Clinical Neuroscience 4:295-301(1997)
Clinical Spectrum of Leber's Hereditary Optic Neuropathy
John B. Kerrison and Nancy J. Newman

 
 ^  Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by mutations in the mitochondrial genome. Primary mutations are located at nucleotide positions 3460, 11778, and 14484 in genes encoding subunits of Complex I of the respiratory chain. Molecular diagnosis has expanded the spectrum of the LHON phenotype and prompted investigation into optic neuropathies due to demyelinating disease, glaucoma, tobacco/alcohol amblyopia, and nutritional optic neuropathy. While mitochondrial mutations are for LHON disease expression, other genetic or epigenetic factors must play a role in disease penetrance and expression. Prodeterminants of disease include heteroplasmy, an X-linked vision susceptibility locus, environmental factors, and secondary mitochondrial mutations.

Clinical Neuroscience 4:295-301, 1997. 1997 Copyright: Wiley-Liss, Inc.

hereditary optic neuropathy; optic nerve; Leber; heteroplasmy; mitochondria

 ^  The discovery that Leber's hereditary optic neuropathy (LHON) segregated in a nonmendelian, maternal pattern [van Senus 1963] [Erickson 1972] [Wallace et al 1970] [Nikoskelainen et al 1987] suggested a disorder of mitochondrial inheritance [Nikoskelainen et al 1984a] [Egger and Wilson 1983]. Using a candidate approach, Wallace and coworkers screened the mitochondrial genome from several LHON pedigrees and discovered a point mutation at nucleotide position 11778 responsible for the majority of cases [Wallace et al 1988] [Singh et al 1989]. The discovery of the molecular basis of LHON has provided insights into the heterogeneous clinical spectrum of disease that may result. Furthermore, it is evident that other determinants. whether genetic or epigenetic, play a role in disease penetrance and expression. The advent of molecular diagnosis has prompted investigation into the role of mitochondrial DNA (mtDNA) mutations in optic neuropathies due to demyelinating disease, glaucoma, and malnutrition. The purpose of this paper is to review clinical and pathologic features of LHON, the application of mtDNA testing to patients with optic neuropathies other than LHON, and the potential influences on disease penetrance.

 ^   Mitochondrial mutations found in LHON patients, considered to be of principle importance in disease pathogenesis, must alter an evolutionarily conserved amino acid and be absent in controls [Wallace et al 1988] [Howell et al 1991a]]. Three missense mutations at nucleotide positions 3460 [Huoponen et al 1991] [Howell et al 1991a], 11778 [Wallace et al 1988], and 14484 [Johns et al 1992a] involving NADH dehydrogenase (ND) subunits 1, 4, and 6, respectively, of Complex I, fulfill these criteria and account for 85-90% of mutations worldwide [Howell et al 1994a] [Newman 1997]. In one study, no primary mutation was found in 21% of affected individuals from Finland [Nikoskelainen et al 1996]. The 11778 mutation is responsible for 31-89% of LHON pedigrees in Europe, North America, and Australia and 90% of LHON pedigrees in Japan. The 3460 and 14484 mutations each account for approximately 10-15% of cases. Clinical manifestations of LHON with reference to each of these mutations have been reported [Newman et al 1991] [Johns et al 1992b 1993a] [Oostra et al 1994] [Riordan-Eva et al 1995]. Statistically meaningful comparisons between these groups are difficult due to small numbers and bias of ascertainment; however, patients in all of these groups appear similar with regard to several features.

 ^   Men are more frequently affected with visual loss than women, comprising 80-90% of case series [Newman et al 1991] [Oostra et al 1994] [Riordan-Eva et al 1995]. Analysis of 85 LHON families demonstrated no statistically significant differences in ratios of affected males to affected females with respect to mutation [Harding et al 1995]. With the exclusion of index cases and sibships less than 50 years old, the best estimate of recurrence risk is 30% to brothers and 8% to sisters of index cases. Affected females are more likely to have affected children, particularly daughters, than unaffected female carriers [Harding et al 1995]. These data suggest the possibility of an X-linked susceptibility locus (see below).

 ^   The onset of visual loss typically occurs between the ages of 15 and 35 years in most pedigrees. However, molecularly confirmed LHON has been reported in patients as young as 5 and as old as 80 [Newman 1997]. This broad range of ages may occur even within the same pedigree. There are no differences in the age of onset between different mutation groups and be tween secondary and index cases. The age of onset in females is slightly later than in males [Harding et al 1995].

 ^  Vision loss is, typically painless but may be associated with headache, Uhthoff's symptom (transient worsening with warmth or exercise), eye discomfort, photopsias, limb parasthesias, and dizziness [Newman et al 1991] [Riordan-Eva et al 1995]. Simultaneous, bilateral vision loss is reported in approximately 50% of cases. In eyes with sequential loss, the average interval to involvement of the second eye is 3 months but may rarely remain monocular up to 16 years of follow-up [Nikoskelainen et al 1996]. The vision loss typically reaches its nadir within 2 months but may be slowly progressive over a period of greater than 8 weeks. Visual acuity typically deteriorates to worse than 20 /200 but may range from 20/20 to no light perception. Associated with vision loss is progressive red-green dyschromatopsia. Pupillary light responses are relatively preserved in comparison with those in patients with other optic neuropathies [Wakakura and Yokoe 1995]. Visual field defects are typically central or cecocentral absolute scotomas surrounded by a narrow rim of relative scotoma. The classic fundus appearance of circumpapillary telangiectatic microangiopathy, swelling of the nerve fiber layer around the disc, and absence of leakage from the disc on fluorescein angiography [Smith et al 1973] [Nikoskelainen et al 1982b, 1984b]] may be observed in 50% to 60% of affected patients [Newman et al 1991] [Riordan-Eva et al 1995] as well as in "presymptomatic" cases and asymptomatic maternal relatives [Nikoskelainen et al 1982a, 1984b]. With time, the hyperemia and peripapillary nerve fiber layer swelling resolve, leaving temporal pallor and papillomacular nerve fiber layer dropout.

