Peripheral nervous system in gyrate atrophy of the choroid and retina with hyperornithinemia.

OBJECTIVE: To evaluate peripheral nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinemia (GA). BACKGROUND: GA is an inborn error of amino acid metabolism caused by mutations in the enzyme ornithine aminotransferase. Patients with GA have hyperornithinemia, progressive centripetal loss of vision, minor CNS abnormalities, and type II muscle fiber atrophy with accumulation of tubular aggregates. The authors previously showed that muscle and brain creatine stores are depleted in the patients with GA. METHODS: The authors searched evidence of peripheral nervous involvement in 40 patients with GA (mean age 31.6 +/- 16.3 years; range 5 to 74 years) by using neurography, quantitative sensory threshold testing, and evoked potential testing. RESULTS: Neurography revealed abnormalities in 21 (53%) of the patients. The abnormalities associated with the severity of the ophthalmologic changes and the age of the patients. With quantitative sensory threshold testing, abnormal large-fiber function was found in seven (18%) and abnormal small-fiber function was found in four (10%) patients. Somatosensory evoked potential and brainstem auditory evoked potential responses were abolished in five patients. CONCLUSIONS: These findings of peripheral nervous system involvement in GA suggest that GA is a systemic disease affecting not only CNS but also the peripheral nervous system.

Ophthalmologic heterogeneity in subjects with gyrate atrophy of choroid and retina harboring the L402P mutation of ornithine aminotransferase.

OBJECTIVE/PURPOSE: To investigate clinical variation in a genetically homogenous group of subjects with gyrate atrophy of choroid and retina with hyperornithinemia (GA). The group was made up of homozygotes and compound heterozygotes for mutation L402P in the ornithine aminotransferase (OAT) gene. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-five Finnish subjects (18 men) with GA with a mean age of 33 years (range, 5-74 years) carrying the Finnish founder mutation L402P. METHODS: All subjects were examined between 1993 and 1995. The analysis was composed of, in addition to careful clinical evaluation, studies of visual fields with Goldmann perimeter, photographing of the eye fundi, and corneal electroretinography (ERG) recordings. MAIN OUTCOME MEASURES: The changes in eye fundi, visual acuity, cataract changes in the lens, visual field constriction, and ERG responses were determined. RESULTS: Myopia, early cataracts, and highly abnormal ERG were typical for the GA subjects. The changes progressed rather uniformly with age. However, visual acuity, funduscopic findings, and visual fields showed great phenotypic variation. Despite the great interindividual variation, both eyes of each subject were always similarly affected. CONCLUSIONS: This study of 35 subjects with GA carrying a single mutation shows that the ophthalmologic symptoms and findings vary widely. The data also reveal that GA subjects are already affected by severe visual impairment in young adulthood. However, the diagnosis is often made very late.

Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia.

In gyrate atrophy of the choroid and retina with hyperornithinaemia (GA), a genetically determined deficiency of ornithine delta-aminotransferase activity leads to high ornithine concentrations in body fluids. GA is characterized by centripetally progressing retinal and choroidal destruction and selective atrophy with tubular aggregates in type II skeletal muscle fibres. These findings have been suggested to be mediated by hyperornithinaemia-induced deficiency of high-energy creatine phosphate. As abnormal brain magnetic resonance images and electroencephalograms are found in another disorder of creatine metabolism, guanidinoacetate methyltransferase deficiency, we investigated the central nervous system involvement in GA, which seems to be associated with a milder degree of phosphocreatine deficiency. We compared 23 untreated GA patients with age-matched healthy controls, and with 9 patients who had received creatine or creatine precursor supplementation daily for several years. The mean age of the patients (32 +/- 18 years) was similar to that of the controls (36 +/- 22 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 GA patients, and 70% of the patients had premature atrophic changes, with a striking increase in the number of Virchow's spaces. Of the patients whose EEG was recorded, 58% had abnormal slow background activity, focal lesions or high-amplitude beta rhythm (> 50 microV). The EEG findings were not associated with the MRI changes or with the age or the sex of the patients. Early degenerative and atrophic brain changes and abnormal EEG are thus features of GA, in addition to the well-characterized eye and muscle manifestations.

Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia.

BACKGROUND: Eye fundus destruction and type II muscle fiber atrophy in gyrate atrophy of the choroid and retina with hyperornithinaemia (GA) may be mediated by elevated ornithine concentrations which strongly inhibit creatine biosynthesis. This results in deficiency of creatine phosphate (PCr), a key intracellular energy source, as we have demonstrated in skeletal muscle of the patients by 31P magnetic resonance spectroscopy (31P MRS). MATERIALS AND METHODS: Possible correction of the relative PCr deficiency by long-term daily exogenous supplementation of creatine or its precursors was investigated in four GA patients receiving creatine and in five patients treated with guanidinoacetic acid-methionine combination. The relative PCr concentration, expressed as PCr/Pi (Pi; inorganic phosphate) or as PCr/ATP ratios, was compared with the values of untreated GA patients, and matched healthy volunteers. RESULTS: Muscle PCr/Pi ratios (mean +/- SD) of the untreated and creatine supplemented GA patients and controls were 4.9 +/- 1.4, 7.9 +/- 0.4 and 8.4 +/- 1.3. Guanidinoacetate-methionine combination was similarly effective (respective PCr/Pi ratios: 4.9 +/- 0.7, 6.3 +/- 1.1 and 10.7 +/- 2.8). CONCLUSION: Supplementation with creatine or creatine precursors almost normalised low muscle PCr/Pi ratios of patients with GA.

Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia.

OBJECTIVE: To analyze in vivo brain creatine (Cr) content in gyrate atrophy of the choroid and retina with hyperornithinemia (GA). BACKGROUND: GA is caused by inherited deficiency of ornithine-delta-aminotransferase activity. Patients lose their vision by middle age and develop selective atrophy of type II skeletal muscle fibers. As demonstrated by MRS, the patients' skeletal muscles have diminished stores of high-energy Cr phosphate. Minor structural and electrophysiologic abnormalities in the brain of these patients also imply that the CNS may be affected. METHODS: The authors acquired proton MR spectra of the basal ganglia of 22 healthy control subjects and 20 GA patients. Nine patients received supplementary Cr or its precursors, and one child was on an arginine-restricted diet to normalize plasma ornithine concentration. The ratios of N-acetylaspartate (NAA) to Cr, NAA to choline (Cho), and Cho to Cr, and the ratios of NAA, Cho, and Cr to tissue water were calculated. RESULTS: NAA/Cr (Cho/Cr) in the untreated and treated patients and control subjects were (mean +/- SD) 3.3+/-0.4, 2.0+/-0.4, and 1.5+/-0.7 (1.9+/-0.3, 1.3+/-0.4, and 0.9+/-0.2), indicating that Cr content in untreated GA patients was proportionally and markedly diminished, and partially corrected by therapy (p < 0.0001). NAA/Cho was similar in all three groups. Cr/water in the untreated patients was only 46%, and increased to 75% of the control ratios in the treated patients (p < 0.0001). CONCLUSIONS: Hyperornithinemia-associated Cr deficiency in GA also affects the CNS, further supporting the possibility that Cr deficiency also has a pathogenetic role in the retina. The deficiency was partially corrected by Cr supplementation and an arginine-restricted diet.

Muscle creatine phosphate in gyrate atrophy of the choroid and retina with hyperornithinaemia--clues to pathogenesis.

