Journal of Neuro-Ophthalmology, December 1988, Volume 8, Issue 4

Does sporadic Leber's disease exist?

This study gives some illustrative case reports of the difficulties in the diagnosis of Leber's hereditary optic neuroretinopathy. It underlies the importance of careful family history and search for peripapillary microangiopathy in the maternal relatives of patients suspected to suffer from Leber's disease. The article casts doubt on the existence of so-called sporadic Leber's disease.

Journal of Clinical Neuro-ophthalmology 8(4): 225-229, 1988. Does Sporadic Leber's Disease Exist? Eeva Nikoskelainen, M.D., Kari Nummelin, B.S., and Marja-Liisa Savontaus, ph. D. © 1988 Raven Press, Ltd., New York This study gives some illustrative case reports of the difficulties in the diagnosis of Leber's hereditary optic neuroretinopathy. It underlies the importance of careful family history and search for peripapillary microangiop­athy in the maternal relatives of patients suspected to suffer from Leber's disease. The article casts doubt on the existence of so-called sporadic Leber's disease. Key Words: Hereditary eye disease-Leber's disease­Maternal inheritance-Microangiopathy-Optic atro­phy- Sporadic disease. From the Departments of Ophthalmology (E.N., K.N.) and Biology and Department of Medical Genetics (M.-L.S.), Univer­sity of Turku, Turku, Finland. Address correspondence and reprint requests to Dr. E. Ni­koskelainen at Department of Ophthalmology, University of Turku, 20520 Turku, Finland. 225 Leber's optic neuroretinopathy is a hereditary condition usually affecting young men and leading to a permanent and serious visual impairment of the central vision. The mechanism of inheritance is still unknown, but genealogical studies have sug­gested that it is a maternally inherited disease (1). The clinical course of Leber's disease has several stages. The optic atrophy with large centrocecal field defects develops only at the final stage. Peri­papillary microangiopathy visible in the early stages is an important "marker" of the condition. A high number of asymptomatic offspring in the female line also have microangiopathy (1-3). Since 1978, we have prospectively followed Finnish families with Leber's disease. Our diag­nostic criteria have been based on positive family history and typical fundus changes as described in our previous reports (1,3). So far, the study in­cludes 15 families with Leber's disease. Several pa­tients with "sporadic Leber's disease" were de­tected at the early stages of the study, but neuro­ophthalmological examinations of maternal relatives have later revealed that most of these pa­tients were members of typical Leber families. The present paper underlines the importance of careful family history and search for peripapillary microangiopathy in the maternal relatives of pa­tients suspected of suffering from sporadic Leber's disease. PATIENTS AND METHODS Our present material includes the cases of three patients with a typical course of Leber's disease in which the family history was negative but the ex­amination of the maternal relatives revealed peri­papillary microangiopathy. Case 1 was a 24-year-old man first examined in 1984 because of progressive visual loss in his left eye. The visual acuity in the left eye was 0.4 at first examination. There was a relative centrocecal field 226 E. NIKOSKELAINEN ET AL. defect, dyschromatopsia, and delayed visually evoked potentials in the affected eye. The disc was slightly elevated with peripapillary hemorrhages and mild microangiopathy (Fig. 1). Optic nerve function in the right eye were initially normal, but the disc was hyperemic and there was mild peri­papillary microangiopathy. Three months later, the right eye also developed optic nerve dysfunc­tion and during the following months the man be­came permanently blind because of severe optic atrophy. The neurological examinations including computerized tomography of the brain were unre­vealing. In the last eye examination in 1987, the patient had 0.1 vision in both eyes. In both visual fields, there was a large absolute centrocecal sea- :"",/ Vol. 8, No.4, 1988 toma. Both fundi revealed severe optic atrophy. Except for bilateral optic atrophy, he has remained in good general health without any neurological symptoms. The family history had no records of optic nerve diseases. The patients's mother had died from breast cancer several years earlier and her three brothers were unavailable for the study. The mother has also two sons from an earlier marriage. One of them-an asymptomatic 40-year-old man­was initially examined in 1984. Optic nerve func­tion was normal, but the right fundus showed peripapillary microangiopathy (Fig. 2). He has re­mained asymptomatic and there has been no change in optic nerve function nor in his fundi. We FIG. 1: (A) The le~t fundus of case 1 in the acute stage. The diSC and peripapillary nerve fiber layer are swol­len. Mild peripapillary microangiopathy (arrows) is seen below the disc, where some hemorrhages also Occur. Below, the fluorescein angiogram of the same eye In the acute stage. Microangiopathy is more visi­ble In the fluorescein angiogram. Above right, the same fundus 5 months later when severe optic atro­phy has developed. The right fundus showed similar changes. SPORADIC LEBER'S DISEASE 227 FIG. 2. Left: The right fundus of the asymptomatic half-brother to case 1 showing peripapillary microangiopathy (arrow), which is more visible in a fluorescein angio­gram (right). have