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Show ! oumal of Clillical Neuro- ophthalmology 12( 1): 15- 16, 1992. Evidence for a Metabolic Trigger for Leber's Hereditary Optic Neuropathy A Case Report L. G. DuBois, M. Ed., co, COMT and S. E. Feldon, M. D. '( j 1992 Raven Press, Ltd., New York A 9- year- old girl with recently diagnosed juvenile onset diabetes mellitus presented with signs and symptoms of bilateral optic neuropathy, Leber's hereditary optic neuropathy was suspected on the basis of a strong family history. Subsequent mitochondrial DNA testing was positive. Visual recovery occurred once the diabetes was well controlled. This case suggests that such metabolic compromise that occurs in diabetes may precipitate the clinical expression of Leber's optic neuropathy, Key Words: Leber's Disease- MitochondriaMetabolism in Leber's. From the Departments of Ophthalmology ( L. G. D., S. E. F.) and Neurological Surgery ( S. E. F.), University of Southern California School of Medicine and the Doheny Eye Inshtute, Los Angeles, California. . Address correspondence and repnnt requests to Dr. S. E, Feldon, Doheny Eye Institute, 1355 San Pablo Street, Los Angeles, CA 90033, USA. 15 Leber's hereditary optic neuropathy ( Leber's) is a maternally inherited, mitochondrial DNA ( mONA) mutation characterized clinically by its bilateral occurrence; it primarily affects men ( penetrance is approximately 60- 85%). The age of onset has been reported as early as the second decade of life and as late as the seventh ( 1). In the vast majority of cases, the disorder begins before the fifth decade, Sporadic cases of Leber's have been reported in the absence of a positive family history, but in these seemingly sporadic occurrences asymptomatic family members are often found to have the characteristic retinal microangiopathy ( 2). Gene mapping techniques have recently been used to identify a mutation site for Leber's. There is strong evidence that a guanine- to- adenine mutation at locus 11778 on mitochondrial DNA causes this disorder ( 3). This single nucleotide mutation causes the conversion of a highly conserved arginine to a histine amino acid at Codon 340 and eliminates an SfaNI site ( the basis for a diagnostic DNA probe). The mutation itself has been purported to be a necessary, but not sufficient, condition to produce overt symptoms. It has been shown that the mutant mONA exists in variable proportions among family members. In addition, the amount of mutant mONA varies within different tissues in individual patients ( 4). It is presumed that a high proportion of mONA mutations in the optic nerve will eventually precipitate visual loss as the mitochondria fail to meet the energy requirements of those retinal neurons. The following case report addresses the relationship between the onset of metabolic dysfunction such as that which occurs with diabetes and the changes in intracellular milieu that unmask the ocular disorder. CASE REPORT A 9- year- old girl was referred for " rapidly decreasing vision" that occurred over 4 months. At 16 L. G. DuBOIS AND S. E. FELDON the time of presentation, the best corrected visual acuity was 20/ 200 00 and 20/ 200 as; color vision was markedly reduced so that only 1 of 15 AO pseudoisochromatic plates were correctly identified for each eye. There was an enlarged physiologic blind spot in the visual field of the left eye, and there were central scotomata bilaterally. Temporal disc pallor was present on the right, and diffuse disc pallor was present on the left; if there had been early telangiectasis, it was no longer apparent. There was nerve fiber layer loss in both eyes. Electroretinography, magnetic resonance imaging, and computed tomography were normal, but the visual evoked potential was abnormal. In addition to ophthalmologic symptoms, the patient had mild diffuse muscular weakness and was recently diagnosed as having juvenile onset diabetes mellitus; there was no indication of mitochondrial myopathy found on muscle biopsy, and a genetic probe was not performed. The maternal family history was positive for clinically diagnosed Leber's in an aunt, a sister, and a male cousin. The patient's brother suffered from a muscular dystrophy of unknown etiology. The proband's blood and hair analyses were positive for the