| OCR Text |
Show Journal of'A'euro- Ophthalmology 20( 4): 229- 233, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Visual Loss and Recovery in a Patient With Friedreich Ataxia Syndee J. Givre, MD, PhD, Michael Wall, MD, and Randy H. Kardon, MD, PhD A 15- year- old boy with genetically confirmed Friedreich ataxia had binocular, painless loss of visual acuity and visual field over 6 months. This was attributed to optic neuropathy on the basis of norma] multifocal electroretinography ( MERG) and development of optic disc pallor. Magnetic resonance imaging of the brain and orbits was normal. Approximately 10 months after the onset of visual loss, the patient noted spontaneous improvement that was documented by visual acuity and visual field testing. To our knowledge, this is the first reported case of marked visual loss with partial recovery in genetically confirmed Friedreich ataxia and the first recording of a MERG in such a patient. CASE REPORT A 15- year- old boy with genetically confirmed Friedreich ataxia ( FRDA) sought treatment at the Pediatric Ophthalmology Clinic at the University of Iowa Hospitals and Clinics for 2 to 3 months of gradually progressive, painless visual loss OS. He was otherwise in his usual state of health. According to the parents, the patient began experiencing clumsiness at the age of 9 years. Within 4 years, he was confined to a wheelchair because of problems with balance. FRDA was diagnosed at the age of 15 years, when genetic analysis indicated approximately 1,000 repeats of the GAA repeat region of each allele of the frataxin gene. Associated conditions included mild left ventricular hypertrophy and scoliosis. He also had a history of peptic ulcer disease with positive serology for Helicobacter pylori. His only medication was cisapride ( Propulsid, Janssen Pharmaceuticals, Titusville, NJ). Ten months before presentation, the best- corrected acuity documented at a local optometrist's office was 20/ 30 OD and 20/ 30 OS. On presentation, best- corrected visual acuity was 20/ 30- 1 OD and 20/ 70- 2 OS. Color Manuscript received January 26, 2000; accepted June 27, 2000. From the Departments of Ophthalmology ( S. J. G, R. H. K., and M. W.) and Neurology ( M. W.), University of Iowa Hospitals and Clinics, Iowa City, Iowa. Address correspondence and reprint requests to Dr. Randy H. Kardon, University of Iowa Hospitals and Clinics, Department of Ophthalmology, PFP, 200 Hawkins Drive, Iowa City, IA 52245. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, NY. Dr. Kardon is a Lew R. Wasserman Scholar ( Research to Prevent Blindness). vision was significantly decreased OU when using Ishi-hara plates ( 3/ 14 plates OD; 2/ 14 plates OS). Critical foveal flicker fusion, a measure of optic nerve conduction, was moderately depressed at 20.6 Hz ± 3.3 Hz OD and 17.0 Hz ± 5.7 Hz OS ( normal ~ 30 Hz). Extraocular motility was full OU, and the patient was orthophoric in all fields of gaze. Kinetic perimetry ( Goldmann bowl perimeter) results from the first visit are shown in the top row of Figure 1. There was generalized depression, OS worse than OD. The slit- lamp and fundus examinations were normal OU, including optic disc appearance. A multifocal electroretinogram ( MERG) was obtained to help differentiate between retinal and optic nerve dysfunction. This test records the topographic electrical response from the photoreceptors and bipolar cells of the retina ( 1). It indicated normal retinal function within the central 50° ( diameter) of field. DNA analysis for known mutations associated with Leber hereditary optic neuropathy was negative. Magnetic resonance imaging ( MRI) of the brain and orbits without and with contrast was normal; there was no enhancement of the optic nerves. Despite this, a trial of corticosteroids, intravenous followed by oral, was instituted. There was no improvement, and over the next few months, the