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.

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.

Vigabatrin, a gabaergic antiepileptic drug, causes concentric visual field defects.

OBJECTIVE: To determine whether there is a causal link between vigabatrin treatment and concentric visual field defects and to evaluate the prevalence of these visual field constrictions. BACKGROUND: While the GABAergic antiepileptic drug (AED) vigabatrin was being clinically developed, only rare cases (less than 1:1000) of symptomatic visual field constriction and retinal disorders were reported. During 1997 to 1998, concentric visual field constrictions were described in case reports of mostly drug-resistant epilepsy patients receiving vigabatrin concurrently with other AEDs. METHODS: Ophthalmologic tests including Goldmann perimetry were performed on 32 adult patients on long-term successful vigabatrin monotherapy (treatment duration 29 to 119 months) and on 18 patients on carbamazepine monotherapy (treatment duration 32 to 108 months). Eighteen healthy adults served as controls. RESULTS: None of the patients complained about vision problems when asked to participate into the study. Thirteen out of the 32 (40%) epilepsy patients treated with vigabatrin monotherapy had concentrically constricted visual fields (9% severely, 31% mildly constricted), whereas none of the carbamazepine monotherapy patients or normal controls presented with a visual field defect (chi-square test, p = 0.0001). The extents of the visual fields were significantly constricted in vigabatrin group as compared with the visual fields of the patients in carbamazepine group or healthy controls (analysis of variance, Scheffe F-test, significant at 99%). CONCLUSIONS: The use of vigabatrin seems to increase the risk of a unique and specific pattern of bilateral, mainly asymptomatic visual field constriction. This risk should be considered when using vigabatrin. Visual field testing should also be performed before treatment and during routine follow-up for patients on vigabatrin.

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.

Papillary hypertrophy of the upper tarsal conjunctiva during contact lens wear: a 4-month study with ethyl-6-O-decanoyl-glucoside.

PURPOSE: We studied the potential effect of ethyl-6-O-decanoyl-glucoside (EDG) on papillary hypertrophy in contact lens wearers who were recruited on the basis of papillary hypertrophy and a long history of contact lens wear. The contact lens care solutions were 0.00025% chlorhexidine acetate (CHX) with or without 0.005% EDG. METHODS: Nineteen subjects wearing both ionic and non-ionic contact lenses for 6-18 hours used either CHX or CHX+EDG as a cleaning and disinfecting agent. CHX and CHX+EDG was used simultaneously by each subject but in different eyes during two consecutive periods of 8 weeks. Symptoms and signs were recorded at three examinations during the study. The protein content of contact lenses and tryptase activity of tear fluids were measured. RESULTS: The degree of papillary hypertrophy did not decrease in either the CHX or CHX+EDG groups. Also, there were no differences in protein content of lenses nor tryptase activity of tear fluids in either group. There was a significant correlation between papillary hypertrophy and tryptase activity during the study. CONCLUSIONS: Despite the earlier finding that EDG prevents development of papillary hypertrophy in contact lens wearers, EDG still cannot reverse established signs of papillary hypertrophy.

Ophthalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy.

OBJECTIVE: The purpose of the study was to determine the nature and course of ophthalmic abnormalities in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a recently discovered disorder of mitochondrial fatty acid beta-oxidation. STUDY DESIGN: The study design was a cohort (case series). PARTICIPANTS: A retrospective review of the records of 15 children who had died during their first 2 years was performed. Also performed were a longitudinal reanalysis and cross-sectional clinical examination of four long-term survivors aged 5 to 31 years. MAIN OUTCOME MEASURES: Visual acuity, refraction, visual fields, ophthalmoscopy, fluorescein angiography, biometry, corneal topography, electroretinography (ERG), visual-evoked potentials (VEPs), color vision, and dark adaptation were measured. RESULTS: In seven children, ophthalmoscopic findings were within normal limits at 3 days to 13 months of age (median, 4.8 months). In 11 children, a granular retinal pigment epithelium (RPE), with or without pigment clumping in the macula, was seen at 4 months to 5 years of age (median, 9 months). Two long-term survivors, 16 and 31 years of age, eventually had circumscribed atrophy of the choroid, RPE, and retina, which coincided with a posterior staphyloma type 1. They had progressive axial myopia starting at 6 and 12 years of age and later paracentral scotomas leading to poor central vision. They suffered from early difficulty with mesopic vision, glare, and a severe generalized color vision deficiency that started as a tritanomaly. A third survivor was mildly myopic at 5 years of age. All four surviving patients had visually insignificant, flake-like supranuclear opacities in the lens. The ERG initially was normal but deteriorated during the first decade and later was unrecordable. The VEP responses remained fairly normal. Initially, angiography showed no blockade of the choroidal fluorescence because of the thin RPE. Filling of choroidal vessels was delayed, and the choriocapillaris and, later, larger choroidal vessels in the posterior pole became nonperfused. CONCLUSIONS: In LCHAD deficiency, the fundus is normal at birth (stage 1). Soon, however, pigment dispersion occurs in the RPE (stage 2), followed by circumscribed chorioretinal atrophy, occlusion of choroidal vessels, and deterioration of central vision, often with relative sparing of the peripheral fundus (stage 3). Finally, posterior staphylomas and central scotomas may develop (stage 4). Developmental cataract, progressive myopia, and deterioration of visual fields and color vision are new findings in LCHAD deficiency. The chorioretinopathy and abnormal ERG precede the development of myopia and posterior staphyloma, which, in turn, coincide with the loss of macular vision. The authors postulate that the RPE or choriocapillaris is primarily affected. Awareness of the characteristic ocular features is important because of an opportunity for dietary treatment, genetic counseling, and prenatal diagnosis.

