Clinical Features of Chinese Sporadic Leber Hereditary Optic Neuropathy Caused by Rare Primary mtDNA Mutations

Objective: The primary aim of this study was to describe clinical features of Chinese sporadic Leber hereditary optic neuropathy (LHON) caused by rare primary mitochondrial DNA (mtDNA) mutations. Methods: We characterized a Chinese patient cohort with rare primary mtDNA mutations at Beijing Tongren Hospital between 2015 and 2018. The clinical features of these patients were retrospectively recorded and analyzed. Results: Sixteen patients with LHON who had the selected rare primary mutations, including m.4171C>A (3 patients), m.10197G>A (1 patient), m.14459G>A (4 patients), and m.14502T>C (8 patients), were evaluated. The mean age at disease onset was 15 ± 6 years, and the male to female ratio was 15:1. Of 32 eyes of all patients, 75% (24/32) had a worst Snellen best-corrected visual acuity ≤0.1 (worse than 20/200), while 67% (2/3) who were carrying the m.4171C>A mutation experienced significant visual improvement. In addition, 40% (2/5) of patients with LHON carrying only m.14502T>C mutation had only mild visual impairment. Isolated manifestations of LHON was present in 94% (15/16) of all patients; 1 patient with the m.14459G>A mutation had LHON plus dystonia. Brain MRI T2 short tau inversion recovery sequences demonstrated optic atrophy in 62.5% (10/16); increased T2 signal in the optic nerve was found in 38% (6/16) of patients. The patient with LHON plus dystonia demonstrated optic atrophy and increased T2 signal in basal ganglia. Conclusion: Patients with LHON and rare primary mutations have diverse clinical phenotypes. Those with the m.4171C>A mutation are more likely to have a good visual prognosis, while the m.14502T>C mutation may play a synergistic role in disease onset. Increased signal in the optic nerve on MRI is not rare, and this feature should not exclude LHON as the potential cause for optic neuropathy.

Original Contribution Clinical Features of Chinese Sporadic Leber Hereditary Optic Neuropathy Caused by Rare Primary mtDNA Mutations Shilei Cui, MD, PhD, Ling Yang, MD, PhD, Hanqiu Jiang, MD, PhD, Jingting Peng, MD, PhD, Jun Shang, MD, Jiawei Wang, MD, PhD, Xiaojun Zhang, MD, PhD Objective: The primary aim of this study was to describe clinical features of Chinese sporadic Leber hereditary optic neuropathy (LHON) caused by rare primary mitochondrial DNA (mtDNA) mutations. Methods: We characterized a Chinese patient cohort with rare primary mtDNA mutations at Beijing Tongren Hospital between 2015 and 2018. The clinical features of these patients were retrospectively recorded and analyzed. Results: Sixteen patients with LHON who had the selected rare primary mutations, including m.4171C.A (3 patients), m.10197G.A (1 patient), m.14459G.A (4 patients), and m.14502T.C (8 patients), were evaluated. The mean age at disease onset was 15 ± 6 years, and the male to female ratio was 15:1. Of 32 eyes of all patients, 75% (24/32) had a worst Snellen best-corrected visual acuity #0.1 (worse than 20/200), while 67% (2/3) who were carrying the m.4171C.A mutation experienced significant visual improvement. In addition, 40% (2/5) of patients with LHON carrying only m.14502T.C mutation had only mild visual impairment. Isolated manifestations of LHON was present in 94% (15/16) of all patients; 1 patient with the m.14459G.A mutation had LHON plus dystonia. Brain MRI T2 short tau inversion recovery sequences demonstrated optic atrophy in 62.5% (10/16); increased T2 signal in the optic nerve was found in 38% (6/16) of patients. The patient with LHON plus dystonia demonstrated optic atrophy and increased T2 signal in basal ganglia. Conclusion: Patients with LHON and rare primary mutations have diverse clinical phenotypes. Those with the m.4171C.A mutation are more likely to have a good visual prognosis, while the m.14502T.C mutation may play a synergistic role in disease onset. Increased signal in the optic Department of Neurology (SC, HJ, JP, JW, XZ), Beijing