visual acuity and visual fields continued to worsen. The worst recorded acuities were 20/ 200 OD and 20/ 100- 2 OS, 5 months after the onset of visual symptoms. At this time, the patient was unable to detect the critical foveal flicker fusion stimulus with either eye. Goldmann perimetry results had also worsened ( see second row of Fig. 1). The pattern of visual field loss on Goldmann perimetry recordings obtained several months apart was repeatable except for deepening of existing relative scotomata. This provides evidence that the vision loss was physiologic. Approximately 10 months after his symptoms began, the patient and his family members independently noted an improvement in his visual functioning. He became able, for example, to read a clock located at a fixed distance from his bed, which he previously had been unable to see. On examination, his visual acuity was 20/ 125 OD and 20/ 80+ 3 OS. Three months later, the acuity had improved to 20/ 50- 2 OD and OS. Goldmann perimetry from this day showed recovery of the III4e and I4e isopters centrally OD and was essentially unchanged OS ( see the bottom row of visual fields in Fig. 1). Both optic discs showed mild temporal pallor. 229 230 S. J. GWREETAL. Initial Visit Visual Acuity 20/ 70" Visual Acuity 20/ 30 One Month Later Visual Acuity 20/ 100" Visual Acuity 20/ 200 Recovery FIG. 1. Results of kinetic ( Goldmann bowl) perimetry. Responses to the V4e, Ill4e, I4e and I3e stimuli are shown in purple, brown, blue and black, respectively. The results OD are printed on the right and the results OS are printed on the left and the visual acuity of each eye is printed below the visual field. The top row is the examination results from the patient's first visit. There was generalized constriction OU. One month later, as shown in the second row, there was further constriction and deepening of existing scoto-mata. After improvement in visual acuity OD, there was also recovery of the response to the HI4e and I4e stimuli as shown in the bottom right visual field. The visual field OS was essentially unchanged despite improvement in visual acuity. Visual Acuity 20/ 50 Visual Acuity 20/ 50 Regarding possible factors related to recovery, no recent change in diet or medication was noted. The only change in lifestyle had been a reduction in the patient's level of physical activity because of immobilization after a T2- sacral spine fusion for scoliosis. The surgery had been performed 3 months before the onset of visual improvement. DISCUSSION In the past, patient diagnosis and the classification of hereditary ataxias was made difficult by the presence of overlapping clinical features among the various entities and by incomplete understanding of the underlying genetics. Early case series of FRDA were likely contaminated with misdiagnosed patients. Despite this, and even before the identification of the genetic defect, distinguishing features of this disorder had been agreed on ( 2- 5). FRDA is an autosomal recessive disorder that usually presents at the time of puberty and almost always before the age of 25 years. Typically, there is progressive truncal and limb ( upper and lower) ataxia and loss of tendon reflexes in the legs. Axonal, sensory neuropathy, reduction in joint position or vibration sense in the legs, dysarthria, and extensor plantar responses often occur as well. Associated problems include scoliosis, pes cavus, cardiomyopathy, and diabetes mellitus. Not all patients have all of these findings, and the exact signs required for the diagnosis of FRDA are still a matter of debate. Before the availability of genetic testing, most authors relied on data from the clinical series of Geoffroy et al. ( 3) and Harding ( 4). Neuropathologic investigation has indicated involvement of the cerebellum, spinal cord, and peripheral nerves ( 6,7). Neuroradiologic abnormalities may be absent or include atrophy of the