 ^   Most patients suffer permanent, profound vision loss and do not experience further insults. However, even after a period of stability lasting up to several years, some patients may experience recovery of excellent vision in one or both eyes [Stone et al 1992]. These patients may have a gradual clearing of their central vision or the sudden opening of a few degrees within the central scotoma resulting in a "fenestrated scotoma" [Mackey 1994]. Color vision may likewise improve [Nikoskelainen et al 1996]. Younger patients have the best prognosis for visual recovery [Mackey and Howell 1992] [Riordan-Eva et al 1995]. The LHON phenotype appears to be uniform with respect to mutation except in the rates of spontaneous recovery. The 14484 mutation carries the best prognosis for recovery with estimated rates as high as 50% [Johns et al 1993a]. The 11778 mutation carries the worst prognosis for recovery with rates estimated at 4k [Newman et al 1991] [Stone et al 1992]. Nikoskelainen et al. [1996] emphasized that 23% of 106 affected eyes had a favorable outcome with a visual acuity better than or equal to 20/50.

 ^   The use of molecular diagnosis in patients with unexplained bilateral optic neuropathy without the "classic" LHON presentation has expanded the LHON phenotype. These "atypical" cases have been outlined by Nikoskelainen et al [1996]. Some patients may present with a subclinical bilateral optic atrophy with a favorable visual outcome. Others may present with a chronic slowly progressive course without an acute phase. These presentations comprise a minority of cases.

 ^   In most patients with LHON, vision loss is the only clinical manifestation. Some patients may have cardiac conduction abnormalities including preexcitation syndromes, such as Wolf- Parkinson-White and Lown-Ganong- Levine [Nikoskelainen et al 1985, 1994]], or prolongation of the corrected QT interval [Ortiz et al 1992]. Palpitations, syncope, and sudden death may occur in these patients [Nikoskelainen et al 1985, 1994] [Bower et al 1992]. Hearing loss and skeletal abnormalities such as thoracic kyphosis have been reported [Wallace et al 1970] [Mackey 1994] [Nikoskelainen et al 1995]. Minor neurologic symptoms may be present in some patients, including tremor, mild cerebellar ataxia, pathologic reflexes and sensory neuropathy [van Senus 1963] [Wilson 1963] [Funakawa et al 1995] [Nikoskelainen et al 1995]. More severe neurologic symptoms, including a multiple sclerosis (MS)-like syndrome (see below), have been reported in some pedigrees [Wallace 1970]. Those pedigrees in which LHON-like optic neuropathy occurs along with more severe neurologic symptoms have been designated Leber's "plus" [Newman 1993]. Additional mitochondrial point mutations have been identified in some Leber's "plus" pedigrees [Howell et al 1991b] [Jun et al 1994] [Shoffner et al 1995]. In a large Australian pedigree, designated Queensland 1, in which LHON was associated with juvenile encephalomyelopathy, ataxia, spasticity, and posterior column signs, a mutation at mtDNA position 4160 of the NDI gene was found in association with the mtDNA 14484 mutation [Howell et al 1991b]. Three pedigrees in whom optic atrophy was associated with dystonia have been associated with a complex I mutation involving the ND6 subunit at mtDNA position 14,459 [Jun et al 1994] [Shoffner et al 1995].

 ^  Other clinical studies have helped to characterize the LHON phenotype but are of limited diagnostic usefulness. Fluorescein angiography demonstrates a lack of leakage at the optic nerve head despite swelling [Smith et al 1973] [Nikoskelainen et al 1984b]. Pattern-reversal visual evoked potentials (VEPS) may show absent or prolonged latencies and decreased amplitudes [Newman et al 1991] [Riordan-Eva et al 1995]. Flash electroretinograms are typically normal in affected patients although occasional patients have abnormal scotopic function or b wave attentuation [Newman et al 1991] [Riordan-Eva et al 1995]. Brainstem auditory evoked potentials (BAEPS) may be nonspecifically abnormal in affected patients [Mondelli et al 1990]. BAEPs and VEPs may be abnormal in asymptomatic maternal relatives as well [Mondelli et al 1991]. Electroencephalograms are normal [Newman et al 1991]. Cerebrospinal fluid analysis is typically normal except in those patients with a MS syndrome [Newman et al 1991] [Riordan-Eva et al 1995]. Similarly, brain CT and MRI are normal except in individuals with a MS-like syndrome [Harding et al 1992] or dystonia [Shoffner et al 1995]. In vivo phosphorus magnetic resonance spectroscopy has demonstrated defective brain and muscle metabolism in 11778 LHON patients [Cortelli et al 1991] and asymptomatic carriers [Barbirolo et al 1995].

