Giacinto Triolo1, Maria Lucia Cascavilla1, Francesco Bandello1.
1 Scientific Institute San Raffaele, Milan, Italy
The clinical histories of 4 members of the same family were presented and discussed. A high penetrance of visual disturbance in the female members was detected (Figure1). Early onset of visual loss and complete visual recovery were common characteristics in this family.
Proband: subject #III-4
A 4-year-old boy (Figure 1, subject #III-4) was referred to the Neuro-Ophthalmology Unit of the San Raffaele Hospital, Milan, on February 2013.
The mother said that in September 2012 her son suddenly started complaining about poor vision few days after an episode of high fever, but she was not able to establish whether the problem involved one or both eyes, nor which of the two eyes was affected first.
The past medical history was unremarkable. An MRI of head and orbits was already available at the time of our evaluation, and it was unremarkable as well.
The family history was the following: the child’s mother (#II-3) and one of her 2 sisters (#II-1), along with the grandmother (#I-1), were previously diagnosed with childhood “retro-bulbar optic neuritis”. All of them were treated with systemic steroids, with successful outcomes according to the patients. The third sister (#II-2) did never complain for ocular symptoms.
The child’s baseline clinical examination (6 months after the presumed clinical onset) revealed best corrected visual acuity (BCVA) of 0.1 in his right eye and of 0.01 in his left eye. Stereopsis was absent using LANG test; no afferent pupillary defect was detectable.
The anterior segment was within normal limits; the fundus examination showed mild temporal optic disc pallor in both eyes, with reduced retinal nerve fibers reflex in the temporal quadrants and mildly blurred optic disc margins at the disc poles, without evidence of peripapillary microangiopathy (Figure 2).
Despite the childhood onset, given the family history, the typical symptoms and the optic discs appearance, the patient was screened for mithocondrial DNA mutations associated with LHON. The mutation in polypeptide ND6 (T14484C) was found to be positive.
On March 2013 Idebenone o.s. 45 mg t.i.d was prescribed. The patient was followed up at 9, 12, 18, 24, 36, 42, and 54 months from the clinical onset. BCVA and color vision (Ishihara test) data per each follow up visit are shown in the Table.
At the 12-months follow up visit, the patient showed an improvement in BCVA in both eyes. Slowly, both BCVA and color vision continued to improve, until they reached normal values at the 54-months follow up visit (Figure 3). The stereopsis was also measurable. The visual field performed in the same data showed centrocecal scotoma with good preservation of the foveal sensitivity (Figure 3).
Subjects #I-1, #II-1, and #II-3 – Childhood classical acute LHON
Due to the mtDNA mutation finding in the proband, all the female patients of the family were visited.
The patients #I-1, #II-1, #II-3 experienced early bilateral acute visual loss at the age of 15, 12 and 6, respectively. A diagnosis of retrobulbar optic neuritis was made and all of them reported a visual recovery after systemic steroids treatment, as previously mentioned.
Their clinical features at the time of our visit (OCT, optic disc color picture, and VF, when available) are summarized in Figures 4-6.
The proband’s grandmother (I-1) at the age of 65 years presented visual acuity of 0.2 in her right eye and 0.6 in her left eye. The color vision was within normal limits (Ishihara test 12/12 OU) and OCT showed temporal RNFL thinning and diffuse ganglion cell-inner plexiform layer (GC-IPL) reduction (Figure 4).
The proband’s aunt (II-1), visited at the age of 44 years, presented good visual acuity (0.8 in her right eye and 1.0 in her left eye) and normal color vision perception (Ishihara test 12/12 OU). The VF showed the persistence of mild central scotoma (right eye> left eye; figure 5) and the optic disc was mildly pallid. The OCT confirmed RNFL thinning in the temporal sectors and diffuse GC-IPL thinning in the macular region (Figure 5).
The proband’s mother (II-3) presented early onset visual loss (BCVA 0.3 in both eyes) and slowly progressive recovery up to normal values after 18 months. At the age of 33, her visual acuity was 1.0 in both eyes, her color vision perception was normal (Ishiara 12/12 OU) and mild temporal pallor was detectable at fundus examination (Figure 6). The VF showed the persistence of a centrocecal scotoma in both eyes (Figure 6). The OCT detected RNFL thickness reduction in the temporal and inferior sectors associated with diffuse macular GC-IPL thinning (Figure 6).
The mtDNA analysis was extended to all of them and they were found to be positive to ND6 (T14484C) mutation. So, their previous diagnosis of optic neuritis was changed in childhood classical acute LHON with visual recovery.
Subject #II-2 – subclinical LHON
The proband’s aunt never complained visual symptoms, her visual acuity at the age of 43 years was 1.0 in both eyes, the VF and the Ishihara test were within normal limits. The only signs were mild temporal pallor of the optic disc and temporal RNFL and perifoveal GC-IPL thinning detectable with OCT (Figure 7). The same mtDNA mutation was found and subclinical LHON was diagnosed.
Most of the family members presented childhood subacute LHON with complete visual recovery. A case of subclinical LHON was also reported. The unusual high female penetrance is peculiar, mostly in 14484 mtDNA mutation and in childhood (Newman NJ, 1993). A pedigree with high prevalence in girls has been previously described (Thieme H et al, 1999). The typical subacute LHON presentation of the young boy suggested the correct diagnosis also in their relatives. Usually, acute visual loss in female with subsequent complete visual recovery after steroid therapy characterizes optic neuritis. For this reason, the female relatives of this family were previously misdiagnosed with optic neuritis. The atypical early recovery of visual acuity in LHON makes difficult differential diagnosis with optic neuritis. However, LHON should be always excluded in cases of familiar history of bilateral visual loss.
A similar misdiagnosis was previously described in a male patient (Hsu TK et al, 2014). The recovery of vision is more likely with an early onset of visual loss before the median age of 27 years and in patients carrying the 14484 mtDNA mutation (Newman NJ et al, 1991; Oostra RJ et al, 1994).
The presence of the mutation, together with the typical optic disc temporal pallor and the OCT findings confirm the diagnosis of LHON. The recovery after steroids therapy was likely an incidental finding.
Figure 1. Genealogic tree of the family. III-4 is the proband.
Figure 2. Sub-acute stage in the 4-year-old boy (III-4): 6-months from the presumed onset. Optic discs color retinography and Cirrus HD-OCT retinal nerve fiber layer (RNFL) analysis. Note the large disc size (2.23 mm2 in right eye and 2.52 mm2 in the left eye) and the thinning od the RNFL in the temporal sectors. The normative data is not available in patients with age inferior to 18 years old in Cirrus HD-OCT, so the optic disc data and RNFL thickness are not highlight with different colors.
Figure 3. Chronic stage of the same patient of figure 2 at the age of 8-year-old (54-months from the onset). Optic discs color retinography, Heidelberg SD-OCT retinal nerve fiber layer (RNFL) analysis and visual field. Note the mild temporal pallor of the discs, the RNFL thinning and the centrocecal scotoma.
Figure 4. Optic nerve and macular OCT of the chronic stage of patient I-1. Temporal RNFL thinning and diffuse ganglion cell-inner plexiform layer reduction is detectable.
Figure 5. Optic nerve OCT, macular OCT and HVF of the chronic stage of patient II-1. Mild central scotoma (right eye> left eye) is detectable by HVF. The OCT shows RNFL thinning in the temporal sectors and diffuse ganglion cells thinning in the macular region.
Figure 6. Optic disc color retinography, OCT and visual field of the chronic stage of patient II-3. Not the mild temporal pallor of the optic disc and the centrocecal scotoma in both eyes. The OCT shows RNFL thickness reduction in the temporal and inferior sectors associated with diffuse GC-IPL thinning.
Figure 7. Optic nerve OCT, macular OCT and HVF of the subclinical LHON patient (II-2). The OCT shows temporal RNFL and perifoveal ganglion cell layer thinning. The VF is within normal limits.
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