brainstem ( mostly medullary) and cerebellum ( 8). J Neuro- Ophthalmol, Vol. 20, No. 4, 2000 VISUAL LOSS AND RECOVERY IN A PATIENT WITH FRIEDREICH ATAXIA 231 Neuro- ophthalmologic manifestations of FRDA include oculomotor abnormalities such as nystagmus, ocular flutter, and impairment of the vestibulo- ocular reflex ( 9- 11) as well as vision loss with optic atrophy ( 3,4,12, 13). The degree and mechanism of vision loss has not been well characterized; nor has it been investigated in a detailed, controlled manner. When it has been addressed, authors, usually nonophthalmologists, have reported on visual acuity and optic atrophy as assessed by ophthalmoscopy or visual evoked potentials ( VEP). Table 1 summarizes the available data on visual loss in FRDA since 1976. By this time, a reasonable consensus on the clinical characteristics of the disorder had been reached, so the papers cited likely only include FRDA patients. The most extensive clinical review of vision loss is probably that of Carroll et al. ( 12), who measured at least visual acuity in 22 patients. None had acuity worse than 20/ 80. Fourteen of the 22 had prolongation of the PI00 latency on VEPs. Fifteen patients had fundus examinations, and mild to moderate optic disc pallor was observed in nine of them. Three patients underwent full-field electroretinography; all showed ' just subnormal' responses not thought to be significantly contributing to the abnormal VEPs. Based on these data and similar, though less systematically investigated, findings by other authors, the mechanism of vision loss in FRDA is presumed to be an optic neuropathy ( Harding [ 4] did report one patient with a peripheral retinal pigmentary disturbance). Abnormalities of the optic tract and lateral geniculate nucleus have been observed at postmortem histologic examination ( 6). The affected gene in FRDA has been mapped to chromosome 9ql3- q21.1 ( 14- 16) and the encoded protein, frataxin, identified ( 17,18). Ninety- four percent to 98% of FRDA patients are homozygous for an expansion of the GAA repeat region of the gene ( 13,18). Normally, there are 7 to 22 GAA repeats in this region of the FRDA gene. Patients with FRDA have, on average, 600 to 800 TABLE 1. Summary of studies since 1976 containing information on vision in Friedreich ataxia Parameters measured Study Visual acuity Optic atrophy VEP abnormality Color vision Visual field Andermann et al., 1976 Geoffroy et al., 1976 Carroll et al., 1981 Harding et al., 1981 Livingston et al., 1981 Durr et al., 1996 Montermini et al., 1997 3/ 58 ( 5%) Patients with " markedly decreased visual acuity" 22/ 50 ( 44%) Patients with decreased visual acuity which we found to be almost always due to partial optic atrophy" ( a) 27/ 43 ( 63%) Eyes " normal" ( b) 7/ 43 ( 16%) Eyes worse than 20/ 20 but equal to or better than 20/ 50 ( c) 9/ 43 ( 21%) Eyes worse than 20/ 50 14/ 115 ( 12%) Patients had " normal" vision but optic atrophy 15/ 115 ( 13%) Patients had " mildly decreased vision" and optic atrophy 6/ 115 ( 5%) Patients had " severely decreased vision" and optic atrophy ( d) 15/ 42 ( 36%) Eyes 20/ 20 or better ( e) 19/ 42 ( 45%) Eyes worse than 20/ 20 but equal to or better than 20/ 50 ( f) 8/ 42 ( 19%) Eyes worse than 20/ 50 " reduced" in 13% of 140 genetically confirmed patients 4/ 58 ( 7%) Patients 10/ 18 Eyes from ( a) 5/ 6 Eyes from ( b) 5/ 5 Eyes from ( c) Total 35/ 115 ( 30%) patients 33% Eyes from ( d) 53% Eyes from ( e) 38% Eyes from ( f) 21% of 109 Patients with genetically confirmed FRDA 52% of eyes from ( a) 86% of eyes from ( b) 100% eyes from ( c) 5 of 13 Patients with normal vision had reduced color plates " Mapping of the visual field" was normal in all 15 patients tested 33% eyes from ( d) Normal in 19/ 19 patients ( 2 patients with 20/ 200 vision not tested) Normal in 19/ 19 patients ( 2 patients with 20/ 200 vision not tested) 100% eyes from ( f) FRDA, Friedrich