Ocular Manifestations of PNPT1-Related Neuropathy

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Ocular Manifestations of PNPT1-Related Neuropathy Helen J. Kuht, BMedSci, Kevin A. Thomas, MBChB, MRCGP, Michael Hisaund, BMedSci, Gail D. E. Maconachie, BMedSci, PhD, Mervyn G. Thomas, MBChB, PhD I nherited optic neuropathies are genetically heterogeneous often arising due to mitochondrial dysfunction with an estimated prevalence of 1 in 10,000 (1). Leber hereditary optic neuropathy (LHON) and dominant optic atrophy are the most common inherited optic neuropathies. Retinal phenotype can range from asymptomatic peripheral “salt and pepper” changes to severe visual field constriction due to optic atrophy (1). Polyribonucleotide nucleotidyltransferase 1 (PNPT1), on chromosome 2p16.1, encodes the protein polynucleotide phosphorylase (PNPase) located in the mitochondrial intermembrane space. PNPase is involved in RNA import to the mitochondria, maintaining mitochondrial homeostasis, and preventing the cell from entering oxidative stress. Mutations in PNPT1 have been associated with autosomal recessive isolated nonsyndromic sensorineural hearing loss (OMIM 614934) and early onset combined oxidative phosphorylation deficiency 13 (OMIM 614932). Associated characteristics may include developmental delay, severe hypotonia, muscle atrophy, choreoathetotic movements, optic atrophy, and nystagmus (2,3). To date, the morphological characteristics of the optic nerve and fovea, using optical coherence tomography (OCT), have not been described in PNPT1 mutations. This is because of the severity of the motor phenotype that often leaves the patient wheelchair bound and thus not accessible to a table-mounted OCT. Using handheld OCT (HH-OCT) and a handheld fundus camera, we investigated the detailed morphological Department of Neuroscience, Psychology and Behaviour (HJK, MH, GDEM, MGT), The University of Leicester Ulverscroft Eye Unit, University of Leicester, RKCSB, Leicester, United Kingdom; Market Rasen Surgery (KAT), Lincolnshire, United Kingdom; and Division of Ophthalmology and Orthoptics (GDEM), University of Sheffield, Sheffield, United Kingdom. Supported by the Medical Research Council (MRC), London, UK (grant number: MC_PC_17171) and the Fight for Sight (grant ref: 5009/5010 and 24NN181). M.G.T is supported by the NIHR (CL2017-11-003). The sponsor or funding organization had no role in the design or conduct of this research. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Mervyn G. Thomas MBChB, PhD; E-mail: [e-mail] Kuht et al: J Neuro-Ophthalmol 2021; 41: e293-e296 characteristics of the fovea and optic nerve in a family with PNPT1 mutation. Five members from a nonconsanguineous Caucasian family (Fig. 1) with mutations in PNPT1 were examined at the Leicester Royal Infirmary, United Kingdom. All underwent an orthoptic examination, slit-lamp examination, dilated fundus examination, and HH-OCT (Leica Envisu C-class, Leica Microsystems) to assess foveal and optic nerve morphology. Fundus images were captured using Pictor (Volk Optical, OH). Visual field assessment was performed in 1 affected individual (II3) using Humphrey visual field perimetry (Carl Zeiss Meditec, Dublin, CA). All 3 affected individuals (II-1, II-2, and II-3) presented with motor developmental delay, hearing deficits (mild– moderate), dysarthria, learning disability, and choreoathetoid movements. II-1 and II-2 were wheelchair bound with a more severe phenotype compared with II-3, who was able to mobilize with a walker. Clinical genetic testing identified the following compound heterozygous PNPT1 mutations (NM_033109.5): c.1528G.C p.(Ala510Pro) and c.2212C.T p.(Arg738Cys) segregating with the phenotype. The Ala510Pro and Arg738Cys variants have previously been described as pathogenic (2,3). Reduced visual acuity and color vision was observed in all 3 affected patients (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A405). Pupil reflexes were normal. Fundus examination identified a pale tessellated fundal appearance with temporal disc pallor and peripapillary atrophy (PPA) (Fig. 1). This was most severe in II-1 and II2 compared with II-3. II-1 and II-2 also had pigmentary changes at the macula. II-2 had facial dysmorphic features, including downslanting palpebral fissures. HH-OCT identified significant thinning of the retinal nerve fiber layer (RNFL) in all peripapillary quadrants in all affected patients (Fig. 2 and see Supplemental Digital Content, Fig E1, http://links.lww. com/WNO/A406). Consistent with the temporal pallor seen on funduscopy, the most severely affected quadrant on OCT was the temporal region that represents the papillomacular bundle (Fig. 2 and see Supplemental Digital Content, Fig E1, http://links.lww.com/WNO/A406). Correlating with the structural changes described, we observe a centrocecal scotoma on perimetry in II-3 (Fig. 2). e293 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Pedigree of the family with compound heterozygous PNPT1 mutations. Fundus photographs of the left eye of II-1 (B), II-2 (C), and II-3 (D) showing peripapillary atrophy (white arrow) and temporal pallor of the optic disc. Individual II-2 had a tilted myopic disc. Foveal optical coherence tomograms of II-2 (E) and I-2 (F) showing difference in retinal nerve fiber layer (yellow arrow) and overall atrophy of the macula (E). Plots of central retinal thickness (G) and nerve fiber layer thickness (H) from foveal tomograms of affected patients and normative data are shown for the HH-OCT. Individual II-1 is the most severely affected as demonstrated by the thickness plots (G, H). The x axis represents distance in mm from the foveola. Interestingly, foveal OCT revealed significant reduction in overall foveal thickness suggestive of foveal atrophy. This was most severe in patient II-1 in comparison with II-2 and II-3. Both parents demonstrated a best-corrected visual acuity of 20.100 logMAR or better, and there was no evidence of any optic nerve atrophy or