ABSTRACT
A 29-year-old female with no family history presented with bilateral progressive blurred vision. Her symptoms appeared at 12-years-old and her visual acuity had since deteriorated from 0.6 to 0.2 bilaterally with decreased critical flicker frequency and bilateral central scotomas. She did not have a relative afferent pupillary defect. Fundoscopy revealed no distinct disc hyperaemia, atrophy, or peripapillary telangiectatic vessels. The retinal nerve fibre layer appeared normal on optical coherence tomography in each eye; however, loss of the interdigitation zone and the disruption of the ellipsoid zone at the fovea were observed in both eyes. Multifocal electroretinography revealed decreased amplitudes at both macula regions. Mitochondrial deoxyribonucleic acid analysis identified an m.14502T>C mutation, one of the primary mutations causing Leber’s hereditary optic neuropathy (LHON). Despite the presence of a marked LHON mutation, however, she was clinically diagnosed as having an occult macular dystrophy. There have only been five previous case reports, all of which were sporadic, which detail the clinical characteristics of the m.14502T>C mutation. The m.14502T>C phenotype is somewhat consistent with that of the other major mutations, including young onset, bilateral progressive visual impairment, and a typical LHON fundus. Nevertheless, m.14502T>C alone has an extremely low penetrance and its phenotype may be minimal or subclinical, as seen in our case. Since little is known about the clinical course of the m.14502T>C mutation it may be possible that the LHON phenotype may appear in later stages of life. Moreover, m.14502T>C may function as a modifier gene, which alters the phenotype of other coexisting major LHON mutations, including penetrance and the severity of the disease, through synergistic effects.
KEYWORDS: Leber’s hereditary optic neuropathy, mitochondrial mutation, optic neuropathy, occult macular dystrophy, hereditary optic neuropathy, mitochondrial genetics
Introduction
Leber’s hereditary optic neuropathy (LHON) is one of the most prevalent inherited optic neuropathies resulting in bilateral visual impairment.1 Over 90% of LHON cases harbour one of the three major mitochondrial deoxyribonucleic acid (mtDNA) mutations m.11778 G>A, m.3460 G>A, and m.14484T>C, although other primary variants have also been identified.1,2 Due to the unique nature of mitochondrial genetics, a great variation in LHON phenotype is seen clinically.1
We report a case of clinically diagnosed occult macular dystrophy harbouring an m.14502T>C mtDNA mutation, one of the primary mutations causing LHON, with minimal clinical characteristics.
This study was approved by the Institutional Review Board of the University of Tokyo (approval number: 2217) and conducted in accordance with the tenets of the Declaration of Helsinki.
Case report
A 29-year-old Chinese female, with no history of trauma, presented with bilateral, progressive, painless blurred vision. Her ocular symptoms first appeared at 12 years of age and had gradually progressed over the years. Optic neuropathy was suspected previously, but no definitive diagnosis had been made. She had no family history of visual impairment within three generations of her ancestry. She was a non-smoker and a social drinker without any dietary restrictions.
Her Snellen best-corrected visual acuity at onset was 0.6 bilaterally, which progressed to 0.2 by the time of the initial visit at our service. There was a decrease in the critical flicker frequency (CFF) values at 16.3 Hz in the right and 15.5 Hz in the left eye. Central scotomas were observed bilaterally on the Humphrey Field Analyser 10–2 programme (Figure 1). No evident colour vision deficiency was observed on the Farnsworth D-15 test. Her pupillary light reflexes remained prompt and no relative afferent pupillary defect was observed. Slit-lamp examination of the anterior segment was unremarkable with normal intraocular pressures. Fundoscopy revealed bilateral myopic fundi with small and tilted optic discs. No evident disc hyperaemia or peripapillary telangiectatic blood vessels were observed (Figure 2).
Figure 1.
Humphrey Field Analyser 10–2 visual field test result shown as grey scale and pattern deviation probability maps. Central scotomas can be seen bilaterally with overall decreased mean deviation values.
L = left eye; MD = mean deviation, PSD = pattern standard deviation; R = right eye.
Figure 2.
Fundoscopic image (top) showed bilateral myopic retinal changes and small, tilted optic discs bilaterally with no evident hyperaemia or swelling. Peripapillary telangiectatic blood vessels cannot be observed. Optical coherence tomography images (middle) showing loss of the interdigitation zones and the disruption of the ellipsoid zones at the fovea in both eyes (yellow asterisks). The vessels in Haller’s layer were slightly larger in the left eye. Optic disc thickness maps (bottom) do not reveal any bilateral thinning of the retinal nerve fibre layer in the papillomacular bundles.