ataxia; VEP, visual evoked potential. J Neuro- Ophthalmol, Vol. 20, No. 4, 2000 232 S. J. GIVRE ET AL. GAA repeats ( 13,18,19). The number of GAA repeats is inversely proportional to the age of onset and time until confinement to a wheelchair and directly proportional to the presence and severity of some clinical signs ( 13,18, 19,20). Campuzano et al. ( 18) found frataxin to be expressed in human heart, liver, skeletal muscle, pancreas, and central nervous system. This, for the most part, corresponds to the sites of pathology in FRDA. In developing mice, in situ hybridization indicated expression of frataxin transcripts in brown adipose tissue ( which contains many mitochondria; see later discussion), brains, spinal cord, liver, heart, and kidney ( 21). Both a yeast homologue of frataxin, YHF1, and a mouse homologue have been studied ( 21- 23) In these organisms, as well as in human tissue culture lines, the protein localizes to mitochondria. Deletion of the YHF1 gene in yeast leads to decreased production of mitochondrial DNA and hypersensitivity to oxidative stress. Specifically, Babcock et al. ( 22) found that YHF1 gene deletion results in iron accumulation in mitochondria. It has been postulated that expression of abnormal frataxin in mitochondria could lead to an overload of iron, which, in turn could result in damage to mitochondrial DNA, production of toxic hydroxyl radicals or, simply, interference with the respiratory chain ( 22,24). Recently, in vivo phosphorous magnetic resonance spectroscopy showed decreased adenosine triphosphate ( ATP) production in calf muscles of FRDA patients as compared with normal controls ( 25). This same study showed a negative correlation between the rate of mitochondrial ATP production and the number of GAA repeats in the FRDA genes of patients. Based on abnormal biochemical studies in patients with FRDA, this disorder was thought to involve mitochondrial energy deprivation long before the gene and its product had been determined ( 26). Although FRDA is linked to the nuclear genome, it may share a final- common- pathway mechanism with optic neuropathy linked to mitochondrial inheritance, such as Leber hereditary optic neuropathy ( LHON) or with acquired optic neuropathies such as the Cuban epidemic optic neuropathy. The exact ways in which mitochondrial dysfunction leads to optic nerve damage are unknown. In LHON, it has been postulated to involve disruption of axonal transport ( 27,28). Two features of the case described in this report are unusual. First, our patient's visual acuity loss was profound as compared with that of most patients reported in the literature. This may be related to the large number of GAA repeats on both alleles that his genetic analysis revealed. His early age of onset and the early age at which he required a wheelchair support this. Whether the variability in optic atrophy seen in FRDA is related to the duration of disease or the number of GAA repeats is still in question ( 13,20). Second, there was partial recovery of visual acuity and visual fields. This has not been previously documented in the literature. The mechanism is unknown but may be similar to the mechanism of spontaneous recovery of vision, which has been noted in LHON ( 29- 33). REFERENCES 1. Sutter EE, Tran D. The field topography of ERG luminance components in man: 1. The photopic luminance response. Vis Res 1992; 32: 433- 46. 2. Lubozynski MF, Roelofs RI. Friedreich's ataxia. South Med J 1975; 68: 757- 63. 3. Geoffroy G, Barbeau A, Lemieux B, et al. Clinical description and roentgenologic evaluation of patient's with Friedreich's ataxia. Can J Neurol Sci 1976; 3: 279- 86. 4. Harding AE. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafa-milial clustering of clinical features. Brain 1981; 104: 589- 620. 5. Harding AE. The inherited ataxias. Adv Neurol 1988; 48: 37- 47. 