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• W2023172840 abstract "Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease that presents with acute bilateral simultaneous or sequential blindness in which the genetic etiology and clinical features are well known,1Newman N.J. Lott M.T. Wallace D.C. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation.Am J Ophthalmol. 1991; 111: 750-762Abstract Full Text PDF PubMed Scopus (356) Google Scholar, 2Johns D.R. Smith K.H. Miller N.R. Leber's hereditary optic neuropathy Clinical manifestations of the 3460 mutation.Arch Ophthalmol. 1992; 110: 1577-1581Crossref PubMed Scopus (143) Google Scholar, 3Johns D.R. Heher K.L. Miller N.R. Smith K.H. Leber's hereditary optic neuropathy Clinical manifestations of the 14484 mutation.Arch Ophthalmol. 1993; 111: 495-498Crossref PubMed Scopus (220) Google Scholar, 4Riordan-Eva P. Sanders M.D. Govan G.G. et al.The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation.Brain. 1995; 118: 319-337Crossref PubMed Scopus (415) Google Scholar the pathogenesis is not understood,5Brown M.D. Allen J.C. Van Stavern G.P. et al.Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations.Am J Med Genet. 2001; 104: 331-338Crossref PubMed Scopus (68) Google Scholar, 6Brown M.D. The enigmatic relationship between mitochondrial dysfunction and Leber's hereditary optic neuropathy.J Neurol Sci. 1999; 165: 1-5Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 7Cock H.R. Cooper J.M. Schapira A.H. Functional consequences of the 3460-bp mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.J Neurol Sci. 1999; 165: 10-17Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar and no treatments are available to prevent, reverse, or restore vision loss. The vision loss occurs typically in young adulthood and does not recur. During the acute stage of vision loss, patients sometimes display a characteristic papillopathy consisting of peripapillary telangiectasia, swelling of the retinal nerve fiber layer (RNFL), and absence of leakage on fluorescein angiography,8Smith J.L. Hoyt W.F. Susac J.O. Ocular fundus in acute Leber optic neuropathy.Arch Ophthalmol. 1973; 90: 349-354Crossref PubMed Scopus (139) Google Scholar, 9Nikoskelainen E. Hoyt W.F. Nummelin K. Ophthalmoscopic findings in Leber's hereditary optic neuropathy II. The fundus findings in the affected family members.Arch Ophthalmol. 1983; 101: 1059-1068Crossref PubMed Scopus (115) Google Scholar although many have normal-appearing fundi.Leber's hereditary optic neuropathy is caused by missense mutations in proteins that form large complexes that reside in the inner mitochondrial membrane. Through a series of reactions, electrons pass along these complexes to lower energy states, and the resultant energy is exchanged efficiently to pump hydrogen ions across the membrane. This sets up an electrochemical potential gradient across the membrane, whose energy is harnessed to make adenosine triphosphate, the energy currency of cells.Mitochondrial genetic disease differs from genetic diseases caused by mutations in nuclear DNA, where the likelihood of inheriting disease is governed by Mendelian rules of segregation and independent assortment of alleles. In mitochondrial genetic disease, all offspring inherit the same maternal mitochondrial genes, with only a few exceptions. Thus, all siblings harbor the same genetic defect, yet only some, particularly males, ever develop blindness.Apart from these curious features, why is it important that we continue to investigate LHON? First, it is an acquired bilateral blinding disease that is devastating to those affected. Second, it is evident that mitochondrial function is germane to retinal ganglion cell biology and other optic nerve diseases.Savini et al, through their diligent work comparing RNFL thickness in asymptomatic carriers with controls, provide new insights into an old observation.10Savini G, Barboni P, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber's hereditary optic neuropathy mutations. Ophthalmology 2005;112:127–31.Google Scholar Over 2 decades ago, Nikoskelainen et al ophthalmoscopically observed that asymptomatic carriers manifested a papillopathy with peripapillary microangiopathy and RNFL thickening, concluding that these individuals were mildly affected.11Nikoskelainen E. Hoyt W.F. Nummelin K. Ophthalmoscopic findings in Leber's hereditary optic neuropathy I. Fundus findings in asymptomatic family members.Arch Ophthalmol. 