also studied the three sisters of the proband but these examinations gave normal results. Case 2 was a 59-year-old woman who experi­enced progressive visual loss in her left eye in 1985. Two months later, similar symptoms devel­oped in her right eye. In the first eye examination at our institution, visual acuity already was finger counting at 2 m. Both visual fields had a large ab­solute centrocecal scotoma. The pattern of evoked visual potentials was unrecordable and the flash evoked visual potentials were markedly disturbed bilaterally. Both fundi had hyperemic discs with peripapillary microangiopathy. The pupils were reactive to light. The intraocular pressures were 17 mmHg and the biomicroscopy was unrevealing. Neurological examinations including computer­ized tomography of the brain were normal. During the following months, bilateral optic atrophy de­veloped. Her last eye examination in 1987 showed finger counting vision due to severe bilateral optic atrophy (Fig. 3). She denied any visual problems in the family. She was the only child in the family. Her mother as well as her only uncle had died and no eye exam­inations of them exist. The proband had a 37-year-old daughter in 1985, who also was examined by us. She had no visual complaints, optic nerve function was normal, but both fundi showed peripapillary microangiopathy (Fig. 4). Her condition has remained unchanged. Case 3 was a 21-year-old man who experienced visual loss in his left eye in 1978. The initial eye examination showed left optic nerve dysfunction and fundus findings were suggestive of Leber's disease. Three months later, the right eye also de­veloped similar symptoms. Bilateral permanent blindness developed during the following months. At present, he is permanently blind due to severe bilateral optic atrophy. His general health is unre­markable without any neurological symptoms. His family history was poorly known because immediately after her birth, his mother was put in a children's home and she was adopted at the age of 5 years. The neuro-ophthalmological examina­tion of the asymptomatic woman revealed peri­papillary microangiopathy but normal optic nerve functions. The proband had one brother who was asymptomatic. He had normal optic nerve func­tion but mild peripapillary microangiopathy. COMMENTS Leber's disease is considered to be a maternally inherited condition. Men never transmit the dis­ease. Up to 100% of the daughters to carrier fe­males become carriers themselves (1,4,5). About one-half of the sons to a carrier woman in Finnish families with Leber's disease develop optic atro­phy, but 27% of asymptomatic men have peripap­illary microangiopathy. Eighteen percent of the daughters to a carrier female develop optic atrophy while 32% are asymptomatic but have peripapil- JClill Neuro-ophthalmol, Vol. 8, No.4, 1988 228 E. NIKOSKELAINEN ET AL. FIG. 3. The fundus pictures of case 2, when bilateral optic atrophy is fully developed. The discs are pale. The arterioles are narrow. There is marked retinal nerve fiber loss. lary microangiopathy. It is therefore most impor­tant to examine siblings and other maternal rela­tives of a patient, when the clinical symptoms and signs suggest Leber's disease even if the family history is negative. The recent article by Lopez and Smith (2) is also illustrative in this regard. Except for bilateral optic atrophy, the patients with Leber's disease are usually otherwise healthy. Occasionally, various neurological symptoms oc­cur (6). A recent genealogical evaluation has shown that electrocardiographic (ECG) abnormal­ities are unusually common in the offspring of the female carriers (1). Thus, an abnormal ECG can give additional information suggestive of the diag­nosis. During our 10 year follow-up together with ge- FIG. 4. The fundus pictures of the asymptomatic daughter of case 2. Peripapillary mlcroanglopathy most marked below the discs is shown with arrows. SPORADIC LEBER'S DISEASE 229 nealogical evaluations and neuro-ophthalmologi­cal examinations of maternal relatives, our so­called sporadic cases have decreased to three per­sons. In all these cases, the family history has been complicated. The detection of peripapillary micro­angiopathy in their maternal relatives suggests a hereditable Leber's disease in all of them. Conse­quently, we believe that sporadic Leber's disease does not exist but the condition is always transmit­ted by carrier women. Acknowledgment: This study was supported by grants from the Paulo Foundation, Helsinki, the Finnish Culture Foundation (Turku), and the Sigrid Juselius Foundation (Helsinki). REFERENCES 1. Nikoskelainen E, Savontaus ML, Wanne OP, KatiJa M, Nummelin KU. Leber's hereditary optic neuroretinopathy, a maternally inherited disease. A genealogic study in four pedigrees. Arch OphthalmoI1987;105:665-71. 2. Lopez PF, Smith JL. Leber's optic neuropathy. Newobser­vations. JClin Neuroophthalmol 1986;6:144-52. 3. Nikoskelainen E, Hoyt WF, Nummelin KU. Ophthalmo­scopic findings in Leber's hereditary optic neuropathy: I. Fundus findings in asymptomatic family members. Arch OphthalmoI1982;100:1597-1602. 4. Yamanaca H. The mode of inheritance of Leber's disease. Nippon Ganka Gakkai Zasshi 1971;75:193Q-6. 5. Seedorf T. The inheritance of Leber's disease: A genealog­ical follow-up study. Acta Ophthalmol 1985;63:135-45. 6. Went LN. Leber's disease and variants. In: Vinken PJ, Bruyn CW, eds. Handbook of clinical neurology, Vol. 13. Am­sterdam: North-Holland Publishing Co., 1972:9~llO.