Ocular Manifestations of PNPT1-Related Neuropathy.

Abstract

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 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). 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.