 ^   The availability of molecular diagnostic testing has aided the clinical diagnosis of LHON. Bilateral optic neuropathies presumed secondary to demyelinating disease, glaucoma, or malnutrition have been investigated for the presence of mtDNA mutations [Harding et al 1992] [Cullom et al 1993] [Hirano et al 1994] [Rizzo 1995] [Brierly et al 1996]. In some cases, patients with actual LHON had been previously misdiagnosed. In others, it is possible that the pathogenesis of the disease might involve mitochondrial energy production such that mtDNA mutations might influence the disease process.

 ^  Patients with primary LHON mutations may present with a MS-like syndrome including cerebrospinal fluid lymphocytic pleocytosis with oligoclonal bands and multiple white matter lesions on MRI [Harding et al 1992] [Flanigan and Johns 1993] [Olsen et al 1995]. Harding et al [1992] proposed that the optic nerve damage in these patients could be immunologically mediated and that mitochondrial genes might contribute to MS susceptibility. However, no association was found between LHON and HLA-DR genotype [Govan et al 1994]. Furthermore, testing of large groups of MS patients has found no association with the 11778 mtDNA mutation in Japan or the 3460 and 11778 mt DNA mutations in England [Kellar-Wood et al 1994] [Nishimura et al 1995]. It may be that coincidental demyelinating disease in a patient harboring a primary LHON mutation can cause profound visual loss rather than typical optic neuritis (Mackey, personal communication).

 ^  Some atypical patients with LHON may have a slowly progressive course [Nikoskelainen et al 1996]. We and others have observed patients in whom LHON has been confused with low-tension glaucoma [Lauer et al 1985]. Glaucoma, which is characterized by insidious visual field loss and optic nerve atrophy with characteristic cupping, is most commonly associated with raised intraocular pressure. However, one-third of patients with glaucomatous optic neuropathy have a normal intraocular pressure [Klein et al 1992]. Some of these patients may be unrecognized cases of LHON. In one study, cupping of the optic nerve was noted in LHON [Ortiz et al 1992]. Alternatively, others have suggested that factors other than intraocular pressure must play a role in the optic nerve damage in low-tension glaucoma patients, perhaps an underlying mitochondrial dysfunction. Brierly et al. [1996] investigated a group of eight low-tension glaucoma patients for the possibility of a systemic defect in mitochondrial function. These patients had normal oxidative phosphorylation assessed from skeletal muscle biopsies, and they lacked all of the primary LHON mutations. Although the results of this study demonstrated no systemic defect in mitochondrial function in low tension glaucoma, optic nerve mitochondrial function could be compromised in these patients by local factors [Brierly et al 1996].

 ^  The theory that LHON patients must excede a tissue-specific energy utilization threshold to manifest disease has led some to conclude that malnutrition and envirornmental toxins may play a role in the development of vision loss in susceptible patients. In clinical series, the prevalence of alcohol consumption ranges from 14% to 67% and for tobacco consumption from 46% to 75% [Newman et al 1991] [Johns et al 1992b, 1993a] [Riordan-Eva et al 1995]. A series of patients diagnosed with tobacco-alcohol amblyopia was subsequently determined to have LHON by molecular genetic testing [Cullom et al 1993]. Monozygotic twins who were discordant for vision loss associated with the mtDNA 11778 mutation have been reported [Newman et al 1991] [Johns et al 1993b]. Anecdotal reports exist as to the presence of a traumatic or metabolic insult preceding vision loss [Du-Bois et al 1992] [Johns et al 1992b, 1993a]. Rizzo [1995] presented a patient with bilateral optic neuropathy who had vitamin B12 deficiency and the mtDNA 1448j mutation in whom vision improved to 20/20 following treatment. In contrast to the above reports which suggest a role for epigenetic risk factors in vision loss, wide- spread nutritional deficiency in Cuba did not appear to increase the risk of vision loss in a large pedigree harboring the mtDNA 11778 mutation [Newman et al 1994]. Monozygotic twins concordant for vision loss have also been reported [Nikoskelainen et al 1987] [Harding et al 1995]. No systematic twin studies or statistical analysis of alcohol consumption, tobacco smoking, and enviromnental factors as a risk factor for vision loss in susceptible patients have been performed. However, most clinicians recommend that their patients refrain from alcohol and tobacco consumption.

 ^   Neuropathologic studies of LHON have only been performed on tissues long after the acute injury. These studies have demonstrated atrophy of the optic nerve, nerve fiber, and ganglion cell layers [Wilson 1963] [Adams et al 1966] [Kwittken and Barset 1958] [Bruyn et al 1992] [Kerrison et al 1995]. Although several ofthese studies have reported more wide spread neuropathologic changes including atrophy of the posterior funiculi, corticospinal tracts, striatum, putamen, lateral caudate, and substantia nigra, these patients had Leber's "plus" rather than a clinical disorder limited to the optic nerves, and these studies were performed prior to molecular testing. Whether patients with isolated optic atrophy have more widespread neuropathologic abnormalities is not known [Kerrison et al 1995]. Electron microscopy has demonstrated electron-dense calcium mitochondrial inclusions within ganglion cells in a patient from the Queensland 1 pedigree with the combined mtDNA 4160 and 14484 mutations [Kerrison et al 1995]. Similar inclusions were not observed in a study of a patient with the mtDNA 11778 mutation [Sadun et al 1996]. Several ultrastructural studies of muscle have demonstrated sub-sarcolemmal collection and enlargement of mitochondria, proliferation of cristae, and paracrystalline inclusions [Sadun et al 1994] [Nikoskelainen et al 1984a] [Federico et al 1988] while others have failed to find abnormalities [Novtny et al 1986].