mtDNA haplotype analysis in Finnish families with leber hereditary optic neuroretinopathy.

The mitochondrial DNA (mtDNA) sequence variation of 24 Finnish Leber hereditary optic neuroretinopathy (LHON) probands was characterized by sequencing and restriction endonuclease analyses. All LHON-associated substitutions and Caucasoid haplogroup-specific mutations were screened in the families. Analysis of the mtDNAs revealed that the Finnish LHON families have two unique features: an absence of the ND6/14484 mutation and a high number of families (10/24) without the primary mutations ND1/3460 and ND4/11778. Furthermore, the LHON families showed considerable mtDNA heterogeneity: among 24 families 22 haplotypes were detected. Overall, the haplogrouping of LHON families was similar to other European populations. However, the frequency of ND4/11778-positive families in haplogroup J was high, which may indicate that background mutations in this haplogroup together with the ND4/11778 primary mutation promote the penetrance of LHON.

Mutations in subunit 6 of the F1F0-ATP synthase cause two entirely different diseases.

A lowered efficiency of oxidative phosphorylation was recently found in a Leber hereditary optic neuropathy (LHON) proband carrying a mutation in the mtDNA gene for subunit 6 of the membrane-bound F0 segment of the F1F0-ATP synthase [9]. This phenotype was transferred to cytoplasmic hybrid cells together with the mutation, proving its functional significance. Increasing the respiratory rate in the mitochondria from this mutant raised the ATP/2e- ratio back to normal values. A different mutation in the same mtDNA gene has been found in patients with the NARP syndrome [10]. Although the ATP/2e- ratio is also decreased in this mutant, in this case an increase in the respiratory rate could not compensate for it. Whilst both mutations affect subunit 6 of the proton-translocating F0 segment, the LHON mutation induces a proton leak whereas the NARP mutation blocks proton translocation. Hence, the latter will have much more destructive metabolic consequences in agreement with the large clinical differences between the two diseases.

Tissue distribution of the ND4/11778 mutation in heteroplasmic lineages with Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is a maternally inherited eye disease most commonly caused by mitochondrial DNA (mtDNA) point mutation at position 11778, 3460, or 14484. Approximately 14% of families show heteroplasmy for the pathogenic mutations but little is known about the mutational burden in different tissues of these heteroplasmic individuals. Consequently, estimating the risks of visual loss is difficult. This study presents quantitative mutation analyses of tissues representing all embryonal layers in two families heteroplasmic for the 11778 mutation. These analyses show that a high amount of mutated mtDNA in leukocytes is correlated with a high proportion of mutated mtDNA in other tissues.

Evaluation of glaucoma patients referred to a university clinic during one year.

PURPOSE: In the spring of 1994, the post-referral waiting time for glaucoma patients at our institution was approximately 7 months. In an attempt to evaluate and possibly reduce this waiting time we compared the referral criteria to the actual treatment requirements of 472 patients admitted for glaucoma in 1995. RESULTS: 175 patients were referred as glaucoma suspects, 134 as chronic simple glaucoma, and 123 as capsular glaucoma. In addition, 40 patients were referred as other types of glaucoma. Elevated IOP was the main criterion for referral in 133 (76%) of glaucoma suspects. The diagnosis of glaucoma could not, however, be confirmed in 54 (31%) glaucoma suspects. 93 (69%) patients with simple open angle glaucoma and 103 (84%) patients with capsular glaucoma were also referred because of IOP > or = 22 mmHg. Maximally tolerated medication was not used by 44% of open angle glaucoma patients at time of referral. CONCLUSION: The clinical follow-up of glaucoma patients and glaucoma suspects should primarily take place at an ophthalmologist's office and the new effective glaucoma drugs and laser treatments should also be more actively in use. The cooperation between the referring ophthalmologists and the university clinic should be improved. Hospitalisation turned out to be unnecessary because, with a few exceptions, all procedures could have been performed on an out-patient basis, which is a general practice in most glaucoma clinics today. The university clinic should focus only on those patients who need special evaluation or surgical treatment.

An expanded CAG repeat sequence in spinocerebellar ataxia type 7.

