|
Leber's hereditary optic neuropathy (LHON) is a hereditary optic nerve disorder that typically affects young adults and frequently leads to social blindness. The disease is usually acute or subacute and presents with optic nerve inflammatory signs such as hyperemia with blurred optic disc with peripapillary retinal vascular involvement, followed months later by progressive optic nerve atrophy. LHON is always bilateral, affecting both eyes simultaneously or with intervals of several months. The inheritance pattern is unique and is transmitted through females, with family history showing a pattern of maternal inheritance.[1,2] A clinically confirmed diagnosis of LHON is feasible when there is a maternally inherited family history of bilateral, acute or subacute inflammatory optic nerve disease. Without this, the diagnosis is difficult, particularly in cases of nonfamilial or insidious, chronic progressive disease. In recent years, diagnostic problems in LHON have been overcome with molecular analyses of mitochondrial DNA (mtDNA). Point mutations of mtDNA are now known to be pathognomonic for LHON, including mutations at np3460, np11 778 and np14 484, which are strongly linked to the disease.[3-5]Thus, the mtDNA mutation provides a powerful diagnostic aid for LHON, in particular, clinically otherwise undefined optic nerve disease. This paper reports some clinical data to further elucidate the diagnostic value of mtDNA assessment.
METHODS
A total of 79 unrelated cases were the patients for mtDNA analyses: 16 cases of LHON, the diagnosis of which was made based on clinical features and a positive family history compatible with maternal inheritance; 44 cases of etiology-unknown, bilateral optic neuritis with negative family history; 2 cases of alcohol amblyopia; 4 cases of possible multiple sclerosis; 5 cases of autosomal dominant optic atrophy; 4 cases of primary open-angle glaucoma; 3 cases of spinocerebellar degeneration; 1 case of ethambutol-induced optic neuropathy.
In addition to routine ophthalmic examination, peripheral blood was obtained after informed consent and examined for mtDNA by methods described elsewhere.[6,7]In brief, three mtDNA mutations were studied which have been confirmed to be pathogenic for LHON: point mutations at np3460, 11 778 and 14 484. PCR fragments of mtDNA encoding subunits of NADH CoQ reductase, subunit 1 (np3153 to np3551, ND[1]), subunit 4 (np10 991 to np11 914, ND[4]) and subunit 6 (np14 464 to np14 671, ND[6]), were amplified by polymerase chain reaction amplification. A mutation primer pair was used for ND[6] amplification. Target mutations were examined by PCR-restriction detection with appropriate restriction endonucleases: 3460 mutation using the Bsa HⅠ site in ND[1]; 11 778 mutation using the Sfa NⅠ site in ND[4]; 14 484 mutation using the Sau3 AⅠ site in ND[6].
RESULTS
Detection of mtDNA mutation
Thirty-one (39.2%) of 79 unrelated cases showed a mutation at 11 778. None of the cases showed a mutation at 3460 or 14 484. Table 1 shows the incidence of mtDNA mutations in the three groups divided according to the clinical diagnosis.
Group A consisted of 16 cases that were diagnosed as probable LHON because they had not only acute or subacute, bilateral optic neuritis but also an obvious family history compatible with maternal inheritance. Each case in this group showed a mtDNA 11 778 mutation, as expected for LHON, but none showed the 3460 or the 14 484 mutation.
Group B included a series of 44 cases that had nonfamilial, bilateral optic nerve disease which was undefined for any etiology or clinical entity but not readily excluded for LHON. Thirteen (29.5%) of this group showed the mtDNA 11 778 mutation. All the mtDNA 11 778 mutation-positive patients were males. Clinical information of this group is shown in Table 2.
Table 2 (Patients No. 1-20) shows that of the 20 patients with acute episodes of optic neuropathy, eleven (55.0%) were positive for mtDNA 11 778 and had an age of acute onset of 24.2 years. The mtDNA 11 778 mutation-negative patients had an age of acute onset of 29.1 years.