 ^  While defects in oxidative phosphorylation has been demonstrated by in vivo phosphorus magnetic resonance spectroscopy and in vitro muscle and blood samples [Parker et al 1989] [Larsson et al 1991] [Majander et al 1991] [Toscano et al 1992] [Cortelli et al 1991], how mitochondrial mutations manifest the LHON phenotype is the focus of ongoing study. No animal models of the disease are available. Questions regarding disease pathogenesis are intrinsically related to the issue of disease penetrance. Specifically, why do some offspring not develop vision loss despite harboring a pathogenic mutation and why is a disproportionate number of males affected? Factors proposed to influence disease penetrance include heteroplasmy, an X-linked vision loss susceptibility locus, environmental factors, and secondary mitochondrial mutations. While the influence of environmental factors is discussed above, the significance of secondary mutations is discussed in another article in this issue.

 ^   Heteroplasmy is a term used to describe the coexistence of mutant and normal mtDNA within the same cell. At each division, a cell's population of mitochondria may drift towards pure normal, pure mutant or remain mixed. The degree of heteroplasmy may differ among tissues [Lott et al 1990]. It has been suggested that a heteroplasmic individual may have a lower risk of vision loss within a pedigree due to a protective effect of normal mitochondria. Heteroplasmy is assayed by densitometry of restriction digests, single strand conformation polymorphism, and counting the proportion of mutant and normal subclones of polymerase chain-reaction (PCR)-derived DNA from the white blood cell (WBC) fraction of whole blood [Howell et al 1991b] [Smith et al 1993] [Mashima et al 1995]. The proportion of mutant DNA in the optic nerve has been determined in two LHON cases. In a patient from the Queensland 1 pedigree in whom all members tested were homoplasmic for the 4160 and 14484 mutations, all clones derived from formalin-fixed optic nerve tissue contained both mutations [Kerrison et al 1995]]. In another patient heteroplasmic for the 11778 mutation in blood, all optic nerve and refinal clones were mutant [Howell et al 1994b]. No studies on optic nerve or retina from asymptomatic patients at risk for vision loss have been performed.

 ^  Large reviews of molecularly confirmed LHON patients found the incidence of heteroplasmy in blood to be low [Newman et al 1991] [Harding et al 1995]. Evaluation of 75 LHON patients with the 11778 mutation and 101 asymptomatic family members demonstrated a higher prevalence of heteroplasmy in nonaffected individuals [Smith et al 1993]. This was not statistically significant as the overall incidence of heteroplasmy was low. In addition, heteroplasmic patients with vision loss were phenotypically no different from homoplasmic patients. In another study, heteroplasmy was detected in 4% of 124 affected-patients and 13.6% of 140 unaffected matrilineal relatives [Harding et al 1995] . Therefore, heteroplasmy, as assessed in the WBC fraction of whole blood, may have a protective effect in some family members, but the overall frequency is low. It cannot fully explain the differences in disease penetrance among family members.

 ^   While secondary mitochondrial mutations may potentially influence disease expression or penetrance, nuclear-encoded factors may modify disease penentrance as well. The male predominance in LHON has prompted investigators to propose a two-locus mitochondrial and X chromosome- linked nuclear gene model of inheritance, taking into account X-chromosome inactivation [Bu and Rotter 1991]. Segregation analysis has demonstrated that the inheritance of LHON is consistent with this model [Bu and Rotter 1991] [Nakamura et al 1993]. Bu and Rotter evaluated 31 published pedigrees and estimated a 40% prevalence of homozygosity among affected females, penetrance in heterozygous females of 0.11 due to X-chromosome inactivation, and an X-linked gene frequency of 0.08 [Bu and Rotter 1991]. Similar analysis of Japanese pedigrees estimated an X-linked gene frequency 0.10 and a penetrance of 0.196 among heterozygous females [Nakamura et al., 1993]. The difference in estimated penetrance among heterozygous females was attributed to ethnicity [Nakamura et al 1993]. Analysis of 85 molecularly confirmed LHON pedigrees was consistent with the model of Bu and Rotter [Harding et al 1995].

 ^   Despite the results of segregation analysis, linkage analysis with X-chromosome markers have been unsuccessful. Early linkage studies of LHON assumed simple X-chromosome inheritance and found no linkage to a panel of X-chromosome markers [Chen et al 1989]. Initial evaluation of several Finnish families linked LHON to a locus on the short arm of chromosome X (DXS7) with a maximum lod score of 2.48 at a recombination fraction of 0 [Vilkki et al 1991]. A lod score above 2 is considered significant for X-linked disorders. However, re-evaluation of this data set after revision of pedigrees, use of stricter liability class criteria, and separation of families according to mtDNA mutations failed to demonstrate linkage [Juvonen et al 1993]. Two other studies failed to demonstrate linkage to X chromosomal markers as well [Sweeney et al 1992] [Carvalho et al 1992]. One possible explanation for the inability to demonstrate an X-linked locus is the incorrect estimation of penetrance in heterozygous females. All studies estimated the penetrance in heterozygous females of 0.01 in contrast to the estimate of 0.11 by Bu and Rotter [Juvonen 1993] [Sweeney et al 1992] [Carvalho et al 1992]. We agree with Nikoskelainen et al. [1996] that the X-linked hypothesis merits further investigation.