mONA marker. Subsequent clinical and genetic evaluation of the three relatives, the proband's mother, and her brother supported a diagnosis of Leber's in all five, although not all had visual symptoms. Once hyperglycemia was stabilized with subcutaneous insulin administration, the patient recovered visual function within 9 months. Visual acuity improved to 20/ 25 00 and 20/ 60 as; color discrimination improved to 7/ 15 AO pseudoisochromatic plates on the right and 4/ 15 plates on the left. The optic discs remained pale. DISCUSSION Based on the non- Mendelian inheritance pattern for mONA, it may be postulated that variations in the number of mutant mitochondria or perhaps the proportion of mutations within a mitochondrion explains the variable expression of Leber's within a given family. It is presumed that the onset of the disorder signals the end of the mitochondria's ability to generate sufficient energy for enough cells to maintain " normal" visual function. During the period preceding the rapid decline in vision of a patient with Leber's, or during the lifetime of an asymptomatic " carrier" of the mutation, the deficiency in energy production by the mutant mitochondria might be partially compensated by the increase in nutrients delivered by telangiectatic vessels. Indeed, the telangiectasis of normally small vessels in the retina might be a response to JClin Neuro- crphfhalmol, Vol. 12. No. 1, 1992 the early degeneration of cells due to unrnet energy requirements. If, in addition to a genetically fragile intracellular environment, the added insult of an external " hit" exists, then the cell may not be able to maintain its borderline viability. This, we believe, is the mechanism for the visual loss and subsequent recovery in the very young female Leber's patient in our case report. The combination of genetic and metabolic alteration of mitochondrial respiration at the onset of diabetes in our patient may have initiated the onset of her neuropathy. Reestablishing the normal metabolic milieu with exogenous insulin probably restored the function of enough viable neurons to restore visual function. Although genetically normal cerebral tissue mitochondria are not metabolically affected by a chronic hyperglycemic, insulindeficient condition, a change in mitochondrial anion transporter function is known to occur in diabetes and may affect the deregulation of transport proteins in coordination with metabolic enzymes ( 5,6). In addition, substantial decreases ( 2035%) in calcium ion uptake by mitochondria in diabetic rats have been reported ( 7), suggesting a loss in aerobic glucose oxidation. The eventual mild improvement of visual function in patients with Leber's is well documented. The reversal of severe visual loss in our patient when her metabolic " trigger" for Leber's was discovered and treated suggests the existence of a precipitating, but treatable, environmental event. It therefore becomes important, with the early diagnosis of Leber's, to fully evaluate the patient in order to discover any treatable secondary condition such as anemia, toxicity, inflammation, and nutritional deficiencies. If an optimum cellular environment can be established, perhaps the visual consequences of Leber's will remain minimal or even improve to subclinical status. REFERENCES 1. Adams JH, Blackwood W, Wilson J. Further clinical and pathological observations on Leber's optic atrophy. Brain 1966; 89: 15- 26. 2. Nikoskelainen E, Nummelin K, Savontaus ML. Does sporadic L~ ber's disease exist? JClin Neuro- aphtha/ mo/ 1988; 8: 225- 9. 3. Smgh G, Lott MT, Wallace DC. A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy. N Engl JMed 1989; 320: 1300- 5. 4. Lott ~ T, Volj. avec AS: Wallace DC. Variable genotype of Leber s hereditary optic neuropathy patients. Am JOphthalmol 1990; 109: 625- 31. 5. Pelligrino OA, Becker GL, Miletich OJ, Albrecht RF. Cerebral mitochondrial respiration in diabetic and chronically hypoglycemic rats. Brain Res 1989; 479: 241- 6. 6. Kapl~ RS, . Oliveira OL, Wilson GL. Streptozotocin- induced alterations m the levels of functional mitochondrial anion transport proteins. Arch Biochem Biophys 1990; 280: 181- 91. 7. G~ blat L,. Stoppa~ AO. Diab~ tes y transporte de calcio en ffiltocondnas hepaticas. MedlClna ( B Aires) 1989; 49: 21- 7. |