Tongren Hospital, Capital Medical University, Beijing, China; and Medical Research Center (LY, JS), Beijing Tongren Hospital, Capital Medical University, Beijing, China. nerve on MRI is not rare, and this feature should not exclude LHON as the potential cause for optic neuropathy. Journal of Neuro-Ophthalmology 2020;40:30–36 doi: 10.1097/WNO.0000000000000799 © 2019 by North American Neuro-Ophthalmology Society L eber hereditary optic neuropathy (LHON) is a maternally inherited disease associated with a complex I defect caused by mitochondrial DNA (mtDNA) point mutation. To date, there exists a list of “top 19” point mutations that are generally accepted as primary LHON mutations (http://www.mitomap.org/). Of these, the 3 most common primary mutations (m.11778G.A/MTND4, m.3460G.A/MT-ND1, and m.14484T.C/MTND6) constitute approximately 90% of all LHON cases, while the rest of the 16 mutations are known as rare primary mutations (1). Although the clinical features and many possible treatments for LHON caused by the 3 most common primary mutations have been well-studied, especially in the case of the m.11778G.A mutation (2–5), there exists only a very small amount of clinical data on the subject of patients with LHON with rare primary mutations. At present, although there are not many cases published involving rare primary mutations, the literature shows obvious clinical phenotypic diversity. In this investigation, we report and review the clinical features of LHON caused by rare primary mutations; these characteristics include age at onset, sex, worst best-corrected visual acuity (BCVA), clinical phenotype, and neuroimaging features. The authors report no conflicts of interest. PATIENTS AND METHODS Address correspondence to Shilei Cui, MD, PhD, Department of Neurology, Beijing Tongren Hospital, Capital Medical University, NO. 1 Dongjiaominxiang Street, Dongcheng District, Beijing, 100730 China; E-mail: [e-mail] This study was performed with the approval of the ethics committee of Beijing Tongren Hospital, Capital Medical University. Each patient signed an informed consent form 30 Cui et al: J Neuro-Ophthalmol 2020; 40: 30-36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution and was treated in accordance with the tenets of the Declaration of the Helsinki. Venous blood samples of patients with a clinical diagnosis of LHON were collected at Beijing Tongren Hospital from January 2015 to April 2018. DNA samples were extracted from the venous blood, and sequencing of mtDNA fragments targeting the “top 19” mutations was performed. The top 19 primary LHON mutations reported in MITOMAP include (https://www.mitomap.org/foswiki/bin/view/ MITOMAP/MutationsLHON): m.11778G.A, m.3460G.A, m.14484T.C, m.3376G.A, m.3635G.A, m.3697G.A, m.3700G.A, m.3733G.A, m.4171C.A, m.10197G.A, m.10663T.C, m.13051G.A, m.13094T.C, m.14459G.A, m.14482C.A, m.14482C.G, m.14495A.G, m.14502T.C, and m.14568C.T. The clinical diagnostic criteria of LHON for participation in mutation screening were as follows (1): 1) bilateral acute or subacute painless central visual loss, 2) bilateral central or centrocaecal scotoma on visual field testing, 3) visual evoked potentials confirming optic nerve dysfunction, and 4) exclusion of optic neuropathy with known causes and retinopathy by way of detailed ophthalmological and neurological examinations (slitlamp biomicroscopy, intraocular pressure measurement, fundus photography, optical coherence tomography, brain and optic nerve MRI, lumber puncture, and cerebrospinal fluid analysis). We retrospectively reviewed the clinical data and results of mtDNA screening. Clinically diagnosed LHON patients with rare primary mutations were enrolled in this study, and visual and neurological outcomes were measured. m.14459G.A–positive patient whose clinical manifestations were decreased vision with dystonia. In this study, 81% (13/16) of patients received highdose corticosteroid therapy as part of their clinical care. Of the 32 eyes included in this study, 