L = left eye; R = right eye, RNFL = retinal nerve fibre layer.
Optical coherence tomography (OCT; Swept-source OCT, Topcon Corporation, Tokyo, Japan) revealed no optic disc abnormalities, including swelling or atrophy of the peripapillary retinal nerve fibre layer (RNFL) (Figure 2); however, loss of the interdigitation zone and the disruption of the ellipsoid zone at the fovea were observed in both eyes (Figure 2). The vessels in Haller’s layer were slightly dilated in the left eye, although no choroidal thickening was observed. Analysis of the ganglion cell layer did not reveal thinning in the macula region. Full-field electroretinography (ERG) was normal; however, multifocal ERG revealed decreased amplitudes at the macula regions (Figure 3).
Figure 3.
Multifocal electroretinogram showing decreased amplitudes at the macula regions bilaterally.
L = left eye; R = right eye.
Mitochondrial genome analysis was negative for all three major LHON mutations; however, an m.14502T>C (p.Ile58Val) mutation of the mtDNA was identified. The per cent heteroplasmy of her mtDNA was below the limit of quantification (less than 20%).
Despite the presence of a primary LHON mutation, she was clinically diagnosed as having an occult macular dystrophy from the OCT and multi-focal ERG findings, although she refused to be tested for the RP1L1 gene mutation.
Discussion
In LHON, selective degeneration of the retinal ganglion cells occurs, especially within the papillomacular bundle (PMB) as a result of mitochondrial dysfunction due to their high metabolic activities.1 Typical fundoscopic features of acute LHON include: RNFL thickening, usually beginning at the PMB in the temporal quadrant; vascular tortuosity; and peripapillary telangiectatic blood vessels without leakage on the fluorescein angiography.1 In the chronic phase, optic nerve pallor, as well as PMB and macular thinning, can manifest after 6 to 36 weeks.1 However, the diagnosis of LHON solely from ocular exams may be difficult as the fundus appears normal in 20–40% of the cases.1,2
The m.14502T>C mutation is one of the primary LHON mutation registered on the MITOMAP database (https://www.mitomap.org/foswiki/bin/view/MITOMAP/MutationsLHON). On the other hand, there are only a few previous reports, all in the Chinese population, which describes its clinical features.3–7
Table 1 summarises the previously reported clinical presentations of the m.14502T>C mutation. The age of onset ranged from 2- to 30-years-old, with most of them having their first symptoms during the teenage period. All patients experienced moderate-to-severe bilateral visual acuity loss. Despite our case, all previous cases of the m.14502T>C mutation presented with typical fundoscopic features of LHON. Interestingly, the penetrance of the m.14502T>C phenotype was extremely low for cases which only had the m.14502T>C mutation alone; whereas, those with another concomitant mutation (m.14484T>C, m.11778 G>A, or m.3635 G>A) had higher penetrances. For instance, the Chinese family described by Zhang et al., harbouring both the m.14502T>C and m.14484T>C mutations, showed 100% penetrance of the LHON phenotype over three generations.5 Another Chinese family reported by Qian et al., harbouring the m.11778 G>A and m.14502T>C mutations, showed a penetrance of 35.5%.6
Table 1.
Previously reported cases with the m.14502T>C mitochondrial DNA mutation.
| Case number | Sex | Age at onset | BCVA (Right/Left) |
LHON fundal appearance* | mtDNA mutations present |
Inheritance | |
|---|---|---|---|---|---|---|---|
| Current case | - | F | 12 | 0.2/0.2 | No | m.14502T>C | Sporadic |
| Guo et al.3 | - | M | 14 | 0.6/0.1 | Yes | m.14502T>C | Sporadic |
| Zhao et al.4 | 1 | F | 11 | 0.1/0.1 | Yes | m.14502T>C | Sporadic |
| 2 | M | 2 | 0.1/0.1 | Yes | m.14502T>C | Sporadic | |
| 3 | F | 30 | 0.3/0.2 | Yes | m.14502T>C | Sporadic | |
| Zhang et al.5 | 1 | M | 18 | 0.04/0.06 | Yes | m.14502T>C m.14484T>C |
Matrilineal |
| 2 | M | 17 | 0.04/0.04 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| 3 | F | 16 | 0.08/0.06 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| 4 | F | 17 | 0.12/0.12 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| 5 | M | 17 | 0.1/0.12 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| 6 | M | 17 | 0.1/0.1 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| 7 | M | 16 | 0.08/0.08 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| 8 | M | 18 | 0.1/0.1 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| 9 | F | 18 | 0.12/0.15 | Yes | m.14502T>C m.14484T>C |
Matrilineal | |
| Qian et al.6 | - | M | 17 | 0.01/0.01 | Yes | m.14502T>C m.11778 G>A |
Matrilineal |
| Jin X et al.7 | 1 | M | 14 | 0.1–0.15/0.1–0.15 | Yes | m.14502T>C m.3635 G>A |
Matrilineal |
| 2 | M | 15 | 0.1–0.15/0.1–0.15 | Yes | m.14502T>C m.3635 G>A |
Matrilineal |
BCVA = best-corrected visual acuity; F = female; LHON = Leber’s hereditary optic neuropathy; M = male; mtDNA = mitochondrial deoxyribonucleic acid.
*LHON fundus includes any of the following: optic disc atrophy; optic disc swelling; tortuosity of the retinal vessels; circumpapillary telangiectatic microangiopathy; and swelling of the retinal nerve fibre layer.
Although m.14502T>C alone may still cause LHON phenotypes, including early onset of painless progressive bilateral vision loss with typical fundoscopic features, the penetrance of this single mutation is considered to be extremely low, possibly insufficient to produce the clinical features of LHON, as seen in our case.3,4
Others have reported that m.14502T>C could function as a modifier mutation which alters the clinical presentation and penetrance of other major LHON mutations.5,6 The three major primary mutations m.11778 G>A, m.3460 G>A, and m.14484T>C encode the subunits of the respiratory-chain complex I in the mitochondria.1 Interestingly, the m.14502T>C and the m.14484T>C mutations both occur within the ND6 gene of the mitochondrial genome, which plays a role in the assembly and the structural maintenance of complex I.5 The coexistence of the two mutations creates a synergistic effect, which alters the clinical features of m.14484T>C, including the absence of marked male gender bias, decreased rate of visual recovery, and the complete penetrance of phenotype.5 Moreover, the penetrance of m.11778 G>A occurring in the ND1 gene may also be modulated by the m.14506T>C mutation,1 although complete penetrance was not achieved possibly due to the genetic distance between the two mutations which may have weakened their synergistic effect.6
In our case, some clinical features suggesting LHON were observed, including an early onset of bilateral visual acuity impairment with gradual exacerbation, low CFF values, and the presence of pupillary light reflexes. A previous study by Borrelli et al. suggested an increase in choroidal thickness as a feature of acute stage LHON, which could precede the thickening of the RNFL.8 In our case, although the Haller’s vessels appeared to be slightly more dilated in the left eye, there was no marked difference in the choroidal thickness nor thickening of the RNFL between the two eyes. Furthermore, it is suggested that a decrease in the choroidal thickness is a feature of later stages of LHON, which correlates with the thinning of the RNFL,8,9 neither which was observed in our case. Therefore, such subtle difference in the Haller’s layer between the two eyes may have just been an anatomical variation in our case. Other typical fundoscopic features of LHON were not observed in our case. This may be due to the extremely low penetrance of the m.14502T>C mutation alone, consistent with previous reports.3,4 Nevertheless, diagnosis of LHON solely from ocular examination may be difficult.1,2 Moreover, environmental risk factors such as smoking, alcohol intake, and poor dietary habits were not prominent in our case, all of which may play an important role in the expression of the LHON phenotype, especially in rare variant mutations.2 Furthermore, our case as well as previously reported m.14502T>C mutations were all of Chinese descent; hence, a geographical bias may also be present.
Although the cause of visual impairment in our case was clinically diagnosed as an occult macular dystrophy, the diagnosis was not confirmed by genetic analysis as the patient refused to be tested for the RP1L1 gene mutation.10 It may be possible that the clinical presentation of m.14502T>C may have been sub-clinical or was masked by the clinical ocular macular dystrophy, although no combined case of LHON and RP1L1 mutation positive ocular macular dystrophy has been reported so far. Since there are only a few reports on the clinical features of the m.14502T>C mutation, it may be possible that LHON phenotype may appear in different stages of life.
In conclusion, we report a sub-clinical case of m.14502T>C mutation in LHON, which by itself has extremely low penetrance and may be insufficient to produce a typical LHON phenotype; however, it may play an important role in altering the clinical characteristics and penetrance of other major mutations.
Funding Statement
The authors reported there is no funding associated with the work featured in this article.
Disclosure statement
No potential conflict of interest was reported by the authors.
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