foveal abnormalities. Using HH-OCT for the first time in PNPT1 mutations has allowed us to highlight peripapillary RNFL thinning in all quadrants with a predilection for the temporal quadrant, e294 which signifies loss of the papillomacular bundle. We also describe foveal atrophy for the first time in patients with PNPT1 mutations. The functional consequence of these structural changes includes reduced visual acuity, reduced color vision, and centrocecal scotoma. Parvocellular retinal ganglion cell run in the papillomacular bundle have a much smaller cross-sectional area compared with magnocellular cells thus making them potentially more vulnerable in terms of mitochondrial reserve. All 3 affected Kuht et al: J Neuro-Ophthalmol 2021; 41: e293-e296 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A, D. Fundus photographs of II-3 showing temporal disc pallor. B, C. Corresponding optical coherence tomography scans through the center of the disc showing thinning of the papillomacular nerve fibers (yellow arrow). E. Peripapillary nerve fiber layer thickness plots for II-3 (in microns, mm) showing global reduction of nerve fibers that is most severe in the temporal quadrant. This is further demonstrated in the average thickness values (in microns) in each quadrant (S = superior, N = nasal, I = inferior, and T = temporal). The color signifies reference values for normative data (90% fall within the green band, 4% fall within the yellow band, 5% fall within the white area, and 1% fall within the red band). F. Perimetry in II-3 shows a centrocecal scotoma in the pattern deviation plots for the right and left visual fields. individuals demonstrated a temporal wedge of optic disc pallor and severely thin RNFL in the temporal quadrant thus suggesting profound papillomacular bundle loss. Functionally the parvocellular pathway differs from the magnocellular pathway particularly in relation to the sensitivity of color contrast and spatial frequency. Removal of P cells, through ablation studies in monkey, leads to complete loss of color vision and profound reduction in visual acuity (4). II-1 and II2 had a profound loss of RNFL globally but also within the temporal quadrant (papillomacular bundle); both of them also had the more significant reduction of color vision and visual acuity in comparison with II-3. Interestingly, the motor phenotype was also more severe in II-1 and II-2 compared with II3. Because this is based on cross-sectional data, it is unclear whether this is an age-related phenomenon as both II-1 and II2 are older than II-3. Longitudinal data in LHON revealed the temporal sequence of events that is characterized by an initial increase in RNFL thickness at the time of vision loss and thinning, a later feature (5). Because the family described in this study presented later in life, we are unable to ascertain whether a similar sequence of events occurs in PNPT1 mutations. Longitudinal data would be important, to provide us with a better understanding of PNPT1-related neuropathy and whether the RNFL loss is progressive. This would be possible with the advent of handheld devices in ophthalmology. All 3 affected individuals demonstrated foveal atrophy. This has not been previously reported in patients with PNPT1 mutations. In LHON, the macular thickness has been reported to be reduced and atrophic. Recent evidence from OCT-angiography (OCT-A) suggest that microangiopathy and vascular alterations are not only seen in the peripa- Kuht et al: J Neuro-Ophthalmol 2021; 41: e293-e296 pillary regions but also at the foveal and parafoveal regions in LHON (6). Moreover, the vascular changes identified at the macula in LHON were correlated with the proximal parts of the papillomacular bundle, where the smallest retinal ganglion cell reside and are considered to be most vulnerable to mitochondrial dysfunction. We have not been able to perform OCT-A in our patients; however, we hypothesize that PNPT1 mutations may share a common pathophysiologic mechanism for the development of foveal atrophy. In conclusion, we report compound heterozygous mutations in PNTP1. Because of the severe motor and systemic phenotype associated with this disorder, the ocular characteristics are often overlooked. We have overcome this by using handheld devices in our wheelchair bound patients and have shown for the first time global reduction in peripapillary RNFL thickness that is most severe in the papillomacular bundle. Similarly, we report foveal atrophy for the first time in affected patients with PNPT1 mutations. The severity of the RNFL loss and foveal thickness correlates to the severity of the motor phenotype. Further OCT studies are important to understand the natural history of this disorder. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: H. J. Kuht, K. A. Thomas, and M. G. Thomas; b. Acquisition of data: H. J. Kuht, K. A. Thomas, M. Hisaund, G. D. E. Maconachie, and M. G. Thomas; c. Analysis and interpretation of data: H. J. Kuht, K. A. Thomas, M. Hisaund, G. D. E. Maconachie, and M. G. Thomas. Category 2: a. Drafting the manuscript: H. J. Kuht and M. G. Thomas; b. Revising it for intellectual content: H. J. Kuht, K. A. Thomas, M. Hisaund, G. D. E. Maconachie, and M. G. Thomas. Category 3: a. Final approval of the completed manuscript: H. J. Kuht, K. A. Thomas, M. Hisaund, G. D. E. Maconachie, and M. G. Thomas. e295 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence REFERENCES 1. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81–114. 2. Rius R, Van Bergen NJ, Compton AG, Riley LG, Kava MP, Balasubramaniam S, Amor DJ, Fanjul-Fernandez M, Cowley MJ, Fahey MC, Koenig MK, Enns GM, Sadedin S, Wilson MJ, Tan TY, Thorburn DR, Christodoulou J. Clinical spectrum and functional consequences associated with bi-allelic pathogenic PNPT1 variants. J Clin Med. 2019;8:2020. 3. Alodaib A, Sobreira N, Gold WA, Riley LG, Van Bergen NJ, Wilson MJ, Bennetts B, Thorburn DR, Boehm C, Christodoulou J. 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