75% (24/32) had a worst Snellen BCVA score of 0.1 or worse, and 2 of 3 patients with LHON carrying the m.4171C.A mutation showed significant visual improvement during follow-up. More clinical data of each patient can be found in the following details and in Table 1. m.4171C.A/MT-ND1 Three patients with the homoplasmic m.4171C.A mutation in this study and another case (6) published by our group were all sporadic; 75% (3/4) had a good visual recovery ($0.5). Increased T2 MRI signal in the bilateral optic nerves was observed in 1 patient. Combining the data from previous reports (6–10) and this study, there are currently 22 LHON patients with the m.4171C.A mutation reported (Table 2). According to the data that are currently available, the mean age at onset was 17 ± 7 (10–33) years; the penetrance rate was 14%273%, and the overall visual recovery was 52% (12/23). m.10197G.A/MT-ND3 A 19-year-old male patient was found to carry the heteroplasmic m.10197G.A mutation. This patient’s brain MRI showed increased T2 signal in the optic nerves bilaterally. No obvious visual improvement was found at the 1-year follow-up time point, and no other neurological symptoms were observed during the follow-up period. m.14459G.A/MT-ND6 RESULTS Sixteen patients were diagnosed with LHON who had the rare primary mutations m.4171C.A (3 patients), m.10197G.A (1 patient), m.14459G.A (4 patients), and m.14502T.C (8 patients). Although 3 patients carried heteroplasmic rare mtDNA mutations, the remainder (81%) carried homoplasmic mutations. No family history was found for any patient as part of a detailed pedigree investigation; all patients were thus deemed to have sporadic mutations. The mean age at disease onset was 15 ± 6 years, and the male to female ratio was 15:1. Of the total patient cohort, 94% (15/16) of all patients presented with isolated signs of LHON; 1 patient with an m.14459G.A mutation had LHON plus dystonia. Of note, 75% (12/16) of all patients had both eyes involved simultaneously, and 63% (10/16) of all patients demonstrated optic atrophy on brain MRI T2 short tau inversion recovery (STIR) scans. In addition, increased signal in the optic nerve was found in 38% of patients (6/16), while optic atrophy and a T2 high signal in the basal ganglia were found in a single Cui et al: J Neuro-Ophthalmol 2020; 40: 30-36 There were 4 patients carrying the m.14459G.A mutation. Three cases had isolated LHON (homoplasmic or heteroplasmic), and 1 case was characterized by LHON plus dystonia (homoplasmic). The BCVA scores were most severely decreased to less than 0.1 (20/200 or worse), and no obvious visual improvement was found at 223 years of follow-up. Optic atrophy and increased T2 MRI signal in the bilateral basal ganglia were found in the patient with LHON and dystonia. m.14502T.C/MT-ND6 There were 8 clinically diagnosed patients with LHON carrying the m.14502T.C mutation in our study. Three of these patients also harbored the m.11778G.A mutation; their brain MRI scans showed increased T2 MRI signal in the optic nerves bilaterally. For the 5 patients with LHON who carried only an m.14502T.C mutation, 40% (2/5) of them had relatively mild visual impairment (BCVA $0.3, or 20/63 Snellen equivalent) in comparison with those carrying both the m.14502T.C and m.11778G.A mutations. 31 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 32 Rare Primary Mutations m.4171C.A m.10197G.A m.14459G.A m.14502T.C Cui et al: J Neuro-Ophthalmol 2020; 40: 30-36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Clinical data for each patient that carried rare mtDNA mutations Case Gender Age at Onset, yr m.11778G.A m.3460 G.A m.14484T.C Ho/He Interval Between Eyes Worst BCVA (Right/Left) Spasticity/ Dystonia Neuroimaging Within 3–6 mo 1 2 3 1 1 2 3 4 Male Male Male Male Male Male Male Male 15 12 14 19 16 17 17 3 — — — — — — — — Ho Ho Ho He He He Ho Ho s 3 mo s s 1 mo s s s 0.05/0.05 0.1/0.1 0.05/0.1 0.01/0.2 0.05/0.05 0.1/0.2 0.05/0.05 0.01/0.05 — — — — — — — + 1 2 3 4 5 6 7 8 Male Male Male Male Female Male Male Male 17 24 6 15 16 25 22 5 — m.11778G.A — m.11778G.A m.11778G.A — — — Ho Ho Ho Ho Ho Ho Ho Ho s 2 mo s s s s 3 mo s 0.3/0.4 0.01/0.05 0.1/0.1 FC 30 cm/0.05 0.1/FC 0.4/0.5 0.1/0.1 0.2/0.2 — — — — — — — — ISON OA OA ISON OA ISON OA OA, T2 high signal in BG OA ISON OA ISON ISON OA OA OA Followup, yr BCVA Follow-up (Right/Left) 3 2 3 1 3 3 2 2 0.1/0.1 0.5/0.6 0.6/0.7 0.1/0.3 0.05/0.05 0.1/0.2 0.05/0.05 0.05/0.1 2 3 3 3 2.5 1.5 1 1 0.4/0.4 0.01/0.05 0.1/0.1 0.05/0.05 0.1/0.05 0.4/0.5 0.1/0.1 0.2/0.2 Decimal visual acuity 0.1 = 20/200 Snellen equivalent. BCVA, best-corrected visual acuity; BG, basal ganglia; FC, finger counting; He, heterogeneous; Ho, homogeneous; ISON, increased T2 MRI signal in the optic nerve; L, left; OA, optic atrophy; R, right; s, simultaneous. DISCUSSION *Improvement in visual acuity of up to 0.3 or better in at least 1 eye. He, heterogeneous; Ho, homogeneous; LHON, Leber hereditary optic neuropathy; LS, Leigh syndrome; mtDNA, mitochondrial DNA; NR, not reported. 100% (3/3) 66.7% (2/3) NR NR LHON and LS LHON 9, 12, and 17 12, 14, and 15 3 Ho 3 Ho 3 3 Belarus (10) This study NR 5 France (9) 2 He and 3 NR LHON NR NR 4824, 8794, and 14766 NR 10203, 12358, 14564, 14766, 14841, and 15095 4216, 7632, 10398, 13708, 14766, 15257, 15452A, and 15812 4705, 5263, and 14180 NR 100% (5/5) 100% (1/1) 9.1% (1/11) 14.3%–30.8% NR 73.3% 8, 17, 19, 27, and 1 case NR 15 10, 18, 22, 26, and 32 5 1 5 Korea (7) China (6) China (8) 5 Ho 1 Ho 5 Ho LHON LHON LHON Recovery* Penetrance Phenotype Age at Onset (yr) 4171C.A Ho/He No. of Patients Origin TABLE 2. Clinical features reported for mtDNA mutations with m.4171C.A Other Nonsynonymous mtDNA Mutations Original Contribution Cui et al: J Neuro-Ophthalmol 2020; 40: 30-36 After several decades of continuous research, LHON has become one of the more well-recognized mitochondrial diseases. Neuro-ophthalmologists, ophthalmologists, and neurologists are familiar with the clinical manifestations, genetic characteristics, and visual prognoses of patients with the 3 common primary mtDNA mutations. By contrast, the number of cases of the rarer primary mtDNA mutations that can be characterized is limited. In this study, we characterized the clinical features of a group of LHON patients with rare primary mtDNA mutations; these mutations were m.4171C.A, m.10197G.A, m.14459G.A, and m.14502T.C. In this cohort, all the patients had sporadic mutations with no family history. Patients with LHON carrying the rare primary mutations had diverse clinical phenotypes; thus, the degrees of visual decline and recovery also varied. The following summarizes characteristics and literature review for each of the rare primary mutations. m.4171C.A/MT-ND1 The m.4171C.A/MT-ND1 mutation affects the highly conserved leucine and leads to a substitution with methionine at position 289 (L289M). This was previously proposed as pathogenic in 2 Korean families (7) and also found in patients with LHON from China (6,8), France (9), and Belarus (10). This mutation was only recognized to be related to isolated LHON with good visual recovery until Yang et al (8) and La Morgia et al (10), respectively, reported a pedigree with poor visual recovery and in a case with a clinical phenotype of LHON and Leigh syndrome. Although 1 Chinese LHON family carrying the m.4171C.A/MT-ND1 and the m.14841A.G/MT-ND6 mutations showed an almost complete penetrance and only 9% visual recovery (8), the other published studies and the cases discussed in the present report showed a good visual recovery. As such, the genetic variation of mtDNA, haplogroups, or even nuclear DNA may contribute to the variability in penetrance, visual recovery, and phenotype. According to the data that are currently available, LHON patients with the m.4171C.A mutation are more likely to experience a good visual outcomes. m.10197G.A/MT-ND3 The m.10197G.A mutation modifies a hydrophobic alanine residue into a hydrophilic threonine (A47T) in a highly conserved domain of the ND3 subunit; it