BACKGROUND: In gyrate atrophy of the choroid and retina with hyperornithinaemia (GA), inherited deficiency of ornithine-o-aminotransferase leads to progressive fundus destruction and atrophy of type II skeletal muscle fibres. Because high ornithine concentrations inhibit creatine biosynthesis, the ensuing deficiency of high-energy creatine phosphate may mediate the pathogenesis. MATERIALS AND METHODS: Relative concentrations of inorganic phosphate (Pi), creatine phosphate (PCr) and ATP in resting calf muscle were recorded in 23 GA patients and 33 control subjects using 31P-magnetic resonance spectroscopy (MRS). Eight patients with autosomal recessive retinitis pigmentosa with matched control subjects constituted an additional reference group. RESULTS: The PCr/Pi and PCr/ATP ratios (means +/- SD) were lower for the GA patients than for healthy control subjects [4.66 +/- 0.37 vs. 9.75 +/- 2.17 (P < 0.0001) and 2.85 +/- 0.37 vs. 3.70 +/- 0.50 (P < 0.05) respectively]. In retinitis pigmentosa the respective values were 9.12 +/- 2.57 and 4.25 +/- 0.45. Age and stage of the disease had no effect. CONCLUSION: Muscle 31P-MRS spectra were markedly abnormal in all GA patients.

Gyrate atrophy of the choroid and retina: lymphocyte ornithine-delta-aminotransferase activity in different mutations and carriers.

Deficiency of omithine-delta-aminotransferase (OAT) causes gyrate atrophy of the choroid and retina with hyperornithinemia (GA; McKusick 258870), a progressive autosomal recessive chorioretinal degeneration leading to early blindness. As residual enzyme activity may vary in different mutations of the OAT gene and explain individual variations in disease progression, a sensitive HPLC modification of the OAT assay in lymphocytes was developed, based on measurement of the dihydroquinozolinium reaction product. The OAT activities (ranges) of 43 Finnish GA patients with mutations L402P/L402P, R180T/L402P, N89K/ L402P, and L402P/x (x = previously unknown allele), were <1-10, <1-13, <1-17, and <1 pmol x min(-1) mg protein(-1), respectively. The OAT activities (mean+/-SD) of nine L402P/ wild heterozygotes were 70+/-50 (range 33-193), and those of 15 healthy control subjects 184+/-60 (range 85-291) pmol x min(-1) mg protein(-1). This lymphocyte assay is an easy, rapid, and sensitive method for reliable recognition of GA homozygotes. OAT mutations of the Finnish patients show similar residual enzyme activity in the lymphocytes. OAT activities in the L402P heterozygotes and healthy control subjects overlap, suggesting that, for reliable carrier detection, the OAT alleles have to be studied. However, as all OAT mutations are not known, direct measurement of enzyme activity has a role in heterozygote identification and possibly also in prenatal diagnosis of GA.

Skeletal muscle of patients with gyrate atrophy of the choroid and retina and hyperornithinaemia in ultralow-field magnetic resonance imaging and computed tomography.

Gyrate atrophy of the choroid and retina with hyperornithinaemia (GA), an autosomal recessive disease, affects skeletal muscle in addition to the eye. Muscle biopsy samples show prominent type 2 muscle fibre atrophy. Atrophic fibres also contain accumulations of tubular aggregates in electron microscopy. To evaluate skeletal muscle involvement in detail, the thigh muscles of 7 patients with GA were examined using semi-open conchotome muscle biopsies, computed tomography (CT) and ultralow-field magnetic resonance imaging (MRI) at 0.02 T. In MRI, the T1 and T2 proton relaxation times were measured. Type 2 muscle fibre atrophy was found in all biopsy samples (100%) and tubular aggregates in 6 of the 7 samples studied (87%). The CT density of the muscle tissue was increased in the only child of the study, decreased in 3 elderly subjects, and normal in the remaining 3 patients. Mean T1 relaxation times of the patients were decreased (135 +/- 5 ms) as compared to those of 6 healthy controls (157 +/- 12 ms) (p = 0.002). The T2 relaxation time was slightly increased (40 +/- 3 ms) as compared to the controls (35 +/- 7 ms; not significant, p = 0.3). Our findings suggest that the thigh muscles of the patients with GA universally show changes in CT and MRI studies, but relaxation time measurements gave little additional information on the muscle metabolism.