LHON presents in midlife as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with many missense mutations in the mtDNA that can act autonomously or in association with each ... LHON presents in midlife as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with many missense mutations in the mtDNA that can act autonomously or in association with each other to cause the disease. The 18 allelic variants are MTND6*LDYT14459A (516006.0002); MTND4*LHON11778A (516003.0001); MTND1*LHON3460A (516000.0001); MTND6*LHON14484C (516006.0001); MTCYB*LHON15257A (516020.0001); MTCO3*LHON9438A (516050.0001); MTCO3*LHON9804A (516050.0002 ); MTND5*LHON13730A (516005.0002); MTND1*LHON4160C (516000.0002); MTND2*LHON5244A (516001.0002); MTCOI*LHON7444A (516030.0001); MTND1*LHON3394C (516000.0004); MTND5*LHON13708A (516005.0001); MTCYB*LHON15812A (516020.0002); MTND2*LHON4917G (516001.0001); MTND1*LHON4216C (516000.0003); MTND1*LHON4136G (516000.0002); MTATP6*LHON9101C (516060.0003); MTND4L*LHON10663C (516004.0002). The first 17 of these variants are summarized in Table M1, MIM12. As pointed out by Riordan-Eva and Harding (1995), although the plethora of mtDNA mutations identified in families with LHON had resulted in confusion as to the pathogenic significance of each mutation, it had been established that the 3 primary mutations at basepairs 11778 (516003.0001), 3460 (516000.0001), and 14484 (516006.0001) are present in at least 90% of families. The correlation between the 14484 mutation and a good visual prognosis provides not only hope for affected patients, but also an approach for further research into the pathogenesis of LHON. Yu-Wai-Man et al. (2009) provided a detailed review of LHON and autosomal dominant optic atrophy (OPA1; 165500), with emphasis on the selective vulnerability of retinal ganglion cells to mitochondrial dysfunction in both disorders.
LHON patients present with midlife, acute or subacute, painless, central vision loss leading to central scotoma. Neuroophthalmologic examination commonly reveals peripapillary telangiectasia, microangiopathy, disc pseudoedema, and vascular tortuosity; these features are observed in 58% of patients with the ... LHON patients present with midlife, acute or subacute, painless, central vision loss leading to central scotoma. Neuroophthalmologic examination commonly reveals peripapillary telangiectasia, microangiopathy, disc pseudoedema, and vascular tortuosity; these features are observed in 58% of patients with the nucleotide pair (np) 11778 mutation and occasionally in their asymptomatic maternal relatives. The mean age of onset has been variously reported from 27 to 34 years with a range of 1 to 70 years. The eyes can be affected simultaneously or sequentially, with an average interval between eyes being affected of about 2 months. The progression of each eye can range from sudden and complete vision loss to progressive decline over 2 years, with a mean progression time of about 3.7 months. The final visual acuity can range from 20/50 to no light perception, with the less severe mutations (see Table M1, MIM12) having less extreme outcomes. Thus, the most severely impaired np 11778 patients may have no light perception, the most severe np 3460 patients may retain light perception, the severe np 15257 patients will perceive hand motions, and the severe np 14484 patients will be able to count fingers. The probability of visual recovery also varies in relation to the mutation, with only 4% of np 11778 patients showing recovery an average of 36 months after onset; 22% of np 3460 patients recovering after 68 months; 28% of np 15257 patients recovering after 16 months; and 37% of np 14484 patients recovering after 16 months (Newman, 1993; Newman et al., 1991; Johns et al., 1993). Cullom et al. (1993) found that 2 of 12 patients previously diagnosed as having tobacco-alcohol amblyopia, based on a classic clinical presentation, tested positive for known LHON mutations, one for the 11778 mutation and one for the 3460 mutation. The fact that only a few patients who abuse tobacco and alcohol develop optic neuropathy has suggested an element of individual susceptibility (Carroll, 1944). Cullom et al. (1993) proposed that susceptibility may be the result of an LHON-associated mitochondrial mutation. Sadun et al. (2004) reported the ophthalmologic findings in 192 eyes from 96 maternally related individuals from a 7-generation Brazilian pedigree with LHON and the 11778/haplogroup J mutation. The findings demonstrated a significant influence of environmental risk factors, particularly smoking, for developing LHON and for the severity of its clinical expression. However, smoking did not correlate with the subclinical abnormalities detected in carriers. Moreover, subclinical abnormalities were equally distributed between males and females. Mann et al. (2000) reported peripheral retinal phlebitis in a patient with LHON and the 11778 mutation. In addition to bilateral central visual loss associated with headache, the patient had vitritis, vasculitis, and optic neuritis. She was initially thought to have multiple sclerosis, but laboratory studies failed to substantiate this diagnosis or any other cause of vasculitis. The authors concluded that their report supported the theory that LHON is a neuroretinopathy with a broad spectrum of genotype-specific phenotypes. Sadun et al. (2000) investigated the nerve fiber spectrum in optic nerves of 2 patients with LHON. Total depletion of the optic nerve fibers varied from 95 to 99%. Light and electron microscopy revealed preferential loss of the smallest axons corresponding to the P-cells, the smaller retinal ganglion cells. The authors concluded that the loss of P-cells may explain the clinical features of dyschromatopsia, central scotoma, and preservation of pupillary light response in LHON patients. In a review of the clinical and molecular genetic aspects of LHON, Huoponen (2001) pointed out that peripapillary microangiopathy is present from the beginning and disappears as the disease progresses toward the end stages. Newman-Toker et al. (2003) reported 2 patients with LHON who developed subsequent worsening of visual acuity or visual field constriction several years after onset. One female patient, who presented at age 17 with 20/400 acuity in each eye, had further, painless visual field loss 8 years later; final acuities