1982; 100: 1597-1602Crossref PubMed Scopus (70) Google Scholar, 12Nikoskelainen E.K. Savontaus M.L. Wanne O.P. et al.Leber's hereditary optic neuroretinopathy, a maternally inherited disease A genealogic study in four pedigrees.Arch Ophthalmol. 1987; 105: 665-671Crossref PubMed Scopus (145) Google Scholar This observation has now been confirmed objectively by Savini et al using optical coherence tomography to perform quantitative analysis of RNFL thickness.10Savini G, Barboni P, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber's hereditary optic neuropathy mutations. Ophthalmology 2005;112:127–31.Google Scholar This study is a companion to their study of RNFL thickness in symptomatic LHON.13Barboni P, Savini G, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber's heredity optic neuropathy. Ophthalmology 2005;112:120–6.Google Scholar In the current study, these researchers identified RNFL thickening in unaffected carriers compared with gender- and age-matched controls. Savini et al also note that the pattern of thickening in asymptomatic individuals with LHON mutations (i.e., greater thickening of the temporal RNFL) corresponds to the pattern of vision loss, and that males, who are at greater risk of vision loss than females, have more diffuse involvement than females. These findings suggest that RNFL thickening is integral to the underlying disease pathogenesis.What is the clinical significance of this finding? Patients in this study were unaffected in terms of developing acute symptomatic vision loss. The terms subclinical and preclinical should be considered. Subclinical indicates that the disease is manifest but asymptomatic. Preclinical implies a stage before the onset of disease. Some individuals who harbor LHON mutations have subclinical vision dysfunction despite never having experienced acute symptomatic vision loss. If examined carefully, a patient may be found to have a small scotoma or dyschromatopsia.14Sadun F. De Negri A.M. Carelli V. et al.Ophthalmologic findings in a large pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy.Am J Ophthalmol. 2004; 137: 271-277Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar It is not clear that the clinical evaluation of carriers in this study included color vision testing and static perimetry. Some individuals in the study may have subclinical visual dysfunction. The risk of developing acute vision loss in such patients is not known. Whether or not the RNFL thickening in the patients reported by Savini et al represents a preclinical finding that precedes vision loss, a subclinical finding, or a benign abnormality of no clinical significance can only be determined by careful evaluation and longitudinal follow-up. It is possible that the unaffected patients in this cross-sectional study are survivors, who are at no greater or even reduced risk of developing vision loss.Although the results are statistically significant for the groups as a whole, it is evident from the data presented that not all asymptomatic carriers in this study have thickening of the RNFL. In interpreting the results, it would be useful to know what percent of carriers are within the normal range. For longitudinal studies and clinical application, the degree of thickness would have to be stratified. Finally, it would be useful to know if the presence or absence of thickening correlated with microangiopathy.Most studies looking at potential genetic or environmental modifiers assign affected status to someone who has developed clinically significant vision loss. It may be that reconsidering affection status, taking into account those individuals with subclinical visual dysfunction and/or RNFL thickening, would be worthwhile in future studies.It is evident that there is more to be learned about the natural history of these clinical observations. The finding of RNFL thickening in asymptomatic individuals with the LHON genotype suggests that LHON is not necessarily a monophasic disease but may manifest (1) a latent phase with axonal thickening and normal visual function that may or may not precede clinically significant vision loss, (2) an acute phase of axonal injury with clinically significant loss of visual function, and (3) a chronic phase with spontaneous improvement of vision in some individuals and reduced likelihood of recurrence. Whether subclinically affected patients should be considered latent or acute would depend on the potential for further vision loss. We do not know the clinical significance of RNFL thickening or subclinically affected patients, but follow-up studies should answer this question. Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease that presents with acute bilateral simultaneous or sequential blindness in which the genetic etiology and clinical features are well known,1Newman N.J. Lott M.T. Wallace D.C. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation.Am J Ophthalmol. 1991; 111: 750-762Abstract Full Text PDF PubMed Scopus (356) Google Scholar, 2Johns D.R. Smith K.H. Miller N.R. Leber's hereditary optic neuropathy Clinical manifestations of the 3460 mutation.Arch Ophthalmol. 1992; 110: 1577-1581Crossref PubMed Scopus (143) Google Scholar, 3Johns D.R. Heher K.L. Miller N.R. Smith K.H. Leber's hereditary optic neuropathy Clinical manifestations of the 14484 mutation.Arch Ophthalmol. 1993; 111: 495-498Crossref PubMed Scopus (220) Google Scholar, 4Riordan-Eva P. Sanders M.D. Govan G.G. et al.The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation.Brain. 1995; 118: 319-337Crossref PubMed Scopus (415) Google Scholar the pathogenesis is not understood,5Brown M.D. Allen J.C. Van Stavern G.P. et al.Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations.Am J Med Genet. 2001; 104: 331-338Crossref PubMed Scopus (68) Google Scholar, 6Brown M.D. The enigmatic relationship between mitochondrial dysfunction and Leber's hereditary optic neuropathy.J Neurol Sci. 1999; 165: 1-5Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 7Cock H.R. Cooper J.M. Schapira A.H. Functional consequences of the 3460-bp mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.J Neurol Sci. 1999; 165: 10-17Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar and no treatments are available to prevent, reverse, or restore vision loss. The vision loss occurs typically in young adulthood and does not recur. During the acute stage of vision loss, patients sometimes display a characteristic papillopathy consisting of peripapillary telangiectasia, swelling of the retinal nerve fiber layer (RNFL), and absence of leakage on fluorescein angiography,8Smith J.L. Hoyt W.F. Susac J.O. Ocular fundus in acute Leber optic neuropathy.Arch Ophthalmol. 1973; 90: 349-354Crossref PubMed Scopus (139) Google Scholar, 9Nikoskelainen E. Hoyt W.F. Nummelin K. Ophthalmoscopic findings in Leber's hereditary optic neuropathy II. The fundus findings in the affected family members.Arch Ophthalmol. 1983; 101: 1059-1068Crossref PubMed Scopus (115) Google Scholar although many have normal-appearing fundi. Leber's hereditary optic neuropathy is caused by missense mutations in proteins that form large complexes that reside in the inner mitochondrial membrane. Through a series of reactions, electrons pass along these complexes to lower energy states, and the resultant energy is exchanged efficiently to pump hydrogen ions across the membrane. This sets up an electrochemical potential gradient across the membrane, whose energy is harnessed to make adenosine triphosphate, the energy currency of cells. Mitochondrial genetic disease differs from genetic diseases caused by mutations in nuclear DNA, where the likelihood of inheriting disease is governed by Mendelian rules of segregation and independent assortment of alleles. In mitochondrial genetic disease, all offspring inherit the same maternal mitochondrial genes, with only a few exceptions. Thus, all siblings harbor the same genetic defect, yet only some, particularly males, ever develop blindness. Apart from these curious features, why is it important that we continue to investigate LHON? First, it is an acquired bilateral blinding disease that is devastating to those affected. Second, it is evident that mitochondrial function is germane to retinal ganglion cell biology and other optic nerve diseases. Savini et al, through their diligent work comparing RNFL thickness in asymptomatic carriers with controls, provide new insights into an old observation.10Savini G, Barboni P, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber's hereditary optic neuropathy mutations. Ophthalmology 2005;112:127–31.Google Scholar Over 2 decades ago, Nikoskelainen et al ophthalmoscopically observed that asymptomatic carriers manifested a papillopathy with peripapillary microangiopathy and RNFL thickening, concluding that these individuals were mildly affected.11Nikoskelainen E. Hoyt W.F. Nummelin K. Ophthalmoscopic findings in Leber's hereditary optic neuropathy I. Fundus findings in asymptomatic family members.Arch Ophthalmol. 1982; 100: 1597-1602Crossref PubMed Scopus (70) Google Scholar, 12Nikoskelainen E.K. Savontaus M.L. Wanne O.P. et al.Leber's hereditary optic neuroretinopathy, a maternally inherited disease A genealogic study in four pedigrees.Arch Ophthalmol. 