 ^   In view of the possibility of spontaneous visual recovery in LHON, reports of effective treatment must be interpreted with caution. Present treatment regimens are designed to increase mitochondrial energy production. Agents include naturally occuring cofactors in mitochondrial metabolism and anti-oxidants: coenzyme Q10, succinate, idebenone, vitamin K, vitamin K3, vitamin C, thiamine, and vitamin B2. Limited initial experience with coenzyme Q and succinate in affected patients has been disappointing. At this point, no therapy has been consistently demonstrated to benefit patients with vision loss or to prevent vision loss among their asymptomatic maternal relatives.

 ^   Point mutations in the mitochondrial genome involving various subunits of Complex I of the respiratory chain are necessary for the bilateral loss of central vision seen in LHON, but other factors play a role in disease expression and penetrance. Molecular genetic testing has expanded the clinical spectrum of LHON. Patients may present with subclinical vision loss, progressive vision loss, and subacute vision loss with or without recovery. Age of onset may vary from 5 to 80 years. Factors proposed to influence the risk of vision loss in mutation harboring pedigrees are both genetic and epigenetic: an X-linked factor, secondary mitochondrial mutations, heteroplasmy, nutritional factors, metabolic disease, and toxic exposures. The discovery of the Wallace mutation has inspired considerable research into LHON. As with other genetic disorders, the challenge remains to understand the pathophysiology linking the genetic defect with the patients' clinical manifestations.

Supported in part by a departmental grant (Ophthalmology, Emory University School of Medicine) from Research to Prevent Blindness, Inc., N.Y., N.Y.

Adams JH, Blackwood W, Wilson J (1966): Further clinical pathological observations on Leber's optic atrophy. Brain 89:15-26. PMID 5910901

Barbirolo B, Montagna P, Cortelli P, lotti S, Lodi R, Barboni P, Monari L, Lugaresi E, Frassineti C, Zaniol P (1995): Defective brain and muscle energy metabolism shown by in vivo ³¹P magnetic resonance spectroscopy in nonaffected carriers of 11778 mtDNA mutation. Neurology 45:1364-1369. PMID 7617199

Bower SPC, Hawley 1, Mackey DA (1992): Cardiac arrhythmia and Leber's hereditary optic neuropathy. Lancet 339:1427- 1428. PMID 1350847

Brierly EJ, Griffiths PC, Weber K, Johnson MA, Turnbull DM (1996): Normal respiratory chain function in patients with low tension glaucoma. Arch Ophthalmol 114:142-146. PMID 8573015

Bruyn GW, Bots CT, Went LN, Klirtkhamer PJ (1992): Hereditary spastic dystonia with Leber's hereditary optic neuropathy: Neuropathological findings. J Neurol Sci 113:55-61. PMID 1469456

Bu X, Rotter JI (1991): X-linked and mitochondrial gene control of Leber hereditary optic neuropathy (LHON): Evidence from segregation analysis for dependence on X chromosome inactivation. Proc Natl Acad Sci USA 88:8198- 8202. PMID 1896469

Carvalho MRS, Müller B, Rötzer E, Berninger TI Kommerell C, Blankenagel A, Savontaus ML, Meitinger T, Lorenz B (1992): Leber's hereditary optic neuroretinopathy and the X-chromosomal susceptibility factor: No linkage to DXS7. Hum Hered 42:316-320. PMID 1360941

Chen JD, Cox 1, Denton MY (1989): Preliminary exclusion of an X-linked gene in Leber optic atrophy by linkage analysis. Hum Genet 82(3):203-207. PMID 2731932

Cortelli P, Montagna P, Avoni P, Sangiorgi S, Bresolin M, Moggio M, Zaniol P, Mantovani V, Barboni P, Barbiroli B, Ingaresi E (1991): Leber's hereditary optic neuropathy: Genetic, biochemical, and phosphorus magnetic resonance spectroscopy study in an Italian family. Neurology 41:1211-1215. PMID 1866007

Cullom ME, Heher KL, Miller NR, Sayino Pj, Johns DR (1993): Leber's hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia. Arch Ophthalmol 111:1482-1485. PMID 8240101

DuBois LC, Feldon SE (1992): Evidence for a metabolic trigger for Leber's hereditary optic neuropathy. A case report. J Clin Neuro-Ophthalmol 12:15-16. PMID 1532594

Egger J, Wilson J (1983): Mitochondrial inheritance in a mitochondrial mediated disease. N Engl J Med 309:142-146. PMID 6866014

Erickson RP (1972): Leber's optic atrophy: A possible example of maternal inheritance. Am J Hum Genet 24:348-349. PMID 5063796

Federico A, Manneschi L, Meloni M, Alessandrini C, Bardelli AM, Dotti MT, Sabatelli P (1988): Histochemical, ultrastructural, and biochemical study of muscle mitochondria in Leber's hereditary optic atrophy. J Inher Metab Dis 11 Suppl 2:193-197. PMID 2846962