Expanded CAG repeat sequences have been identified in the coding region of genes mutated in several neurodegenerative disorders, including spinocerebellar ataxia type 1 and Machado-Joseph disease. In all disorders described to date the CAG expansion codes for an elongated polyglutamine chain. An increased polyglutamine chain size leads to a more severe disease, thus correlating with the genetic anticipation seen in repeat expansion disorders. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant spinocerebellar ataxia with anticipation and a progressive degeneration of the cerebellar cortex. Using repeat expansion detection (RED), a method in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA, we have analyzed 8 SCA7 families for the presence of CAG repeat expansions. RED products of 150-240 bp were found in all affected individuals and found to cosegregate with the disease (P < 0.000001, n = 66), indicating strongly that a CAG expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease, we were able to estimate the average expansion size in SCA7 to be 64 CAG copies.

Catalytic activity of complex I in cell lines that possess replacement mutations in the ND genes in Leber's hereditary optic neuropathy.

Short-chain ubiquinone analogues act as electron acceptors and as inhibitors in the lymphoblast mitochondria of ND1/3460 mutants, which indicates structural changes in the ubiquinone-binding domain of Complex I in this mutant. The ND4/11778 mutant and two secondary ND5 mutants studied are associated with reductions of at least 50, 35 and 30% in the catalytic rate constant, respectively. However, the efficiency of oxidative phosphorylation is unaffected in all these ND mutants. The rate of respiration is only slightly limited by Complex I in lymphoblast mitochondria. Consequently, there is a 30-35% reduction in the electron flow through Complex I compared with that through Complex II, and an increased lactate/pyruvate ratio, in the ND1 and ND4 mutants, but these factors were unaffected in the secondary ND5 mutants. Energy metabolism is thus less severely affected in the secondary mutants than in the primary mutants, which supports the division into these two categories. An increased ubiquinone-10 content in the mitochondrial membrane of all the mutants, and enhanced succinate dehydrogenase and citrate synthase activities in the ND4 mutant, are proposed to be compensatory changes. The efficiency of these changes and the level of kinetic limitation of respiration by Complex I in each tissue are proposed to determine the clinical development of the disease.

Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is associated with primary and secondary mutations in mitochondrial DNA. Clinical studies suggest that there is a wide spectrum of clinical expression. METHODS: Fifty-three affected and 131 unaffected maternal relatives from 21 pedigrees with LHON were studied neuro-ophthalmologically and followed over a period of 14 years. Mitochondrial DNA analysis was performed on their blood specimens. RESULTS: Thirty-two affected (60%) individuals from ten families harbored the 11778 mutation and ten individuals (19%) from three families harbored the 3460 mutation. No confirmed primary mutation was detected in 11 (21%) affected individuals from eight families. The visual outcome was better in families with the 3460 mutation than in those with the 11778 mutation. Secondary mutations did not affect the penetrance or the visual outcome. Fifteen patients had a favorable outcome; seven of whom had subclinical disease, two had slowly progressive LHON with a favorable visual outcome, and six had classic LHON with spontaneous recovery. In seven patients, the onset of the disease had been in childhood. These patients had a more favorable prognosis than the adults. Results of eye examinations of asymptomatic maternal relatives showed subclinically affected individuals. CONCLUSIONS: In addition to classic LHON, the disease can manifest itself in three different atypical forms: subclinical disease, slowly progressive LHON with a favorable visual outcome, and LHON with the classic acute stage but spontaneous visual recovery. The current study suggests that the ophthalmologic findings and outcome in LHON are independent of secondary mutations.

Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy.

Previous studies suggest that Leber's hereditary optic neuropathy (LHON) may be a systemic disorder with manifestations in organs other than the optic nerves. To evaluate nervous system involvement 38 men and eight women with LHON were re-examined. The patients were divided into three groups according to mtDNA analysis--namely, patients with the 11778 or with the 3460 mutation and patients without these primary mutations. Fifty nine per cent of patients had neurological abnormalities but there was no significant difference between the three groups. Movement disorders were the most common finding; nine patients had constant postural tremor, one chronic motor tic disorder, and one parkinsonism with dystonia. Four patients had peripheral neuropathy with no other evident cause. Two patients had a multiple sclerosis-like syndrome; in both patients MRI showed changes in the periventricular white matter. Thoracic kyphosis occurred in seven patients, five of whom had the 3460 mutation. In one patient the 3460 mutation was associated with involvement of the brain stem. It is suggested that various movement disorders, multiple sclerosis-like illness, and deformities of the vertebral column may associate pathogenetically with LHON.

Pre-excitation syndrome in Leber's hereditary optic neuropathy.

Pre-excitation syndrome is common in families with Leber's hereditary optic neuropathy (LHON). 24 Finnish families with LHON were screened for the 11778 and the 3460 mitochondrial DNA mutations. 5 of 30 individuals with LHON and the 11778 mutation had the Wolff-Parkinson-White pre-excitation syndrome. None of 10 with the 3460 mutation or of 11 with "other" mutations had this syndrome. Overall, 5 of 51 LHON patients and 9 of 112 symptom-free maternal relatives had Wolff-Parkinson-White syndrome (9%). In paternal relatives, the frequency was 1.6%. Mitochondrial DNA causal for LHON may contribute to pre-excitation syndrome.