1987; 105: 665-671Crossref PubMed Scopus (145) Google Scholar This observation has now been confirmed objectively by Savini et al using optical coherence tomography to perform quantitative analysis of RNFL thickness.10Savini G, Barboni P, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber's hereditary optic neuropathy mutations. Ophthalmology 2005;112:127–31.Google Scholar This study is a companion to their study of RNFL thickness in symptomatic LHON.13Barboni P, Savini G, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber's heredity optic neuropathy. Ophthalmology 2005;112:120–6.Google Scholar In the current study, these researchers identified RNFL thickening in unaffected carriers compared with gender- and age-matched controls. Savini et al also note that the pattern of thickening in asymptomatic individuals with LHON mutations (i.e., greater thickening of the temporal RNFL) corresponds to the pattern of vision loss, and that males, who are at greater risk of vision loss than females, have more diffuse involvement than females. These findings suggest that RNFL thickening is integral to the underlying disease pathogenesis. What is the clinical significance of this finding? Patients in this study were unaffected in terms of developing acute symptomatic vision loss. The terms subclinical and preclinical should be considered. Subclinical indicates that the disease is manifest but asymptomatic. Preclinical implies a stage before the onset of disease. Some individuals who harbor LHON mutations have subclinical vision dysfunction despite never having experienced acute symptomatic vision loss. If examined carefully, a patient may be found to have a small scotoma or dyschromatopsia.14Sadun F. De Negri A.M. Carelli V. et al.Ophthalmologic findings in a large pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy.Am J Ophthalmol. 2004; 137: 271-277Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar It is not clear that the clinical evaluation of carriers in this study included color vision testing and static perimetry. Some individuals in the study may have subclinical visual dysfunction. The risk of developing acute vision loss in such patients is not known. Whether or not the RNFL thickening in the patients reported by Savini et al represents a preclinical finding that precedes vision loss, a subclinical finding, or a benign abnormality of no clinical significance can only be determined by careful evaluation and longitudinal follow-up. It is possible that the unaffected patients in this cross-sectional study are survivors, who are at no greater or even reduced risk of developing vision loss. Although the results are statistically significant for the groups as a whole, it is evident from the data presented that not all asymptomatic carriers in this study have thickening of the RNFL. In interpreting the results, it would be useful to know what percent of carriers are within the normal range. For longitudinal studies and clinical application, the degree of thickness would have to be stratified. Finally, it would be useful to know if the presence or absence of thickening correlated with microangiopathy. Most studies looking at potential genetic or environmental modifiers assign affected status to someone who has developed clinically significant vision loss. It may be that reconsidering affection status, taking into account those individuals with subclinical visual dysfunction and/or RNFL thickening, would be worthwhile in future studies. It is evident that there is more to be learned about the natural history of these clinical observations. The finding of RNFL thickening in asymptomatic individuals with the LHON genotype suggests that LHON is not necessarily a monophasic disease but may manifest (1) a latent phase with axonal thickening and normal visual function that may or may not precede clinically significant vision loss, (2) an acute phase of axonal injury with clinically significant loss of visual function, and (3) a chronic phase with spontaneous improvement of vision in some individuals and reduced likelihood of recurrence. Whether subclinically affected patients should be considered latent or acute would depend on the potential for further vision loss. We do not know the clinical significance of RNFL thickening or subclinically affected patients, but follow-up studies should answer this question." @default.
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