Flanigan KM, Johns DR (1993): Association of the 11778 mitochondrial DNA mutation and demyelinating disease. Neurology 43:2720-2722. PMID 8255489

Funakawa I, Kato H, Terao A, Ichihashi K, Kawashima S, Hayashi T, Mitaffi K, Miyazaki S (1995): Cerebellar ataxia in patients with Leber's hereditary optic neuropathy. J Neurol 242:75-77. PMID 7707093

Govan GG, Smith PR, Kellar-Wood H, Schapira AH, Harding AE (1994): HLA class II genotypes in Leber's hereditary optic neuropathy. J. Neurol Sci 126(2): 193-6. PMID 7853025

Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, McDonald WI, Compston DAS (1992): Occurence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain 115:979-989. PMID 1393514

Harding AE, Sweeney MC, Govan GG, Riordan-Eva P (1995): Pedigree analysis in Leber hereditary optic neuropathy families with a pathologic mtDNA mutation. Am J Hum Genet 57:77-86. PMID 7611298

Hirano M, Cleary JM, Stewart AM, Lincoff NS, Odel JG, Santiesteban R, Santiago Luis R (1994): Mitochondrial DNA mutations in an outbreak of optic neuropathy in Cuba. Neurology 44:843--845. PMID 8190285

Howell N (1994a): Primary LHON mutations: Trying to separate "fruyt" from "chaf." Clin Neurosci 2:130-137.

Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, Taylor L, Turnbull DM (1991a): Leber hereditary optic neuropathy: Identification of the same mitochondrial NDl mutation in six pedigrees. Am J Hum Genet 49:939-950. PMID 1928099

Howell N, Kubacka I, Xu M, McCullough DA (1991b): Leber hereditary optic neuropathy: Involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet 48:935-942. PMID 2018041

Howell N, Xu M, Halvorson S, Bodis- Wollner I, Sherman J (1994b): A heteroplasmic LHON family: Tissue distribution and transmission of the 11778 mutation. Am J Hum Genet 55:203-206. PMID 8023847

Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML (1991): A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 48:1147-1153. PMID 1674640

Johns DR, Neufeld MJ, Park RD (1992a): An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun 187:1551-1557. PMID 1417830

Johns DR, Smith KH, Miller NR (1992b): Leber's hereditary optic neuropathy: Clinical manifestations of the 3460 mutation. Arch Ophthalmol 110:1577-1581. PMID 1444915

Johns DR, Heher KL, Miller NR, Smith KH (1993a): Leber's hereditary optic neuropathy: Clinical manifestations of the 14484 mutation. Arch Ophthalmol 111: 495-498. PMID 8470982

Johns DR, Smith KH, Miller NR, Sulewski ME, Bias WB (1993b): Identical twins who are discordant for Leber's hereditary optic neuropathy. Arch Ophthalmol 111:1491-1494. PMID 8240103

Jun AS, Brown MD, Wallace DC (1994): A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Nati Acad Sci U S A. 91:6206-6210. PMID 8016139

Juvonen V, Vilkki J, Aula P, Nikoskeliinen E, Savontaus ML (1993): Reevaluation of the linkage of an optic atrophy susceptibility gene to X-chromosomal markers in Finnish families with Leber's hereditary optic neuroretinopathy (LHON). Am J Hum Genet 53:289-292. PMID 8317495

Kellar-Wood H, Robertson N, Govan GG, Compston DAS, Harding AE (1994): Leber's hereditary optic neuropathy mitochondrial mutations in multiple sclerosis. Ann Neurol 36:109-112. PMID 8024249

Kerrison JB, Howell N, Miller NR, Hirst L, Green WR (1995): Leber hereditary optic neuropathy: Electron microscopy and molecular genetic analysis of a case. Ophthalmology 102:1509-1516. PMID 9097799

Klein BE, Klein R, Sponsel WE, Franke T, Cantor LB, Martone J, Menage MJ (1992): Prevalence of glaucoma: The Beaver Dam Eye Study. Ophthalmology 99:1499-1504. PMID 1454314

Kwittken J, Barest HD (1958): The neuropathology of hereditary optic atrophy (Leber's disease). The first complete anatomic study. Am J Pathol 34:185-207. PMID 13498139

Larsson NG, Anderson 0, Holme E, Oldfors A, Wahlstrom J (1991): Leber's hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol 30:701-708. PMID 1763894

Lauer SA, Akerman J, Sunness J, Bluth EM, Kim CK (1985): Leber's optic atrophy with myopia masquerading as glaucoma: A case report. Ann Ophthalmol 17:146-148. PMID 3994214

Lott MT, Voljavee AS, Wallace DC (1990): Variable genotype of Leber's hereditary optic neuropathy patients. Am J Ophthalmol 109:625-631. PMID 2346190

Mackey DA (1994): Three subgroups of patients from the United Kingdom with Leber hereditary optic neuropathy. Eye 8:431-436. PMID 7821467

Mackey DA, Howell N (1992): A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Am J Hum Genet 51:1218-1228. PMID 1463007

Majander A, Huoponen K, Savontaus ML, Nikoskelainen EK, Wikstrom M (1991): Electron transfer properties of NADH: ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of Leber hereditary optic neuroretinopathy (LHON). FEBS Lett 292:289-292. PMID 1959619