Of 24 patients without an acute episode of optic neuropathy (No. 21-44 in Table 2), two patients (19-year-old male, 35-year-old male) had the mtDNA 11 778 mutation. These two patients were sporadic and suffered from chronic progressive visual loss since early childhood; one of them showed an associated bilateral, mild maculopathy that made diagnosis more difficult.
Group C was defined by those cases of bilateral optic nerve disease due to various etiologies or entities. Two (10.6%) of the 19 cases in this group showed mtDNA 11 778 mutation; these two cases that had been tentatively diagnosed as alcohol amblyopia, which was then changed to LHON.
An unusual pedigree with mtDNA 11 778 mutation
A 46-year-old man had acute visual loss in the left eye. On examination, the right eye was intact. Corrected visual acuity of the left eye was 0.04, with a dense central scotoma on the Goldmann perimetry; ophthalmoscopy revealed inflammatory signs on the optic disc. Physical, neurologic and radiologic examinations were unremarkable. Oral corticosteroid was ineffective, and the visual loss remained unchanged with progressive pallor of the optic disc. Three months later, the patient had acute visual loss in the right eye. Examination and outcome were similar to the left eye. The ocular history, examination and course of the disease indicated acute, bilateral optic neuritis of undefined nature, and an interview with the patient showed that the parents and six siblings had no specific eye disease. LHON was not excluded, since the patient had the mtDNA 11 778 mutation, which is pathognomonic for the disease. The patient was asked for permission to examine mtDNA in his offspring, and all three (19-year-old f emale, 17-year-old male and 13-year-old female) were found to have the same mtDNA mutation although they were ophthalmologically normal. The patient's wife was free from optic nerve disease. Further family studies were conducted to ass ess this apparently discrepant finding of paternal transmission of the pathognom onic mtDNA mutation. The patient's wife was a second-cousin of the patient and was found to have the mtDNA 11 !778 mutation, indicating that the pathognomonic mtDNA mutation observed in the offspring was transmitted throug h their mother but not through their affected father.
DISCUSSION
Our results confirm that clinically undefined optic nerve disease is not infrequ ently associated with mtDNA mutation, hence establishing a diagnosis of LHON. A large series of LHON patients from a variety of ethnic groups indicated that th e incidence of major pathogenic mtDNA mutations, 11 778, 3460 and 14 484, is 40% to 90%, 8% to 25%, and 10%, respectively.[8]In Japanese LHON patients, the i ncidence of the 11 778 mutation is reported to be 91.7% to 87%, and that of 34 60 or 14 484 mutation is rare.[9,10]The present series of clinically pro bable LHON or possible LHON (Group A and B in Table 1) exclusively carried the 1 1 778 mutation, consistent with previous reports. Yet undefined pathogenic muta tions may be responsible for the remaining cases. An alternate possibility is t hat those cases are not associated with a mtDNA mutation, and are distinct from LHON, representing other clinical entities, including multiple sclerosis and au tosomal dominant optic atrophy in which the mtDNA mutation is not relevant.
LHON cases with a positive family history show inheritance patterns compatible with maternal inheritance. The family described above seems at first irreconcilable with maternal inheritance, but consanguineous marriage of an affected male and a carrier female is consistent with the characteristic transmission of LHON. On the other hand, familial occurrence of acute-onset optic nerve inflammatory disease dose not necessarily lead to a diagnosis of LHON, reserved for yet undefined mtDNA mutations, or for genetic diseases including autosomal dominant optic atrophy or even nongenetic diseases.