is a confirmed pathogenic mitochondrial mutation in both the homoplasmic and heteroplasmic forms (http://www.mitomap.org/). This mutation has been mostly reported to cause Leigh syndrome and dystonia as well as mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes/ Leigh syndrome overlap syndrome. The heteroplasmy can be variable among tissues, although it is usually lower in 33 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution leukocytes (67%–100%), while it showed homoplasmic behavior in the skeletal muscle, liver, and fibroblasts (11– 14). Wang et al (14) reported isolated LHON with or without basal ganglia lesions, but all the pure LHON cases demonstrated onset at 5–8 years of age. The only patient who carried the m.10197G.A mutation in this study was a 19-year-old male patient with a clinical manifestation of pure LHON, except the brain MRI showed an increased T2 signal in the bilateral optic nerves without basal ganglia lesion or other neurological symptoms. No obvious visual improvement was found at the 1-year follow-up time point. Further clinical observations should be made to determine whether or not this patient could develop dystonia or Leigh syndrome at a later date. m.14459G.A/MT-ND6 The m.14459G.A mutation changes a moderately conserved alanine residue to a valine (A72V) within the most evolutionarily conserved region of the ND6 gene; it has been clearly established as pathogenic mtDNA mutation (both heteroplasmic and homoplasmic) in multiple pedigrees expressing a phenotype of variable severity. These phenotypes have ranged from Leigh syndrome to LHON plus dystonia, pure dystonia, pure LHON, or a clinically asymptomatic phenotype (9,15–21). Kim et al (20) reviewed 27 reported cases with a heteroplasmic or homoplasmic m.14459G.A mutation and revealed that the heteroplasmic mutation can be associated with heterogeneous clinical phenotypes, while the homoplasmic mutation can primarily be associated with pediatric-onset dystonia, which is characterized by dystonia, short stature, and pyramidal tract dysfunction. The typical age of onset for these patients is younger than 5 years. Ophthalmopathy was more frequently noted in the heteroplasmic type than in the homoplasmic type. In this study, we reported 3 cases of pure LHON (homoplasmic or heteroplasmic) and 1 case of LHON plus dystonia (homoplasmic). In these patients, the BCVA scores were most severely decreased to less than 0.1 (worse than 20/200), and no obvious visual improvement was found after 223 years of follow-up. The m.14459G.A mutation was previously observed in Hispanic (15), African (16), Caucasian (9,17–19), Korean (20), and Japanese pedigrees (21); to the best of our knowledge, this is the first study in which this mutation has been reported in Chinese patients with LHON. m.14502T.C/MT-ND6 The m.14502 T.C mutation causes a substitution of a highly conserved isoleucine to valine at position 58 in ND6 (I58V). This mutation has been associated with LHON and idiopathic cardiomyopathy. Most reported cases carrying this mutation (with or without 1 of the common primary mutations) belong to Asian families (especially 34 Chinese) (22–27), except for a German patient with LHON who was also found to be carrying rare primary mutation m.3733G.A/MT-ND1 (9). In our study, 3 patients harbored both the m.14502T.C and the m.11778G.A mutations; their visual impairments were more severe than the other 5 patients (only m.14502T.C mutation was positive in this study). Although the m.14502T.C mutation is listed as a rare primary mutation in MITOMAP (http://www.mitomap. org/), the penetrance of visual impairment was extremely low, and the degree of visual impairment was moderate or mild for patients carrying only the m.14502T.C mutation without other common primary mutations. It is also inferred that the m.14502T.C mutation may act in a synergistic role to modulate the phenotypic manifestation of the primary LHON-associated mtDNA mutations (24–27). However, we were unable to determine