were light perception in her right eye and counting fingers at 4 feet in her left. A blood test showed that she had the 11778 mtDNA mutation. Another patient lost vision at age 35 in 1 eye. Visual acuity of 20/200 in the first eye improved over 6 months to 20/40. One year later, visual acuity in the second eye deteriorated to hand motion. One month later, the first eye deteriorated to 20/400. The patient had slow improvement in each eye over a decade to 20/30 in the right and 20/100 in the left. At age 78, acuities dropped to 20/800 in each eye. A blood test revealed the 14484 mtDNA mutation. Although MRI of the brain and orbits are typically normal in patients with LHON, Phillips et al. (2003) described 2 patients with LHON in whom an MRI disclosed abnormal enhancement of the optic nerves or chiasm enlargement. Barboni et al. (2005) used optical coherence tomography (OCT) to study retinal nerve fiber layer (RNFL) thickness in patients with LHON. On the basis of OCT data, the RNFL was thickened in early LHON (ELHON, when the duration of disease was shorter than 6 months) and severely thinned in atrophic LHON (ALHON, when the duration was longer than 6 months). RNFL was likely to be partially preserved in ALHON with visual recovery. The temporal fibers (papillomacular bundle) were the first and most severely affected; the nasal fibers seemed to be partially spared in the late stage the disease. Savini et al. (2005) studied the RNFL thickness, as measured by OCT, in unaffected carriers with LHON mutations. They found a thickening of the temporal RNFL fibers in all subgroups of unaffected carriers. These differences reached statistical significance in patients carrying the 11778 mutation, whereas only a trend was detected in those with the 3460 mutation. Savini et al. (2005) concluded that their findings provided the first evidence indicating the preferential involvement of the papillomacular bundle in subclinical LHON and that males had a more diffuse involvement than females. Reviewing the findings of Barboni et al. (2005) and Savini et al. (2005), Kerrison (2005) concluded that LHON in not necessarily a monophasic disease but may manifest a latent phase with axonal thickening and normal visual function that might precede clinically significant vision loss, an acute phase of axonal injury with clinically significant loss of visual function, and a chronic phase with spontaneous improvement of vision in some individuals and reduced likelihood or recurrence. Ventura et al. (2007) investigated chromatic losses in asymptomatic carriers of the LHON 11778G-A mutation. Sixty-five percent of carriers had abnormal protan (303900) and/or deutan (303800) thresholds; some of those with higher thresholds also had elevated tritan (190900) thresholds (13%). Male carriers had color vision losses with the red-green pattern of dyschromatopsia typical of patients affected with LHON, which included elevation of tritan thresholds as well. This predominantly parvocellular (red-green) impairment was compatible with the histopathology of LHON, which affects mostly the papillomacular bundle. In contrast with male losses, female losses were less frequent and severe. In the most severe losses, the women had instances of diffuse defect. Ventura et al. (2007) suggested that hormonal factors may be of great importance in the pathophysiology of LHON.
While LHON is traditionally considered to be familial, many individuals represent isolated cases. The proportion of cases with family histories have been reported to be 43% for np 11778, to be 78% for np 3460, to be 57% ... While LHON is traditionally considered to be familial, many individuals represent isolated cases. The proportion of cases with family histories have been reported to be 43% for np 11778, to be 78% for np 3460, to be 57% for np 15257, and to be 65% for np 14484 (Newman et al., 1991; Johns et al., 1993). Families homoplasmic for these common mutations generally exhibit reduced penetrance, with the percentage of affected relatives in np 11778 families ranging from 33 to 60%, for np 3460 from 14 to 40%, for np 14484 from 27 to 80%, and for np 15257 from 27 to 80%. The common mutations also show a strong male bias in Europeans, ranging from 80% for np 11778 to 33-67% for np 3460, 68% for np 14484, and 75-100% for np 15257 (see Table M1, MIM12) (Newman et al., 1991; Johns et al., 1993). Interestingly, in Asia, greater than 90% of LHON patients harbor the np 11778 mutation, yet only 58% of the patients are males (Mashima et al., 1993). Estimates of recurrence risks differ between sexes and vary among published reports. Studies based on multiple families have suggested recurrence risks for males to be between 50 and 60%, with one study that followed males to age 50 suggesting a risk of 83%. The comparable risk for women ranges from 8 to 32%. However, the prevalence of singleton families confirmed by molecular testing indicates that these values are over-estimated. Using genetic analysis as the starting point, one Australian study proposed that the risk of visual loss for males with the np 11778 mutation is 20% and for females is 4% (Mackey and Buttery, 1992; Newman, 1993). In familial cases of LHON, all affected individuals are related through the maternal lineage, consistent with the inheritance of human mtDNA (Giles et al., 1980; Case and Wallace, 1981). However, the incomplete penetrance of the clinical phenotype obscures the strict maternal transmission of the mtDNA, and the strong male basis of expression in Europeans (Newman et al., 1991) has frequently led to the erroneous conclusion that the disease results from an X-linked recessive mutation. In fact, most if not all LHON cases are associated with specific mtDNA mutations that occur in isolation or together. Seventeen mtDNA missense mutations have been proposed to contribute to LHON (see Table M1, MIM12), though to varying degrees. Five of these are generally felt to be 'primary' mutations, the presence of which greatly increases the probability of blindness. Each disease mutation is designated by the gene followed by an asterisk (*), a phenotypic descriptor (LDYT means LHON plus dystonia), the nucleotide number, and the disease-associated base. Listed in order from highest to lowest disease-causing potential, these are MTND5*LDYT14459A (Jun et al., 1994), MTND4*LHON11778A (Wallace et al., 