Most of the LHON patients showed typical clinical features with acute onset of optic nerve inflammatory changes followed by optic atrophy in months. The incidence of the mtDNA 11 778 mutation was high in patients with acute optic nerve disease without a family history. It is remarkable that several cases had insidious, chronic progressive disease, which is regarded as one of the atypical clinical forms of LHON.[11]This unusual clinical course might have previously been difficult to diagnose as LHON particularly in isolated cases. In addition, two patients with alcohol amblyopia showed the mtDNA 11 778 mutation. The mtDNA 11 778 mutation has also been detected in patients with multiple sclerosis-like illness or other diseases.[12-14]Assessment of mtDNA would be very beneficial in establishing a diagnosis of such a category of bilateral optic nerve disease.
A variety of pathogenic mtDNA mutations may be involved in the primary pathogenesis of LHON, through which mitochondrial respiratory activities are affected in oxygen-requiring organs and tissues. To date, mtDNA point mutations at np11 778, 3460, 14 484, 4146, and 14 459 have been considered as the major pathogenic mutations associated with LHON.8 It is intriguing that all these primary mutations are located in the coding regions for NADH CoQ reductase subunits. Enzyme-chemical abnormalities of NADH CoQ reductase might be involved in the molecular pathology of LHON. In the case of the mtDNA 11 778 mutation, amino acid replacement may cause inefficient substrate binding of NADH CoQ reductase.[15]
REFERENCES
1. Nikoskelainen E, Sogg RL, Rosenthal AR, et al. The early phase in Leber her editary optic atrophy. Arch Ophthalmol 1977;95:969-978.
2. Nikoskelainen EK, Savontaus ML, Wanne OP, et al. Leber's hereditary optic n euroretinopathy, a maternally inherited disease. A genetic study in four pedigr ees. Arch Ophthalmol 1987;105:665-671.
3. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988;242:1427-1430.
4. Huoponen K, Vilkki J, Aula P, et al. A new mtDNA mutation associated with L eber hereditary optic neuroretinopathy. Am J Hum Genet 1991;48:1147-1153.
5. Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation associat ed with Leber's hereditary optic neuropathy. Biochem Biophys Res Commun 1992;18 7:1551-1557.
6. Isashiki Y, Ohba N, Uto M, et al. Nonfamilial and unusual cases of Leber's hereditary optic neuropathy identified by mitochondrial DNA analysis. Jpn J Oph thalmol 1992;36:197-204.
7. Johns DR, Neufeld MJ. Pitfalls in the genetic diagnosis of Leber's heredita ry optic neuropathy (LHON). Am J Hum Genet 1993;53:916-920.
8. Newman NJ. Leber's hereditary optic neuropathy. New genetic considerations . Arch Neurol 1993;50:540-548.
9. Nakamura M, Ara F, Yamada M, et al. High frequency of mitochondrial ND4 gen e mutation in Japanese pedigrees with Leber's hereditary optic neuropathy. Jpn J Ophthalmol 1992;36:56-61.
10. Mashima Y, Yamada K, Wakakura M, et al. Spectrum of pathogenic mitochondri al DNA mutations and clinical features in Japanese families with Leber's heredit ary optic neuropathy. Curr Eye Res 1998;17:403-408.
11. Nikoskelainen EK, Huoponen K, Juvonen V, et al. Ophthalmologic findings in Leber's hereditary optic neuropathy, with special reference to mtDNA mutations . Ophthalmology 1996;103:504-514.
12. Harding AE, Sweeney MG, Miller DH, et al. Occurrence of a multiple scleros is-like illness in women who have a Leber's hereditary optic neuropathy mitocho ndrial DNA mutation. Brain 1992;115:979-989.
13. Cullom ME, Heher KL, Miller NR, et al. Leber's hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia. Arch Ophthalmol 1993;111:1482-1485.
14. Weiner NC, Newman NJ, Lessell S, et al. Atypical Leber's hereditary optic neuropathy with molecular confirmation. Arch Neurol 1993;50:470-473.
15. Isashiki Y, Ohba N, Uto M, et al. Sequence homology of NADH CoQ reductase subunit Ⅵ with nucleotide-requiring enzymes. Jpn J Ophthalmol 1993;37:39-42.
|
PDF(-)
Rapid Response |