Mashima Y, Saga M, I-Iiida Y, Ogueld Y, Wakakura M, Kudoh J, Shimizu N (1995): Quantitative determination of heteroplasmy in Leber's hereditary optic neuropathy by single-strand conformation polymorphism. Invest Ophthalmol Vis Sci 36:1714-1720. PMID 7601652

Mondelli M, Rossi A, Scarpini C, Dotti MT, Federico A (1990): BAEP changes in Leber's hereditary optic atrophy: Further confirmation of multisystem involvement. Acta Neurol Scand 81:349- 353. PMID 2360403

Mondelli M, Rossi A, Scarpini C, Dotti MT, Federico A (1991): Lober's optic atrophy: VEP and BAEP changes in 16 asymptomatic subjects. Acta Neurol Scand 84:366. PMID 1772010

Nakamura M, Fujiwara Y, Yamamoto M (1993): The two locus control of Leber hereditary optic neuropathy and a high penetrance in Japanese pedigrees. Hum Genet 91:339-341. PMID 8500789

Newman NJ (1993): Leber's hereditary optic neuropathy: New genetic considerations. Arch Neurol 50:540-548. PMID 8489411

Newman NJ (1997): The hereditary optic neuropathies. In Miller NR, Newman NJ (eds): Walsh & Hoyt's Clinical Neuro-Ophthalmology, 5th edition. Baltimore: Williams & Wilkens (in press).

Newman NJ, Lott MT, Wallace DC (1991): The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 111:750-762. PMID 2039048

Newman NJ, Torroni A, Brown MD, Lott MT, Femandez MM, Wallace DC (1994): Epidemic neuropathy in Cuban no associated with mitochondrial DNA mutations found in Leber's hereditary optic neuropathy patients. Am J Ophthalmol 118:158-168. PMID 8053461

Nikoskelainen E, Hoyt WF, Nummelin K (1982a): Ophthalmoscopic findings in Leber's hereditary optic neuropathy. I. Fundus findings in asymptomatic family members. Arch Ophthalmol 100: 1597-1602. PMID 7138328

Nikoskelainen E, Hoyt WF, Nummelin K (1982b): Ophthalmoscopic findings in Leber's hereditary optic neuropathy. II. Fundus findings in affected family members. Arch Ophthalmol 101:1059-1068. PMID 6870629

Nikoskelainen E, Hassinen IE, Paljarvi L, Lang H, Kalimo H (1984a): Leber's hereditary optic neuroretinopathy, a mitochondrial disease? [letter]. Lancet 2:1474. PMID 6151084

Nikoskelainen E, Hoyt WF, Nummelin K, Schatz H (1984b): Fundus findings in hereditary optic neuroretinopathy. III. Fluorescein angiographic studies. Arch Ophthalmol 102:981-989. PMID 6743093

Nikoskelainen E, Wanne 0, Dahl M (1985): Pre-excitation syndrome and Leber's hereditary optic neuroretinopathy [letter]. Lancet 1:696. PMID 2858640

Nikoskelainen E, Savontaus ML, Wanne OP, Katila Mj, Nummelin KU (1987): Leber's hereditary optic neuroretinopathy, a maternally inherited disease. A genealogic study in four pedigrees. Arch Ophthalmol 105:665-671. PMID 3619743

Nikoskelainen EK, Savontaus ML, Huoponen K, Antila K, Hartiala j (1994): Pre-excitation syndrome in Leber's hereditary optic neuropathy [letter]. Lancet 344:857-858. PMID 7916404

Nikoskelainen EK, Marttila RJ, Huoponen K, Juvonen V, Lamniinen T, Sonninen P, Savontaus ML (1995): Leber's "plus": Neurologic abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 59:160-164. PMID 7629530

Nikoskelanien EK, Huoponen K, Juvonen V, Lamminen T, Nummelin K, Savontaus ML (1996): Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology 103:504-514. PMID 8600429

Nishimura M, Obayashi H, Ohta M, Uchiyama T, Hao Q, Saida T (1995): No association of the 11778 mitochondrial DNA mutation and multiple sclerosis in Japan. Neurology 45:1333-1334 PMID 7617193

Novotny EJ, Singh G, Wallace DC, Dorfman LJ, Louis A, Sogg RL, Steinman L (1986): Leber's disease and dystonia. A mitochondrial disease. Neurology 36:1053- 1060. PMID 3736869

Olsen NK, Hansen AW, Norby S, Edal S, Jorgensen JR, Rosenberg T (1995): Leber's hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand 91:326-329. PMID 7639060

Oostra RJ, Bolhuis PA, Wijburg FA, Zom- Ende G, Bleeker-Wagemakers EM (1994): Leber's hereditary optic neuropathy: Correlations between mitochondrial genotype and visual outcome. J Med Genet 31:280-286. PMID 8071952

Ortiz RC, Newman NJ, Manoukian S, Diesenhouse MC, Lott MT, Wallace DC (1992): Optic disk cupping and electro- cardiographic abnormalities in an American pedigree with Leber's hereditary optic neuropathy. Am J Ophthalmol 113:561-566. PMID 1575231

Parkers WD Jr, Oley CA, Parks JK (1989): A defect in mitochondrial electron-transport activity (NADH-coenzyme Q oxidoreductase) in Leber's hereditary optic neuropathy. N Engl J Med 320:1331- 1333. PMID 2497346

Riordan-Eva P, Sanders MD, Govan GG, Sweeney MC, Da Costa J, Harding AE (1995): The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118:319-337. PMID 7735876

Rizzo JF 3rd (1995): Adenosine triphosphate deficiency: A genre of optic neuropathy. Neurology 45:11-16. PMID 7824099

Sadun AA, Kashima Y, Wurdeman AE, Dao J, Heller K, Sherman J (1994): Morphological findings in the visual system in a case of Leber's hereditary optic neuropathy. Clin Neurosci 2:165-172.

