Journal of Neuro-Ophthalmology, September 1991, Volume 11, Issue 3

Difficulty differentiating Leber's from dominant optic neuropathy in a patient with remote visual loss.

A 31-year-old man who inexplicably lost vision as a child was referred for evaluation of bilateral optic atrophy. Other family members had also suffered unexplained visual loss. He had asymmetric impairment of visual acuity, central scotomas, and optic disc pallor. He also had a tritan color vision defect and excavation of the temporal portion of his optic discs, two features that were consistent with autosomal dominant optic atrophy. However, examination of the mitochondrial DNA of the proband and of two of his relatives revealed a mutation at nucleotide 11778, known to be associated with Leber's hereditary optic neuropathy. This case illustrates the difficulty physicians may encounter when trying to clinically differentiate Leber's from dominant optic atrophy in patients with remote visual loss, and it emphasizes the importance of obtaining a molecular assay for a mitochondrial mutation in cases of ambiguously classified hereditary optic neuropathy.

' 011mal of Clulleal NClIro- ophtlllllllwlog. v 11( 3): 152- 157, 1991 © 1991 Raven Press, Ltd., New York Difficulty Differentiating Leber's from Dominant Optic Neuropathy in a Patient with Remote Visual Loss Daniel M. Jacobson, M. D. and Edwin M. Stone, M. D., ph. D. A 31- year- old man who inexplicably lost vision as a child was referred for evaluation of bilateral optic atrophy. Other family members had also suffered unexplained visual loss. He had asymmetric impairment of visual acuity, central scotomas, and optic disc pallor. He also had a tritan color vision defect and excavation of the temporal portion of his optic discs, two features that were consistent with autosomal dominant optic atrophy. However, examination of the mitochondrial DNA of the proband and of two of his relatives revealed a mutation at nucleotide 11778, known to be associated with Leber's hereditary optic neuropathy. This case illustrates the dif­ficulty physicians may encounter when trying to clini­cally differentiate Leber's from dominant optic atrophy in patients with remote visual loss, and it emphasizes the importance of obtaining a molecular assay for a mi­tochondrial mutation in cases of ambiguously classified hereditary optic neuropathy. Key Words: Leber's hereditary optic neuropathy­Dominant optic atrophy- Optic neuropathy- Color vi­sion defect- Tritan color vision defect- Blue- yellow color vision defect- Central scotoma- Maternal inheri­tance- Mitochondrial inheritance- Mutation- DNA­Mitochondria. From the Departments of Neurology and Ophthalmology, Marshfield Clinic, Marshfield, Wisconsin, and Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. Address correspondence and reprint requests to Dr. Daniel M Jacobson at Neuro- ophthalmology ( 4F), Marshfield Clinic, ", n" ': Od~ A\' enue, Marshfield, WI 54449, U, S. A. 152 Leber's optic neuropathy ( LON) and autosomal dominant optic atrophy ( DOA) are the two most common neurologically isolated forms of heredi­tary optic neuorpathy encountered by most clini­cians ( 1). Since no treatment for these disorders is currently available, the major importance of diag­nosing LON and DOA is to provide prognostic information and genetic counseling to affected and unaffected family members. The evaluation of an individual with a suspected hereditary optic neu­ropathy should include ( a) seeking historical and clinical features that may be characteristic for LON or DOA; ( b) evaluating other family members, if possible, in order to confirm a familial disorder; ( c) constructing a pedigree in order to analyze the specific mode of disease transmission; ( d) identify­ing other neurological abnormalities, such as hear­ing loss, peripheral neuropathy, ataxia, and spas­ticity, that may be associated with some forms of hereditary optic neuropathy; ( e) excluding other disorders that affect papillomacular bundle func­tion of both eyes, such as toxic, metabolic, nutri­tional, demyelinative, or compressive optic neu­ropathies; and, ( f) examining the mitochondrial DNA for mutations known to be associated with certain optic neuropathies. Certain clinical features may be highly character­istic of either LON or DOA. Nikoskelainen and colleagues ( 2,3) have outlined the characteristic and progressive ophthalmoscopic and fluorescein angiographic findings in presymptomatic and symptomatic individuals with LON. Most individ­uals with DOA show a tritan ( blue- yellow) color vision defect using the Farnsworth- Munsell 100­hue test ( 4). Kline and Glaser ( 5) emphasized that many affected individuals with DOA have excava­tion of the temporal portion of the optic disc that, in their view, Iris probably pathognomonic of DOA." LEBER'S OPTIC NEUROPATHY 153 Although the onset and progression of visual symptoms differ between LON and DOA, many affected individuals are not fully evaluated early in their course, or are referred electively for a subspe­cialty opinion years later. Properly evaluating an individual with suspected hereditary optic neurop­athy years after the visual loss occurred may be difficult for several reasons. The patient's recollec­tion of historical details concerning the onset and progression of visual symptoms may be incom­plete. Old records containing essential documen­tation of historical and ophthalmoscopic features may be unavailable. In the case of LON, the char­acteristic ophthalmoscopic findings of the symp­tomatic stage resolve over time and are not appar­ent years later. The following case study illustrates the difficulty that may occur when trying to differentiate LON from DOA in an individual with suspected hered­itary optic neuropathy referred years after the vi­suaI loss was first recognized. This report also em­phasizes the importance of seeking molecular con­firmation of a mitochondrial mutation ( 6,7) in all cases of suspected hereditary optiC neuropathy. PATIENTS AND METHODS Methods for Identifying the Nucleotide 11778 Mutation The mitochondrial DNA mutation associated with type I LON was identified using previously described methods ( 8). Briefly, 5- 7 ml of blood were collected in EDTA- containing tubes and transported to the laboratory at room temperature within 48 hours. A Ficoll- Paque gradient was used to separate the platelets and lymphocytes from the red cells ( 9). The DNA was released from the plate­lets by boiling in the presence of non- ionic deter­gents ( 10). A 924 base pair fragment containing nucleotide 11778 was amplified using the polymer­ase chain reaction ( 8). Ten microliters of the poly­merase chain reaction product was digested with 1.5 units of SfaN I at 37° C for 2 hours using the buffer conditions recommended by the suppliers of the enzyme; 15 fLl of the polymerase chain re­action product was digested with 2.5 units of Mae III at 55° C for 2 hours. Samples were electropho­resed for 4 hours at 25 V in a 3% agarose gel. Gels were stained with ethidium bromide and photo­graphed with ultraviolet transillumination. CASE REPORT ( PROBAND) A 31- year- old man was referred for an opinion regarding his long- standing optic atrophy. When he was 10 years old, a school teacher thought he had poor vision. An ophthalmologist found visual acuities of 20/ 50 in both eyes, but no other abnor­malities. During the next several months, the pa­tient recalls that his vision continued to deterorio­ate. When evaluated about 6 months after his poor vision was first detected, his acuity was 20/ 300 in the right eye and 20/ 200 in the left eye. Pallor of both optic discs was noted. A pediatric neurology examination, pneumoencephalogram, cerebrospi­nal fluid analysis, and nuclear medicine brain scan were all normal. Over the next several years, the vision in his right eye gradually improved while the vision in his left eye remained the same. He was followed periodically and carried the diagno­sis of " optic atrophy of unknown cause." He was otherwise healthy. Some family members had suf­fered abrupt visual loss during their second and third decade of life, while others experienced grad­ualloss of vision during their fourth decade of life ( Fig. 1). Our examination revealed a visual acuity of 201 20 - 2 in the right eye and 201200 in the left eye. He was unable to identify any of the 14 pseudoiso­chromatic test plates ( Richmond Products, Boca Raton, Florida, U. S. A.) with either eye. Farn­sworth- Munsell 100- hue testing of his right eye showed a tritan pattern of color confusion ( Fig. 2). Goldmann perimetry showed central and arcuate scotomas in both eyes ( Fig. 3). Both optic discs showed moderate pallor and loss of the central and temporal papillary substance. The grey- colored outline of the underlying lamina cribrosa was vis­ible through the floor of the excavated portions of both optic discs. The peripapillary nerve fiber layer was severely attenuated, but showed no microan­giopathy. The remainder of the ophthalmic and neurologic examination was normal. His electro­cardiogram revealed a nonspecific intraventricular conduction delay. A hereditary optic neuropathy was suspected, but the history and examination did not permit us to establish a definitive diagnosis. A sample of his blood was tested for the nucleotide 11778 mito­chondrial mutation ( 6,7). Evaluation of Other Family Members The proband's mother { III- ll in Fig. 1), 45 years old, was asymptomatic and had normal visual acu­ity. Her optic discs and peripapillary retinas ap­peared normal. She declined testing of her mito­chondrial DNA. One of the proband's sisters ( IV- 5 in Fig. 1), 33 years old, and one of her daughters ( V- 2 in Fig. 1), J Cli" Neuro- ophthalmol. Vol. 11. No. 3. 1991 154 D. M. JACOBSON AND E. M. STONE 6 4 6 10 /' 2 9 V IV III II FIG. 1. Pedigree of the family with Leber's optic neuropathy. The proband is identified by the arrow, females are represented by circles, males are represented by squares, historically affected individuals with abrupt visual loss are identified in black, and historically affected individuals with gradual visual loss are represented as shaded symbols. Further investigation disclosed that these latter individuals had retinitis pig­mentosa. I:::; 8 years old, were both asymptomatic. Their find­ings included normal visual acuity and color vi­sion, normal optic disc appearance, and subtle peripapillary microangiopathy ( Figs. 4 and 5). Both of their electrocardiograms were normal. Samples Figure 6 shows the restriction enzyme digestion patterns for the proband and three of his family members ( III- 8, IV- 5, and V- 2 in Fig. 1). Mae III digests mitochondrial DNA near position 11778 RESULTS of their blood were tested for the nucleotide 11778 mitochondrial mutation. Three elderly maternal aunts ( III- 7- 9 in Fig. 1) were contacted by telephone. They all experienced progressive night blindness beginning in their fourth decade of life. Their local opthalmologist was contacted and reported that all individuals had typical findings of retinitis pigmentosa, in­cluding peripheral visual field loss and pigmentary retinopathy. There were no other symptoms to suggest that any of these individuals had Kearns­Sayre syndrome. A blood sample from one of these family members ( III- 8 in Fig. 1) was submit­ted for analysis of the 11778 mutation. The other historically affected family members ( III- I, III- 2, IV- I, and V- I in Fig. 1) could not be located. •••. 1 J (' I. .1, I' · .... · \ " .!, · 1, ' Il ~ it,: t"".".•.•: · l ., i .11 /:~~:. i : f~ i~;;;: . ,:, 00 ••••' • , II ,111111, I,~, . t · ., ... '.",.", .' ,. Ij I . \ 1: ' 1\ . \ "',;~:,!. . · ":;~~ Il!,.. . ,~' III .1,. 1': 1 .... · "'' · il · '~ I~. ..".",' ll,!\ , ij . ' I" "' 111 II . r I ,.,,; ~ FIG. 2. Farnsworth- Munsell 100- hue color vision test of the right eye showing a tritan ( blue- yellow) axis of confusion. The total error score for this eye was 308. JGin Neuro- opl. thalmol. Vol. II. No. 3, 1991 LEBER'S OPTIC NEUROPATHY 270 LEFT RIGHT FIG. 3. Goldmann perimetry showing bilateral central and arcuate scotomas. 