1988), MTND1*LHON3460A (Huoponen et al., 1991; Howell et al., 1991), MTND6*LHON14484C (Johns et al., 1992, 1993; Mackey and Howell, 1992; Howell et al., 1991), and MTCYB*LHON15257A (Brown et al., 1991; Johns and Neufeld, 1991). Three additional mutations may also be primary, but require confirmation; these are MTND5*LHON13730A (Howell et al., 1993); MTCO3*LHON9438A and MTCO3*LHON9804A (Johns and Neufeld, 1993). Nine other mutations have been found at increased frequencies in LHON patients, but generally in conjunction with one of these primary mutations. Hence, these are felt to be 'secondary' mutations which may interact with the primary mutation to increase the probability of clinical expression. Among the more important of these mutations are MTND5*LHON13708A (Brown et al., 1992; Johns and Berman, 1991); MTND1*LHON3394C (Brown et al., 1992); MTCO1*LHON7444A (Brown et al., 1992); MTND1*LHON4160C (Howell et al., 1991); and MTND2*LHON5244A (Brown et al., 1992). The criteria for ranking the severity of the primary mutations include (a) range of clinical manifestations with mild being LHON alone and the more severe involving LHON plus other neurologic disease; (b) specificity for the disease meaning the proportion of the 'normal' population that harbors the mutation; (c) association with specific mtDNA lineages with the more severe mutations being rapidly eliminated by selection and hence appearing on multiple different haplotypes; (d) co-occurrence with secondary LHON mutations with the more severe mutations able to cause LHON alone while the milder mutations require interaction with secondary mutations to cause disease; (e) heteroplasmy, with the severe mutations appearing repeatedly and hence more likely to be recent and heteroplasmic; (f) amino acid conservation with the more severe variants altering more conserved amino acids; (g) penetrance with the more severe mutations affecting a greater proportion of the maternal relatives; and (f) spontaneous recovery with the milder mutations being more prone to visual recovery (Wallace and Lott, 1993; Newman et al., 1991; Brown et al., 1992; Huoponen et al., 1993; Johns et al., 1993). The MTND6*LDYT14459A mutation (516006.0002) results in the most severe phenotype (see Table M1, MIM12). It was identified by Jun et al. (1994) in the large Hispanic family reported by Novotny et al. (1986) that showed variable clinical manifestations ranging from normal, through late-onset optic atrophy, to early-onset dystonia accompanied by bilateral basal ganglial degeneration (500001). This G-to-A transition is a new mutation that arose on the Native American haplogroup D mtDNA background. It was not found on any of 38 related mtDNA haplotypes nor in 310 control mtDNAs representing the major ethnic groups. The mutation is heteroplasmic in some maternally related family members and converts the moderately conserved alanine at position 72 in MTND6 to a valine. An alanine is found in this position in all mammals, Xenopus, and sea urchin, whereas a serine is present in all other species that have been examined. When the mutation approaches homoplasmy, the penetrance is high, with 48% of maternal relatives manifesting pediatric dystonia, 10% LHON, and 3% LHON plus dystonia (Novotny et al., 1986: Wallace et al., 1985) (see Table M1, MIM12). The next most severe mutation and the most common cause of LHON is MTND4*LHON11778A (516003.0001). It accounts for more than 50% of European cases and 95% of Asian cases, but has not been found in controls (Wallace et al., 1988; Newman et al., 1991). Whereas most individuals with this mutation present with LHON (Newman et al., 1991), 1 patient experienced central vision loss at 37 years of age and cerebellar-extrapyramidal tremor and left-side rigidity associated with bilateral basal ganglial lesions at 38 years of age(Larsson et al., 1991). The mutation has arisen repeatedly on different mtDNA lineages (Singh et al., 1989), and is occasionally found with other LHON mutations (Huoponen et al., 1993). It is frequently heteroplasmic (Lott et al., 1990), converts a highly conserved arginine to a histidine, is about 82% penetrant in males and shows only a 4% spontaneous recovery rate (see Table M1, MIM11) (Newman et al., 1991; Wallace and Lott, 1993; Johns et al., 1993). The MTND1*LHON3460A (516000.0001) mutations account for about 35% of European LHON, and has not been identified in controls (Huoponen et al., 1991; Howell et al., 1991). It has been observed on several mtDNA lineages, occasionally co-occurs with other LHON mutations, is generally homoplasmic, changes a moderately conserved alanine to a threonine, is expressed in 69% of males, and exhibits a 22% spontaneous recovery rate (see Table M1, MIM12) (Howell et al., 1991; Howell et al., 1992; Huoponen et al., 1991; Huoponen et al., 1993; Johns et al., 1993). The fourth primary mutation is MTND6*LHON14484C (516006.0001). This mutation accounts for about 20% of European LHON patients, has not been observed in 250 controls (Johns et al., 1992), and is commonly associated with specific mtDNA lineages, often in association with MTND5*LHON13708A, MTCYB*LHON15257A, or MTND1*LHON3394C. It has been homoplasmic in every case but one (Mackey and Howell, 1992), changes a weakly conserved methionine to a valine, has a penetrance in males of 82%, and a visual recovery rate of 37% (see Table M1, MIM12) (Johns et al., 1993). The mildest primary mutation is MTCYB*LHON15257A (516020.0001). This is found in about 15% of LHON patients, and in 0.3% of the general population (Brown et al., 1992). The mutation has been observed on the same mtDNA lineage, usually together with the MTND5*LHON13708A and MTND6*LHON14484C mutations in all but 1 case (Howell et al., 1993). This mutation is consistently homoplasmic, changes a highly conserved aspartate to an asparagine, has a penetrance in males of 72%, and a probability of visual recovery of 28% (see Table M1, MIM12) (Johns et al., 1993). Five secondary mutations of particular note are MTND5*LHON13708A, MTND1*LHON3394C, MTCO1*LHON7444A, MTND2*LHON5244A and MTND1*LHON4160C. The first 3 mutations are consistently homoplasmic and occur on specific mtDNA lineages prone to LHON. The MTND5*LHON13708A mutation changes a moderately conserved alanine to a threonine, is frequently associated with MTND6*LHON14484C, MTCYB*LHON15257A, and MTND1*LHON3394C mutations, and is found in about 15% of patients and in 4% of controls (Brown et al., 1992; Johns and Berman, 1991). The MTND1*LHON3394C mutation changes a highly conserved tyrosine to a histidine, is commonly associated with MTND6*LHON14484C in French Canadians, and has also been found in 1% of the general population (Brown et al., 1992; Johns et al., 1992). The MTCOI*LHON7444A mutation converts the termination codon of MTCOI to lysine. This extends the polypeptide by 3 charged amino acids, changes the protein electrophoretic mobility, and diminishes the cytochrome c oxidase specific activity 35%. The mutation is found in about 9% of patients, and also in 1% of the general population (see Table M1, MIM12)(Brown et al., 1992). The MTND1*LHON4160C and MTND2*LHON5244A mutations have been observed in individual families and appear to be relatively recent mutations. MTND1*LHON4160C converts a highly conserved leucine to a proline and is associated with the MTND6*LHON14484C mutation (Howell et al., 1991). This combination is associated with amblyopia in more than 80% of family members and with neurodegenerative disease in many individuals. One branch of the family also harbors the MTND1*LHON4136G mutation, which as has been proposed to ameliorate some of the symptoms (Wallace, 1970; Howell et al., 1991). The MTND2*LHON5244A mutation occurred on a MTND6*LHON14484C + MTCYB*LHON15257A haplotype. It changed a highly conserved glycine to a serine (Brown et al., 1992) and probably was an important contributor to the disease in this patient. The remaining LHON mutations are of ambiguous significance. MTCYB*LHON15812A mutation converts a moderately conserved valine to a methionine and is consistently found with MTND6*LHON14484C and MTCYB*LHON15257A mutations on a specific mtDNA lineage (Brown et al., 1992). The MTND1*LHON4216C and MTND2*LHON4917G mutations alter poorly and highly conserved amino acids, respectively, and are in somewhat higher frequencies in LHON patients (Johns and Berman, 1991). Chinnery et al. (2001) described 2 LHON pedigrees that harbored the same novel point mutation within the MTND6 gene at position 14495. The mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on 2 independent occasions. Protein modeling studies indicated that the 7 known mutations in the MTND6 gene that cause LHON lie in close proximity in a hydrophobic cleft or pocket. The authors concluded that this was the first evidence for a relationship between a specific structural domain within a mitochondrial respiratory chain subunit and a specific disease phenotype. They suggested that the MTND6 gene be sequenced in all patients with clinical LHON who do not harbor one of the 3 primary LHON mutations at basepair 11778 (MTND4), 3460 (MTND1), or 14484 (MTND6). Fauser et al. (2002) sequenced the complete mitochondrial DNA in 14 LHON patients with typical clinical features but without a primary mtDNA mutation. The results suggested that the mutation at np 15257 should be included in a routine screening, as well as the ND6 gene (516006), a hotspot for LHON mutations. Fauser et al. (2002) suggested that screening for the secondary LHON mutations at np 4216 and np 13708 might also help in making the diagnosis of LHON, as these changes seem to modify the expression of LHON mutations. The male bias and incomplete penetrance of LHON in Europeans has led to the hypothesis that blindness results when two factors coincide, a maternally inherited mtDNA mutation and an X-linked recessive mutation (308905). In a model based on this hypothesis, the penetrance for females was estimated at 0.11 +/- 0.02, and the frequency of the X-linked gene was estimated at 0.08 (Bu and Rotter, 1991). Support for this model was obtained from X-chromosome linkage studies which revealed a linkage between LHON susceptibility and the DXS7 chromosomal marker, with a LOD score of 2.32 (Vilkki et al., 1991). However, this linkage has not been confirmed by other groups (Chen et al., 1989; Chen and Denton, 1991; Carvalho et al., 1992; Sweeney et al., 1992). Oostra et al. (1994) described the distribution of 7 different mtDNA mutations and the associated clinical findings in 334 LHON patients belonging to 29 families. Mutations described only in LHON at nucleotide positions 11778, 3460, and 14484 were found in 15, 2, and 9 families, respectively. In 3 families, none of these mutations was found. Mutations described in LHON but also in controls at nucleotide positions 15257, 13708, 4917, and 4216 were found in 1, 10, 3, and 12 families, respectively. Combinations of mtDNA mutations were found in most families. In 11 families in which only the 11778 mutation was found, affected males had a mean age of onset of 29.2 years and a mean visual outcome of 0.113. Observations in groups of patients with other mutations indicated that the clinical severity is dependent on the mitochondrial genotype. Mackey et al. (1996) screened 159 LHON families of northern European origin living in Australia, New Zealand, the United Kingdom (including Ireland), the Netherlands, Denmark, and Finland. These pedigrees comprised more than 12,000 maternally related individuals and more than 1,500 affected individuals. In the 159 families, 153 (97%) carried 1 of the 3 previously identified primary LHON mutations at nucleotides 3460 (13% of the 159 LHON families), 11778 (69%), or 14484 (14%). The primary mutation was not identified in the other families. The 15257 mutation occurred in 6 of the 159 LHON families. However, in every one of these instances, it was associated with 1 of the 3 established LHON mutations: 11778 (4 of 78 families), 3460 (1 of 14 families), and 14484 (1 of 23 families). Because it did not occur in isolation of an established primary LHON mutation, the results did not support a primary pathogenic role for the 15257 mutation. Liu et al. (2011) investigated the molecular pathogenesis of LHON in 6 Han Chinese families in which 9 (6 males/3 females) of 86 matrilineal relatives exhibited variable severity and age of onset of optic neuropathy. The average age of onset was 20 years. Molecular analysis of mtDNA in these families identified the homoplasmic ND5 12338T-C mutation (516005.0011) and a distinct set of variants belonging to the Asian haplogroup F2. The 12338T-C mutation was present in the maternal lineage of the 6 pedigrees and not in 178 Chinese controls.
Carelli et al. (2006) evaluated the mtDNA of 87 index cases with LHON sequentially diagnosed in Italy, including an exceedingly large Brazilian family of Italian maternal ancestry. The results revealed that the large majority of the LHON mutations ... Carelli et al. (2006) evaluated the mtDNA of 87 index cases with LHON sequentially diagnosed in Italy, including an exceedingly large Brazilian family of Italian maternal ancestry. The results revealed that the large majority of the LHON mutations in affected Italian families are due to independent mutational events; only 7 pairs of families and 3 triplets of families showed identical haplotypes. Thus, the study confirmed that the preferential association of the LHON mutations 11778/ND4 (516003.0001) with haplogroups J1 and J2 and 14484/ND6 (516006.0001) with haplotype J1 is attributable not to founder events but to a true mtDNA background effect. In the case of the 11778/ND4 mutation, such a role of the mtDNA background was narrowed to the subclades J1c and J2b, which both, intriguingly, harbor unique combinations of amino acid changes in cytochrome b (516020). Carelli et al. (2006) reinvestigated the genealogies of the families with identical haplotypes and were able to reconnect 3 pairs of families, including the Brazilian family and its Italian counterpart, into extended pedigrees. The survey of the 2 control region sites that were heteroplasmic in the Brazilian family showed triplasmy in most cases, but there was no evidence of the tetraplasmy that would be expected in the case of mtDNA recombination. In affected members of a 3-generation Chinese family exhibiting high penetrance and expressivity of visual impairment due to LHON, Qu et al. (2006) identified the homoplasmic 11778G-A mutation as well as a novel secondary homoplasmic mutation, 4435A-G, belonging to the Asian haplogroup D5. In a European multicenter study of 3,613 individuals with LHON from 159 different families, Hudson et al. (2007) found evidence that clinical penetrance of the 3 most common mtDNA mutations is influenced by mtDNA haplotype group. The risk of visual failure was greater when the 11778G-A or 14484T-C mutations were present in haplotype subgroups J2 and J1, respectively, and when the 3460G-A mutation occurred in haplotype K. In contrast, the risk of visual failure was slightly decreased (OR = 0.79) when 11778G-A was present on haplotype H. By examining data from a population-based study (1970-2004), Puomila et al. (2007) estimated that the prevalence of LHON in Finland is 1 in 50,000, and that 1 in 9,000 Finns is a carrier of 1 of the 3 LHON primary mutations (MTND4, 11778G-A; MTND1, 3460G-A; and MTND6, 14484T-C). Spruijt et al. (2006) investigated the genotype/phenotype correlation of the 3 major LHON mutations in the Dutch population. They found that the specific mtDNA mutation did not influence disease penetrance (50% in male subjects; 10-20% in female subjects). Regardless of the acuteness of disease onset, more than 50% of patients with the MTND6 14484C mutation exhibited partial recovery of vision, whereas only 22% of the MTND4 11778A carriers and 15.4% of the MTND1 3460A carriers recovered. The recovery did not take place within the first year after onset and was uncommon after 4 years. In general, onset of LHON is very acute but might be more gradual in 11778A carriers and in children. Spruijt et al. (2006) concluded that the LHON genotype influences the recovery of vision and disease onset but is unrelated to age, acuteness of onset, or gender. By studying the penetrance of LHON in 1,859 individuals from 182 Chinese families (including 1 from Cambodia) with the MTND4 11778G-A mutation (516003.0001), Ji et al. (2008) found that mitochondrial haplogroup M7b1-prime-2 was associated with increased risk of visual loss, whereas the M8a haplogroup was associated with decreased risk of visual loss. Further sequence analysis suggested that the M7b1-prime-2 effect was due to variation in the MTND5 gene, and that the M8a effect was due to variation in the MTATP6 gene.
Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless subacute visual failure that develops during young adult life. Males are four to five times more likely than females to be affected [Yu-Wai-Man et al 2009]....
DiagnosisClinical DiagnosisLeber hereditary optic neuropathy (LHON) is characterized by bilateral, painless subacute visual failure that develops during young adult life. Males are four to five times more likely than females to be affected [Yu-Wai-Man et al 2009].Acute phase Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye; similar symptoms appear in the other eye an average of two to three months later. In about 25% of cases, visual loss is bilateral at onset. The ocular fundus may have a characteristic appearance that includes disk swelling, edema of the peripapillary nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity. These changes can be subtle, and approximately 20% of affected individuals show no fundal abnormalities. Visual acuity is severely reduced to counting fingers or worse in the majority of cases, and visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. Atrophic phase. After the acute phase, the optic discs become atrophic within six weeks of disease onset. Significant improvements in visual acuity are rare, and in most individuals, vision remains severely impaired, within the legal requirement for blind registration. Other findings. The pathologic hallmark of LHON is the selective degeneration of the retinal ganglion cell layer and optic nerve. Although visual failure is the defining clinical feature in this mitochondrial genetic disorder, cardiac arrhythmias and neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in controls [Man et al 2002]. In addition, there is a well-established association between all three primary LHON-causing mtDNA mutations (see Table 1) and an MS-like illness among persons of European origin, especially females [Kellar-Wood et al 1994, Jansen et al 1996, Bhatti & Newman 1999, Palace 2009]. Family history. Affected individuals are often aware of other affected family members, but up to 40% have no family history [Harding et al 1995]. These families most likely represent cases where family history is difficult to trace, given that de novo mutation is rare in LHON [Biousse et al 1997, Man et al 2003]. Electrophysiologic studies (pattern electroretinogram and visual evoked potentials) confirm optic nerve dysfunction and the absence of retinal disease. Note: These ancillary investigations are not usually necessary unless the diagnosis is uncertain.Cranial neuroimaging is necessary to exclude other compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. In individuals presenting with LHON, magnetic resonance imaging (MRI) is often normal but may reveal a high signal within the optic nerves, the latter probably representing slight edema or gliosis in the acute and atrophic phase, respectively. TestingBiochemical studies. Although the three primary LHON-causing mtDNA mutations all affect different respiratory chain complex I subunit genes, the mutations are not always associated with a respiratory chain abnormality that can be measured in vitro [Brown 1999]. The absence of a respiratory chain complex defect therefore does not rule out the possibility of LHON. In a small number of in vivo studies using phosphorus magnetic resonance spectroscopy, the most consistent defect of mitochondrial function was identified in individuals with the m.1778G>A mutation; it was not found among those with the m.3460G>A mutation (Table 1). A striking feature of all the biochemical studies is that none found a significant difference between affected and unaffected individuals with a disease-causing mtDNA LHON-causing mutation. Balancing the current weight of evidence, LHON is associated with a respiratory chain defect that is more subtle than that seen in other mitochondrial genetic disorders. Note: (1) These discrepancies highlight the lack of understanding of the relationship between the mtDNA defect, the biochemical defect, and the clinical phenotype. (2) Biochemical studies have been superseded by molecular genetic testing and these are only indicated when establishing pathogenicity for novel putative LHON-causing mtDNA variants.Table 1. Respiratory Chain Dysfunction in LHONView in own windowMitochondrial DNA MutationIn VitroIn VivoComplex I Activity 1 Respiratory Rate 1 MRS 1 m.3460G>A 60%-80%30%-35%0%m.11778G>A 0%-50%30%-50%75%m.14484T>C 0%-65%10%-20%50%See references in Man et al [2002].1. % of decrease relative to controlsMolecular Genetic TestingGenes. Mutations in the mitochondrial genes that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6, are known to be associated with LHON (Table 5). Mutations in three additional mitochondrial genes, MT-CYB, MT-CO3, and MT-ATP6 are also thought to cause LHON but require further confirmation as they have only been found in single affected individuals or a single family. Clinical testing Targeted mutation analysis Primary pathogenic LHON-causing mtDNA mutations. The primary pathogenic mtDNA mutations described below have been seen only in families with LHON. In one large study [Mackey et al 1996], 90% of individuals with LHON were found to have one of three point mutations of mtDNA: m.11778G>A (MT-ND4) [Wallace et al 1988], m.14484T>C (MT-ND6) [Johns et al 1992a], or m.3460G>A (MT-ND1) [Howell et al 1992]. The prevalence of each mutation varies worldwide, but the m.11778G>A mutation is by far the most common, accounting for approximately 70% of cases among Northern European populations [Mackey et al 1996]. Among French Canadians, the m.14484T>C mutation is the most common cause of LHON as a result of a founder effect [Macmillan et al 1998], but this mutation is relatively uncommon in the United Kingdom and in Scandinavia [Mackey et al 1996, Chinnery et al 2000]. Approximately 10% of individuals with LHON do not harbor one of the three common mtDNA point mutations; further investigation of these families is complex because mtDNA is highly polymorphic [Chinnery et al 1999b, Taylor et al 2003]. A number of putative mtDNA LHON-causing mutations have been described in a single family or singleton cases; however, a novel mtDNA base change cannot be considered pathogenic until it has been observed independently on two or more occasions and only in association with LHON, showing clear segregation with affected disease status.Secondary LHON-associated mtDNA variants (i.e., variants prevalent in the general population that have also been identified at higher frequencies in LHON) (e.g., m.4216T>C, m.13708G>A, m.15257G>A) [Howell et al 1995]; the interpretation and significance of these mtDNA changes is complex, and such testing is therefore not performed routinely. Sequence analysis and mutation scanning detect additional mtDNA nucleotide variants in the remaining 10% of individuals with LHON who do not harbor one of the three most common mtDNA mutations (m.3460G>A, m.11778G>A, and m.14484T>C). Table 2. Summary of Molecular Genetic Testing Used in LHONView in own windowGene SymbolsProportion of LHON Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityMT-ND4~90%Targeted mutation analysism.11778G>A ClinicalMT-ND6m.14484T>C MT-ND1m.3460G>A Select mitochondrial genes 1~10%Sequence analysis / mutation scanning of entire mitochondrial genome 2Other mtDNA sequence variants 31. See Table 5.2. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected.Interpretation of test results. Heteroplasmy, a mixture of mutant and wild-type mtDNA in leukocytes, occurs in approximately 10%-15% of individuals with LHON [Smith et al 1993, Man et al 2003]. Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutant mtDNA in leukocytes, which is easily detected by standard techniques. It is possible that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [Chinnery et al 2001]; however, no rigorous prospective studies have been performed to clarify this possibility.Testing StrategyTo confirm/establish the diagnosis in a probandAn individual suspected of having LHON should have molecular genetic testing for the three common mtDNA point mutations (targeted mutation analysis) [Yu-Wai-Man et al 2009]. If one of the three most common (primary) mtDNA LHON-causing mutations is not identified (m.3460G>A, m.11778G>A, and m.14484T>C), the individual's history and examination findings should be carefully reassessed to confirm the diagnosis. Complete mtDNA sequencing should be carried out if clinical suspicion remains high and there is no evidence of paternal transmission. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersMitochondrial DNA mutations are responsible for a heterogeneous group of inherited diseases (see Mitochondrial Disorders Overview) that often cause a progressive neurologic disorder in association with multi-organ involvement (e.g., diabetes mellitus, cardiomyopathy) [Chinnery & Turnbull 1999, Chinnery et al 1999a].
Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The peak age of onset in LHON varies between the second and third decades of life depending on the published case series, with 95% of those who lose their vision doing so before the age of 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life [Buchan et al 2007]. Males are four to five times more likely to be affected than females, but neither gender nor mutational status significantly influences the timing and severity of the initial visual loss....
Natural HistoryLeber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The peak age of onset in LHON varies between the second and third decades of life depending on the published case series, with 95% of those who lose their vision doing so before the age of 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life [Buchan et al 2007]. Males are four to five times more likely to be affected than females, but neither gender nor mutational status significantly influences the timing and severity of the initial visual loss.In the presymptomatic phase, fundal abnormalities such as peripapillary telangiectatic vessels and variable degrees of retinal nerve fiber layer edema have been previously documented and these can vary with time [Nikoskelainen 1994]. Using optical coherence tomography imaging, thickening of the temporal retinal nerve fiber layer was confirmed in clinically unaffected individuals with an LHON-causing mtDNA mutation, further evidence that the papillomacular bundle is selectively vulnerable in LHON [Savini et al 2005]. On more detailed investigation, some individuals with an LHON-causing mtDNA mutation can also exhibit subtle impairment of optic nerve function including: (a) loss of color vision affecting mostly the red-green system, (b) reduced contrast sensitivity, and (c) subnormal electroretinogram and visual evoked potential [Sadun et al 2006].Following onset of the acute phase, affected individuals report worsening, blurring, or clouding of central vision. Both eyes are affected within six months. The most characteristic feature is an enlarging central or centrocecal scotoma and as the field defect increases in size, visual acuity deteriorates in approximately 80% of persons to the level of counting fingers or worse. Following the nadir, visual acuity may improve; such improvement is more likely in individuals with the m.14484T>C mutation than in those with the m.11778G>A mutation.The atrophic phase is characterized by bilateral optic atrophy and dense central scotomata. Most persons remain severely visually impaired and are within the legal requirements for blind registration [Kirkman et al 2009a].Other neurologic features associated with LHON. Minor neurologic abnormalities (e.g., postural tremor, peripheral neuropathy, nonspecific myopathy, movement disorders) are said to be common in individuals with LHON [Nikoskelainen et al 1995] but are rarely clinically significant. Some individuals with LHON, usually women, may develop a progressive multiple sclerosis (MS)-like illness. In addition to a severe bilateral optic neuropathy, these individuals manifest disseminated central nervous system demyelination, with characteristic periventricular white matter lesions and unmatched cerebrospinal fluid oligoclonal bands [Bhatti & Newman 1999, Horvath et al 2000, Palace 2009]. (See Multiple Sclerosis Overview.)In a few families, mtDNA complex I mutations cause optic atrophy in association with severe neurologic deficits including ataxia, dystonia, and encephalopathy [Jun et al 1994, De Vries et al 1996, Gropman et al 2004, Tarnopolsky et al 2004, Watanabe et al 2006].Two mtDNA complex I point mutations, m.3376G>A and m.3697G>A, have been identified in persons with clinical features of both LHON and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) [Blakely et al 2005, Spruijt et al 2007].Cardiac conduction defects and LHON. A number of studies have shown an increased incidence of cardiac accessory pathways in association with LHON [Nikoskelainen 1994].
Distinct phenotypes are associated with specific LHON-causing mutations:...
Genotype-Phenotype CorrelationsDistinct phenotypes are associated with specific LHON-causing mutations:m.11778G>A generally causes the most severe visual failure with little chance of recovery. m.14484T>C is associated with the best long-term visual outcome. m.3460G>A has an intermediate phenotype. Reported visual recovery rates among persons with LHON are summarized in Table 3.Table 3. Visual Recovery Rates by Mutation in Individuals with LHONView in own windowMitochondrial DNA MutationVisual RecoveryReferencesm.11778G>A 4%-25%Newman et al [1991], Harding et al [1995] m.14484T>C 37%-58%Johns et al [1993], MacMillan et al [1998] m.3460G>A 22%-25%Johns et al [1992b], Harding et al [1995] A multiple sclerosis-like illness has been reported in association with all three primary mtDNA LHON-causing mutations (m.3460G>A, m.11778G>A, and m.14484T>C) (reviewed in Yu-Wai-Man et al [2009]).
If the ophthalmologic assessment (including an assessment of acuity, color vision, visual fields, and electrophysiology) and molecular genetic testing leave any uncertainty about the diagnosis of Leber hereditary optic neuropathy (LHON), further evaluation of the anterior visual pathways and brain with contrast MRI and lumbar puncture are appropriate to exclude other potentially treatable optic neuropathies....
Differential DiagnosisIf the ophthalmologic assessment (including an assessment of acuity, color vision, visual fields, and electrophysiology) and molecular genetic testing leave any uncertainty about the diagnosis of Leber hereditary optic neuropathy (LHON), further evaluation of the anterior visual pathways and brain with contrast MRI and lumbar puncture are appropriate to exclude other potentially treatable optic neuropathies.Acute phase. A wide range of non-genetic causes of bilateral visual failure must be excluded during the acute phase. Atrophic phase. If an individual is only seen at this stage, it can be difficult to exclude other possible causes of optic atrophy, especially if there is no clear maternal family history. In these cases, neuroimaging of the anterior visual pathways is mandatory while awaiting the results of molecular genetic testing. LHON must also be distinguished from other causes of sporadic and inherited optic neuropathies such as deafness-dystonia-optic neuropathy (DDON). This disorder is characterized by prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment seems constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the following evaluations are recommended:Measurement of best corrected visual acuity Assessment of visual fields with static or kinetic perimetryECG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have an LHON-causing mtDNA mutation. However, such a finding does not necessitate further intervention in the absence of cardiac symptoms. It is also recommended to screen for possible associated systemic complications including diabetes mellitus and cardiomyopathy, which can further compound the visual impairment among individuals with LHON.Treatment of ManifestationsManagement of affected individuals is supportive and includes provision of visual aids, occupational rehabilitation, and registration with the relevant local social services. SurveillanceOngoing surveillance of asymptomatic individuals harboring LHON-causing mtDNA mutations is not necessary; however, they should be advised to seek immediate medical attention should they experience any visual disturbance. The frequency of follow-up for affected individuals varies depending on the individual’s circumstances and the availability of healthcare locally.Agents/Circumstances to AvoidIndividuals harboring established LHON-causing mtDNA mutations should be strongly advised not to smoke and to moderate their alcohol intake, avoiding binge-drinking episodes. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationIdebenone. Small case series have reported that oral administration of idebenone (a short-chain synthetic benzoquinone; 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone) and/or vitamin supplementation (B12 and C) can speed up visual recovery and improve final visual outcome in people with LHON [Mashima et al 2000, Carelli et al 2001]. A subsequent report of two individuals with LHON showed no visual benefit from idebenone and multivitamin supplementation [Barnils et al 2007]. To address these conflicting anecdotal findings a phase II, double-blind, randomized placebo-controlled trial was recently completed investigating the efficacy, safety, and tolerability of oral idebenone in LHON – RHODOS (Rescue of Hereditary Optic Disease Outpatient Study). In total, 85 affected individuals harboring one of the three primary mtDNA LHON-causing mutations (m.3460G>A, m.11778G>A, and m.14484T>C) were successfully enrolled into this multicenter study [Klopstock et al, in press]. Research subjects were assigned in a two-to-one randomization ratio to receive either idebenone (at a dose of 300 mg/3x/day) or placebo. This dose of idebenone was found to be safe with no significant drug-related adverse events. Patients with discordant visual acuities (defined as a difference of >0.2 LogMAR between the two eyes) and at highest risk for further visual loss in the least affected eye were more likely to benefit from treatment with idebenone. High-dose oral idebenone should therefore be considered as a treatment option, especially for individuals with LHON with relatively recent disease onset [Klopstock et al 2011]. No experimental data addressing prophylactic use of idebenone among asymptomatic individuals with mtDNA mutations are available.EPI-743. In an open-label study of five patients with acute LHON treated within 90 days of disease conversion, the antioxidant α-tocotrienol-quinone (EPI-743), a vitamin E derivative, has shown early promise [Sadun et al 2012]. An adequately powered, double-blind, randomized placebo-controlled trial is needed to confirm the visual benefit of this agent in both acute and chronic LHON [Sadun et al 2012].Gene therapy. Although key issues of safety and efficacy need to be further addressed before their application to human clinical trials, targeted gene therapy for LHON is being actively explored [Qi et al 2003, Qi et al 2004, Qi et al 2007, Lam et al 2010].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Leber Hereditary Optic Neuropathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameMT-ND6MitochondriaNADH-ubiquinone oxidoreductase chain 6MT-ND4MitochondriaNADH-ubiquinone oxidoreductase chain 4MT-ND1MitochondriaNADH-ubiquinone oxidoreductase chain 1MT-ATP6MitochondriaATP synthase subunit aMT-ND5MitochondriaNADH-ubiquinone oxidoreductase chain 5MT-CYBMitochondriaCytochrome bMT-CO3MitochondriaCytochrome c oxidase subunit 3MT-ND2MitochondriaNADH-ubiquinone oxidoreductase chain 2MT-ND4LMitochondriaNADH-ubiquinone oxidoreductase chain 4LData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Leber Hereditary Optic Neuropathy (View All in OMIM) View in own window 516000COMPLEX I, SUBUNIT ND1; MTND1 516001COMPLEX I, SUBUNIT ND2; MTND2 516003COMPLEX I, SUBUNIT ND4; MTND4 516004COMPLEX I, SUBUNIT ND4L; MTND4L 516005COMPLEX I, SUBUNIT ND5; MTND5 516006COMPLEX I, SUBUNIT ND6; MTND6 516020CYTOCHROME b OF COMPLEX III; MTCYB 516050CYTOCHROME c OXIDASE III; MTCO3 516060ATP SYNTHASE 6; MTATP6 535000LEBER OPTIC ATROPHYMolecular Genetic PathogenesisSee Mitochondrial Disorders Overview.Although Leber hereditary optic neuropathy (LHON) has a well-defined and focal phenotype, the pathophysiology is complex [Howell 1997]. The primary pathology in LHON involves the retinal ganglion cell layer, but it is not known how the mtDNA mutations actually cause such a focal neurodegenerative disease. It is also not known why otherwise entirely healthy individuals suddenly develop optic nerve dysfunction in young adulthood. The incomplete penetrance and predilection for males to lose vision also imply that additional genetic and/or environmental factors must modulate the phenotypic expression of LHON (see Risk Factors for Visual Loss). Alternatively, the gender bias could also result from a combination of subtle anatomic, hormonal, and/or physiologic variations between males and females.Normal allelic variants. See Mitochondrial Disorders Overview. Pathologic allelic variants. See Mitochondrial Disorders Overview. Many different mtDNA mutations have been associated with LHON in the literature and in numerous online databases. Some of these changes are rare polymorphisms and some are common sequence variants in the normal population. Great caution should be exercised in attributing significance to a "rare" LHON-causing mtDNA mutation found in a single affected individual or family.Table 5 includes only those mtDNA mutations that have strong evidence of pathogenicity.Note: The information in Table 5 is provided by the authors of this GeneReview; it has not been reviewed by GeneReviews staff.Table 5. Pathologic Allelic Variants in Mitochondrial DNA Associated with LHONView in own window% of Mutant AllelesMitochondrial DNA Nucleotide Change Gene SymbolProtein Amino Acid ChangeReference Sequences 1 90%m.11778G>AMT-ND4 p.Arg340HisAC_000021.2 NP_536852.1 m.14484T>CMT-ND6 p.Met64ValAC_000021.2 NP_536854.1 m.3460G>AMT-ND1 p.Ala53ThrAC_000021.2 NP_536843.1 10%2m.3635G>A m.3733G>Ap.Glu143Lysm.4171C>Ap.Leu289Metm.10663T>CMT-ND4L p.Val65AlaAC_000021.2 NP_536851.1 m.14459G>AMT-ND6 p.Ala72ValAC_000021.2 NP_536854.1 m.14482C>Am.14482C>G p.Met64Ile m.14495A>Gp.Leu60Ser m.14568C>TSee Quick Reference for an explanation of nomenclature. (Note: The mitochondrial genetic code varies from the genomic genetic code given in the Quick Reference. For the genetic code, gene structure, and other features of the mitochondrial genome see MITOMAP: A Human Mitochondrial Genome Database at www.mitomap.org, 2007). Variants are named according to current nomenclature guidelines (www.hgvs.org). 1. AC_000021.2 is the mitochondrial DNA Cambridge reference sequence [Anderson et al 1982, Andrews et al 1999].2. This represents the group of patients with a clinical diagnosis of LHON but who are not found to harbor one of the three most common mtDNA mutations. This group also includes those mtDNA variants thought to cause LHON, but who require further confirmation for pathogenicity (Table 6).Note: The information in Table 6 is provided by the authors of this GeneReview; it has not been reviewed by GeneReviews staff.Table 6. Putative Pathologic Allelic Variants in Mitochondrial DNA Associated with LHONView in own windowMitochondrial DNA Nucleotide Change Gene SymbolProtein Amino Acid ChangeReference Sequences 2 m.3376G>AMT-ND1m.3635G>AMT-ND1m.3697G>AMT-ND1m.3700G>AMT-ND1m.4025C>TMT-ND1m.4160T>CMT-ND1m.4640C>AMT-ND2m.5244G>AMT-ND2m.10237T>CMT-ND3m.11696G>AMT-ND4m.11253T>CMT-ND4m.12811T>CMT-ND5m.12848C>TMT-ND5m.13637A>GMT-ND5m.13730G>AMT-ND5m.14325T>CMT-ND6m.14568C>TMT-ND6m.14729G>AMT-ND6m.14498C>TMT-ND6m.14596A>TMT-ND6m.9101T>CMT-ATP6 p.Ile192ThrAC_000021.2 NP_536848.1 m.9804G>AMT-CO3 p.Ala100ThrAC_000021.2 NP_536849.1 m.14831G>AMT-CYB p.Ala29ThrAC_000021.2 NP_536855.1 See Quick Reference for an explanation of nomenclature. (Note: The mitochondrial genetic code varies from the genomic genetic code given in the Quick Reference. For the genetic code, gene structure, and other features of the mitochondrial genome see MITOMAP: A Human Mitochondrial Genome Database at www.mitomap.org, 2007). Variants are named according to current nomenclature guidelines (www.hgvs.org). 1. The variants in these genes are thought to be pathogenic in LHON but require further confirmation, as they have been identified only in single affected individuals or a single family. (www.mitomap.org)2. AC_000021.2 is the mitochondrial DNA Cambridge reference sequence [Anderson et al 1982, Andrews et al 1999].Normal gene product. See Mitochondrial Disorders Overview. Abnormal gene product. See Mitochondrial Disorders Overview.