Sadun AA, Sadun F (1996): Leber hereditary optic neuropathy [letter]. Ophthalmology 103(2):201-202. PMID 8594500

Shoffner JM, Brown MD, Stutgard C, Jun AS, Pollock S, Haas RH, Kaufman A, Koontz D, Kiin Y, Graham JR, Smith E, Dixon J, Wallace DC (1995): Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann Neurol 38:163-169. PMID 7654063

Singh G, Lott MT, Wallace DC (1989): A mitochondrial DNA mutations as a cause of Leber's hereditary optic neuropathy. N Engl J Med 320:1300-1305. PMID 2566116

Smith JL, Hoyt WF, Susae JO (1973): Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol 90:349-354. PMID 4746084

Smith KH, Johns DR, Heher KL, Miller NR (1993): Heteroplasmy in Leber's hereditary optic neuropathy. Arch Ophthalmol 111:1486-1490. PMID 8240102

Stone EM, Newman NJ, Miller NR, Johns DR, Lott MT, Wallace DC (1992): Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation. J Clin NeuroOphthalmol 12: 10-14. PMID 1532593

Sweeney MC, Davis MB, Lashwood A, Brockington M, Toscano A, Harding AE (1992): Evidence against an X-linked locus close to DXS7 determing visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy. Am J Hum Genet 51:741-748. PMID 1415219

Toscano A, Harding AE, Cellera C, Vita G, Castagna I, Romeo G, Sweeney MG, Bresolin N, Zeviani M, Messina C (1992): Complex I multiple mitochondrial DNA mutations and biochemical deficiency in Leber's hereditary optic neuropathy. Neurology 42(Suppl 3):266.

Wakakura M, Yokoe J, (1995): Evidence for preserved direct pupillary light response in Leber's Hereditary optic neuropathy. Br J Ophthalmol 79: 442-446. PMID 7612556

Wallace DC (1970): A new manifestation of Leber's disease and a new explanation for its unusual pattern of inheritance. Brain 93 121-132. PMID 5418396

Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK (1988): Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427-1430. PMID 3201231

Wilson J (1963): Leber's hereditary optic atrophy-some clinical and etiological considerations. Brain 86:347-362. PMID 14001038

van Senus AHC (1963): Leber's disease in the Netherlands. Doc Ophthalmol 17:1- 163. PMID 14187151

Vilkki J, Ott J, Savontaus ML, Aula P, Nikoskelainen EK (1991): Optic atrophy in Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to DXS7. Am J Hum Genet 48:486-491. PMID 1998335

 ^  Nancy J. Newman, M.D., is the Director of the Neuro-ophthalmology Unit at the Emory Eye Center; Associate Professor of Ophthalmology and Neurology; and Instructor in Neurosurgery at the Emory University School of Medicine, and lecturer in Ophthalmology at Harvard Medical School. After graduating summa cum laude from Princeton University in 1978, she obtained her master's degree in art history from the Courtauld Institute of Art, University of London in 1980 and her medical degree from Harvard Medical School in 1984. Her postgraduate training in neurology and neuro-ophthalmology was at the Massachusetts General Hospital and the Massachusetts Eye and Ear Infirmary. She is on the editorial board of the American Journal of Ophthalmology, and she is currently coediting the fifth edition of Walsh and Hoyt's Clinical Neuro-Ophthalmology. Dr. Newman's clinical and research interests include diseases of the optic nerve and mitochondrial dysfunction.

 ^   John B. Kerrison, M.D., is a resident In ophthalmology at the Wilmer Ophthalmological Institute, Johns Hopkins Hospital. He graduated summa cum laude from both the Citadel in 1987 and Emory University School of Medicine In 1992. He completed a medical internship at Brigham and Women's Hospital in Boston. He will be pursuing further postgraduate work in neuro ophthalmology at Emory and as assistant chief of service at Wilmer. His research interests include the clinical aspects and molecular genetics of neuro-ophthalmic disorders.

Contract grant sponsor: Research to Prevent Blindness, Inc., N.Y., N.Y.

*Correspondence to: Nancy J. Newman, Emory Eye Center, 1365-B Clifton Rd NE, Suite 3505, Atlanta, GA 30322.

This article was reformatted to HTML by IFOND and republished here with kind permission from Wiley-Liss, Inc., 605 Third Avenue, New York, NY 10158-0012, a division of John Wiley & Sons, Inc.

© 1997 Wiley-Liss, Inc. All rights reserved. No part of this publication may be reproduced in any form or by any means, except as permitted under section 107 or 108 of the 1976 United States Copyright Act, without the prior written permission of the publisher, or authorization through the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923, (508) 750-8400, fax (508) 750-4470. Requests to the publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc.