974⁵⁴ of hyperornithinemia associated with this condition. Since then, the enzyme defect (ornithine aminotransferase, or OAT) has been detected,⁴⁶ the abnormal gene product has been characterized biochemically and enzymatically,^25,27 the gene for the missing enzyme has been cloned,¹⁹ and studies have been performed on a molecular level to uncover the mechanism of the loss of functional gene product.^{1,6,14–18,28–31,34,35,41} OAT is a pyridoxal phosphate–dependent enzyme, and pyridoxine-responsive and -nonresponsive forms of the condition have been described. Over 100 cases of gyrate atrophy have been reported worldwide. Considerable allelic heterogeneity exists for OAT-deficient gyrate atrophy for both pyridoxine-responsive and -nonresponsive cases. Interestingly, the largest group of patients with gyrate atrophy is Finnish, the great majority of whom are homozygous or compound heterozygous for one of two common founder mutations (L402P and R180T), neither of which is pyridoxine-responsive.³⁵ For more extensive coverage of the clinical, biochemical, and molecular genetic aspects of gyrate atrophy, the reader is referred to reviews.^56,61

The electroretinogram (ERG) is severely abnormal in most patients with gyrate atrophy, even in childhood (figures 60.1 and 60.2).^5,29,30,54 Stoppoloni et al.⁵³ reported an allegedly normal ERG in a 3-year, 9-month-old girl, but the technique was inadequately described, and the amplitudes for the patient and the normal ranges were not presented. Rinaldi et al.⁴⁴ reported that the ERG for this same patient at 4 years of age was normal for the left eye (photopic a-wave: 40µV, b-wave: 80µV; scotopic a-wave: 40µV, b-wave: 200µV) but that for the right eye was now subnormal (photopic a- and b-waves: 40µV; scotopic a-wave: 40µV, b-wave: 125µV). However, again the range of normal responses for the technique employed were not given. Most reports, especially those of older patients, describe the ERG as undetectable, but averaging was usually not performed, and the lower limits of detectability were not given for the system used. Patients with pyridoxine-responsive gyrate atrophy have had some of the largest reported ERG amplitudes, with maximal bright white stimulus scotopic and photopic b-wave amplitudes in the 100- to 200-µV and 50- to 65-µV range, respectively (see figures 60.1 and 60.2). For those patients with sizable ERGs, although both rod- and cone-mediated responses are subnormal, the rod responses appear more subnormal than do those from the cone system.^5,23,60 The oscillatory potentials range from moderately to severely subnormal but are often still clearly discernible and, in rare instances, relatively well preserved in comparison with the loss of b-wave amplitude. The implicit times are usually normal, although mild prolongation of cone b-wave implicit can occur (see figures 60.1 and 60.2).⁶³

Figure 60.1.  

ERGs from patients with pyridoxine-responsive (patients 1–3) and pyridoxine-nonresponsive (patient 4) gyrate atrophy. Note that the calibration scale is different in height for the patients compared with the normal ERG. A, Photopic cone and 30-Hz flicker. Note the prolonged implicit time for some of the 30-Hz flicker responses for patients 2 and 3. The calibration scale indicates 100µV vertically and 20ms horizontally for all tracings. The numbers to the left of the normal tracing indicate the intensity of the stimulus in log foot-lambert-seconds. B, Scotopic ERG responses. The calibration scale indicates 200µV vertically and 40ms horizontally for all tracings. The numbers to the left of the normal tracing indicate the intensity in log foot-lambert-seconds for the white light stimuli and in log µJ/cm² steradian for the red and blue light stimuli. (From Weleber RG, Kennaway NG: Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology 1981; 88:316–324. Used by permission.)

Figure 60.2.  

International Society for Clinical Electrophysiology of Vision standard ERGs of a 12-year-old girl with pyridoxine-nonresponsive gyrate atrophy (same patient as in figures 60.4A and 60.5) (left column) and a 38-year-old woman with pyridoxine-responsive gyrate atrophy (patient 2 in figure 60.1) (right column). The responses for the right and left eyes are superimposed. Note that for the patient with pyridoxine-nonresponsive gyrate atrophy, the flicker timing and single-flash cone b-wave implicit times (arrows) are prolonged, the scotopic OPs are profoundly subnormal, and the rod response is indiscernible from noise.

To assess the course of change of visual function outcome variables in patients who might become candidates for gene replacement therapy, Caruso et al.⁷ have studied the rate of decline of static perimetry, kinetic perimetry, and ERG b-wave amplitudes for the ISCEV standard maximum scotopic bright-flash and the 30-Hz flicker responses for patients with pyridoxine-nonresponsive gyrate atrophy. They found that in the 4 to 6 years of follow-up, the visual field half-lives were variable, but the median was 17.0 years for static perimetry and 11.4 years for kinetic perimetry. ERG amplitudes likewise had variable half-lives, but the median was 16 years for the scotopic bright-flash responses and 10.7 years for the flicker responses. Thus, the rates of change of visual function outcome measures in these subjects were slow, indicating that a long-term clinical trial would be needed to assess the efficacy of therapeutic intervention that is intended to preserve existing visual function. The rate of change of visual function outcome measures appears even slower for those rare individuals with pyridoxine-responsive gyrate atrophy (R. G. Weleber, unpublished data, 2003).

The electro-oculogram (EOG) can range from low normal to severely subnormal.^23,54,64 Fast oscillations of the EOG were subnormal for three pyridoxine responders (Weleber and Kennaway⁶¹ and R. G. Weleber, unpublished observations, 1983–1987) (figure 60.3).

Figure 60.3.  

EOG from a normal subject (light to dark ratio 2.26) (top) and a 38-year-old woman with pyridoxine-responsive gyrate atrophy (patient 3) (light-to-dark ratio: 1.25, normal: >1.85) (bottom). (From Weleber RG, Kennaway NG: Gyrate atrophy of the choroid and retina. In Heckenlively JR (ed): Retinitis pigmentosa. Philadelphia, JB Lippincott, 1988, pp 198–220. Used by permission.)