whether other mtDNA or nuclear genes have played roles in disease onset because we did not perform full-length sequencing of the whole mtDNA or nuclear genome. MRI of Optic Nerves The mitochondrial dysfunction caused by LHONassociated mutations particularly damages the retinal ganglion cells, resulting in anatomic changes; these include reduction of the optic nerve diameter, central axonal loss, and sometimes minimal inflammatory changes. It has been clinically observed that optic nerve MRI findings in patients with LHON mainly manifest as optic nerve atrophy (28,29). Detection of increased signal on MRI T2 STIR images of the optic nerves, chiasm, and optic tracts has been reported in patients with LHON in several studies (30–33). Some studies also demonstrate gadolinium enhancement of the optic nerves (33–36); overall, the high signal may present because of axonal degeneration, demyelination, and also damage to the astrocytes and oligodendrocytes. The T2 high-signal lesions have not been associated with time from symptom onset to MRI, mutation type, or gender (30). In our study, 63% (10/16) of the patients demonstrated only optic nerve atrophy on MRI scans, while 38% (6/16) demonstrated increased T2 signal. Many patients with LHON are misdiagnosed with optic neuritis in the early stage, and therefore, receive high-dose steroid therapy. Such therapy is not effective; 81% of patients in our study had received corticosteroids. Investigations of optic nerve MRI findings in LHON demonstrate that the presence of increased T2 signal does not exclude the possibility of LHON. Limitations Except for mtDNA primary mutations, the clinical phenotype was determined by multiple factors, including the degree of heteroplasmy, mtDNA haplogroup, nuclear genetic background, and environmental factors. We presented the clinical characteristics of 16 patients with LHON Cui et al: J Neuro-Ophthalmol 2020; 40: 30-36 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution who harbored rare primary mtDNA point mutations; however, our testing only screened and analyzed the “top 19” primary mtDNA mutations. Although this study can help to confirm the diversity of LHON clinical phenotypes and increase our understanding of the clinical features of LHON patients with rare mtDNA primary mutations, it does not provide data to further explain potential mechanisms of the mutations. The percentage of simultaneous onset of vision loss in both eyes in this case series (75%) was higher than that reported in other clinical series of the 3 primary mutations (25%) (1). Thus, we cannot rule out the possibility of selection bias caused by small sample size from a single research center. CONCLUSION This study reported the clinical features of several patients with LHON harboring rare primary mtDNA mutations, including m.4171C.A/MT-ND1, m.10197G.A/ MT-ND3, m.14459G.A/MT-ND6, and m.14502 T.C/ MT-ND6. Patients with LHON harboring the above mutations have diverse clinical phenotypes. The m.4171C.A mutation more likely leads to a good visual recovery, while the m.14502T.C mutation may act in a synergistic role to modulate the phenotypic manifestations of primary LHON-associated mtDNA mutations. Increased T2 MRI signal intensity within the optic nerve, chiasm, or optic tract was not rare; therefore, this feature should not exclude LHON as the potential cause for optic neuropathy. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: S. Cui and X. Zhang; b. acquisition of data: S. Cui, L. Yang, H. Jiang, and J. Peng; c. analysis and interpretation of data: S. Cui, L. Yang, and J. Shang. Category 2: a. drafting the manuscript: S. Cui, b. revising it for intellectual content: S. Cui, H. Jiang, and J. Wang. Category 3: a. final approval of the completed manuscript: S. Cui, X. Zhang, and J. Wang. ACKNOWLEDGMENTS The authors thank ophthalmologists Lijuan Liu and Wenbin Wei, who referred patients with LHON to our neuro-ophthalmology clinic. REFERENCES 1. 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