6. Oppenheimer DR. Brain lesions in Friedreich's ataxia. Can J Neurol Sci 1979; 6: 173- 6. 7. Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol 1998; 57: 531- 43. 8. Ormerod IEC, Harding AE, Miller DH, et al. Magnetic resonance imaging in degenerative ataxic disorders. J Neurol Neurosurg Psychiatry 1994; 57: 51- 7. 9. Andermann E, Remillard GM, Goyer C, et al. Genetic and family studies in Friedreich's ataxia. Can J Neurol Sci 1976; 3: 287- 301. 10. Monday LA, Lemieux B, St- Vincent H, et al. Clinical and elect-ronystagmographic findings in Friedreich's ataxia. Can J Neurol Sci 1978; 5: 71- 3. 11. Moschner C, Perlman S, Baloh RW. Comparison of oculomotor findings in the progressive ataxia syndromes. Brain 1994; 117: 15- 25. 12. Carroll WM, Kriss A, Baraitser M, et al. The incidence and nature of visual pathway involvement in Friedreich's ataxia, a clinical and visual evoked potential study of 22 patients. Brain 1980; 103: 413- 34. 13. Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996; 335: 1169- 75. 14. Chamberlain S, Shaw J, Rowland A, et al. Mapping of mutation causing Friedreich's ataxia to human chromosome 9. Nature 1988; 334: 248- 50. 15. Fujita R, Agid Y, Trouillas P, et al. Confirmation of linkage of Friedreich ataxia to chromosome 9 and identification of a new closely linked marker. Genomics 1989; 4: 110- 1. 16. Hanauer A, Fujita CR, Driesel AJ, et al. The Friedreich ataxia gene is assigned to chromosome 9ql3- q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15. Am J Hum Genet 1990; 46: 133- 7. 17. Montermini L, Rodius F, Pianese L, et al. The Friedreich ataxia critical region spans a 150- kb interval on chromosome 9ql3. Am J Hum Genet 1995; 57: 1061- 7. 18. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271: 1423- 7. 19. Filla A, De Michele G, Cavalcanti F, et al. The relationship between trinucleotide ( GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet 1996; 59: 554- 60. 20. Montermini L, Richter A, Morgan K, et al. Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion. Ann Neurol 1997; 41: 675- 82. 21. Koutnikova H, Campuzano V, Foury F, et al. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet 1997; 16: 345- 51. 22. Babcock M, de Silva D, Oaks R, et al. Regulation of mitochondria] iron accumulation by Yfhlp, a putative homolog of frataxin. Science 1997; 276: 1709- 12. 23. Wilson RB, Roof DM. Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet 1997; 16: 352- 7. 24. Klockgether T, Evert B. Genes involved in the hereditary ataxias. Trends Neurosci 1998 ; 21: 413- 8 25. Lodi R, Cooper JM, Bradley JL, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA 1999; 96: 11492- 5. J Neuro- Ophthalmol, Vol. 20, No. 4, 2000 VISUAL LOSS AND RECOVERY IN A PATIENT WITH FRIEDREICH ATAXIA 233 26. Barbeau A. Friedreich's ataxia 1980; an overview of the pathophysiology. Can J Neurol Sci 1980; 7: 455- 67. 27. Howell N. Leber hereditary optic neuropathy: mitochondrial mutations and degeneration of the optic nerve. Vision Res 1997; 37: 3495- 507. 28. Sadun A. Acquired mitochondrial impairment as a cause of optic nerve disease. Trans Am Ophthalmol Soc 1998; XCVI: 881- 923. 29. Lissell S, Gise RL, Krohel GB. Bilateral optic neuropathy with remission in young men: variation on a theme by Leber? Arch Neurol 1983; 40: 2- 6. 30. Stone EM, Newman NJ, Miller NR, et al. Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation. J Clin Neuro- ophthalmol 1992; 12[ l]: 10- 4. 31. Riordan- Eva P, Sanders MD, Govan GG, et al. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995; 118: 319- 37. 32. Nikoskelainen E, Huoponen K, Juvonen V, et al. Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology 1996; 504- 14. 33. Yamada K, Mashima Y, Kigasawa K, et al. High incidence of visual recovery among four Japanese patients with Leber's hereditary optic neuropathy with the 14484 mutation. J Neuro- Ophthalmol 1997; 17: 103- 7. / Neuro- Ophthalmol, Vol. 20, No. 4, 2000 |