155 ( 8), only in the presence of the specific mutation initially reported by Wallace and colleagues ( 6). Di­gestion of DNA from an affected patient produces a 138/ 124 base pair doublet, while digestion of DNA from an unaffected individual results in a band at 262 nucleotides. The Wallace mutation was indentified in the proband and two of his relatives ( IV- 5 and V- 2 in Fig. 1), but was not present in his aunt who had retinitis pigmentosa ( III- 8 in Fig. 1). The SfaN I digestion pattern confirmed these results ( Fig. 6). SfaN I cleaves normal mitochon­drial DNA near position 11778, resulting in two fragments 799 and 125 base pairs in size. SfaN I does not digest mitochondrial DNA in the pres­ence of the Wallace mutation. The family member with retinitis pigmentosa ( III- 8 in Fig. 1) had the normal 125 base pair fragment, while the DNA from the proband and two of his asymptomatic FIG. 4. Fluorescein fundus angiogram of the right eye at 15.8 seconds of an asymp­tomatic sister of the proband. Subtle tel­angiectatic vessels are seen mainly in the temporal peripapillary region. , Clill Neuro- ophthalmol. Vol. 11. No. 3. 1991 156 D. M. JACOBSON AND E. M. STONE FIG. 5. Fundus photograph of the right eye of an asymptomatic niece of the proband. Subtle telangiectatic vessels are seen mainly in the superior and inferior peripap­illary region. relatives ( IV- 5 and V- 2 in Fig. 1) who had the Wal­lace mutation remained uncut. DISCUSSION Our initial impression was that the proband had OOA. Marked asymmetry in the visual acuity of affected individuals with OOA has been noted by others ( 5,11). We also felt that the tritan color vi­sion defect and excavated optic disc appearance were features that supported OOA as the under­lying diagnosis. One feature inconsistent with OOA, however, was the spontaneous improve­ment of vision in his right eye. 924~" 662 ~.. 262 ~... 125 ~ 1 2 3 4 5 6 7 8 Mae III SfaN I FIG. 6. Rest~ icti. on enzyme digestion patterns for the proband ( lanes 1 and 5), his asymptomatic sister ( lanes 2 and 6), his asymptomatic niece ( lanes 3 and 7), and a distant relative with retinitis pigmentosa ( lanes 4 and 8). With Mae III digestion, the Wallace mutation is identified by the presence of a 138/ 124 base pair doublet in lanes 1-:- 3. The SfaN I digestion confirms the results from the first four lanes; the relative WIth the normal sequence ( lane 8) has a 125 base pair fragment while the DNA from the three family members who had the Wallace mutation ( lanes 5- 7) remain uncut. i Gin Neuro- ophlhalmol. Vol, 11, No. 3, 1991 LEBER'S OPTIC NEUROPATHY 157 The apparent transmission of visual loss through a male member ( 11- 3 in Fig. 1) of his family is inconsistent with a maternally ( mitochondrial) inherited disorder such as LON ( 12). Further in­vestigation of the apparently affected offspring of this male revealed that the true diagnosis was ret­initis pigmentosa. Furthermore, examination of the mitochondrial DNA from one of the reportedly affected offspring of the proband's male relative allowed us to unambiguously exclude LON as the cause of her visual loss. Our experience with this family underscores the need to validate the clinical features of presumably affected relatives identified from a historically constructed pedigree. While this report does not add to our under­standing of the pathogenesis of LON, it does illus­trate the difficulties one may encounter when try­ing to establish a clinical diagnosis in an individual whose visual loss occurred years earlier. Other problematic patients are those without affected family members and those whose visual loss oc­curs in concert with another disorder known to cause an optic neuropathy affecting papillomacu­lar function ( e. g. nutritional or tobacco- alcohol am­blyopia, multiple sclerosis). We recommend that a molecular diagnosis be sought in all patients with clinically suspected hereditary optiC neuropathy and in young patients with unexplained optic neu­ropathies that affect papillomacular function in both eyes. Acknowledgment: The authors thank Luan Streb and Chris Taylor for their excellent technical assistance and Mary Klingelhoets for her dedicated preparation of this manuscript. This study was supported in part by Re-search to Prevent Blindness, Inc. and Public Health Ser­vice grant EY08426 ( E. M. S.). REFERENCES 1. Miller NR. The hereditary optic neuropathies, In: Miller NR, ed. Walsh and Hoyt's clinical neuro- ophthalmology. Voll, 4th ed. 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