Combined Optic Atrophy and Rod–Cone Dystrophy Expands the RTN4IP1 (Optic Atrophy 10) Phenotype

Optic atrophy 10 (OPA10) is a rare autosomal recessive form of optic atrophy, which clinically is characterized by visual loss starting in early childhood. This condition may be limited to isolated optic atrophy or present additional central nervous system alterations, including epileptic seizures, intellectual disability, growth retardation, and biochemical abnormalities, such as elevated lactate levels (1–4). It is caused by mutations in the RTN4IP1 gene, which encodes a mitochondrial protein implicated in the regulation of retinal ganglion cell dendrite branching, synaptogenesis, and neurite outgrowth, hence important in the development of the inner retina and optic nerve (1,3). In this article, we describe an Italian case with compound heterozygous RTN4IP1 mutations, segregating from each parent, clinically characterized by the previously unreported combination of optic nerve atrophy and macular involvement, with the clinical pattern of rod–cone dystrophy. CASE REPORT A 27-years-old woman presented at age 20 years with poor vision since early childhood with a best-corrected visual acuity (BCVA) of 20/160 in the right eye and 20/32 in the left eye with a low myopia of −1 diopter. The patient did not report photophobia or hemeralopia. At slit-lamp examination, no anterior segment abnormality was present. Intraocular pressure was within normal range. Fundus examination revealed optic disk pallor and retinal pigment epithelium irregularities at the posterior pole. Optical coherence tomography (OCT) showed diffuse thinning of retinal nerve fiber layer (RNFL) with partial fiber preservation in the nasal sector (the mean thickness in the right eye was 69 nm and in the left eye was 60 nm) (Fig. 1). Automated visual field examination revealed a general depression of sensitivity with partial preservation of nasal sectors (Fig. 1). On multimodal imaging, fundus autofluorescence disclosed a central hypoautofluorescence surrounded by a large hyperautofluorescence area (Fig. 2A). The outer nuclear layer (ONL) and inner segment and outer segment (IS/OS) of photoreceptor layers were only detectable in a small subfoveal region, reducing toward the periphery, whereas the external limiting membrane and pigment epithelium band were normal (Fig. 2B). Full-field electroretinography (ERG) examination was characterized by a reduced photopic response (Fig. 2E) together with a deeply altered scotopic response in both eyes (Fig. 2F). Color blindness was present, whereas congenital nystagmus was absent, as well as seizures and any other extraocular abnormality. MRI and Electromyography results were normal. No consanguinity in the family was registered.FIG. 1.: The image shows the scotoma at the automated visual field and thinning of retinal nerve fiber layer at baseline and the progression of retinal nerve fiber layer thinning in the follow-up.FIG. 2.: The image shows the hypoautofluorescence/hyperautofluorescence at fundus autofluorescence (A and C) and the damage of outer nuclear layer and inner and outer segment at an optical coherence tomography scan (B and D) that seem unchanged in the follow-up. Photopic (E and G) and scotopic (G and H) ERG recording reveal the reduction of amplitude in both responses at baseline (A1–B1 amplitude in the right eye 63.12 µV and in the left eye 73.14 µV and ISO-B1 amplitude in the right eye 45.86 µV and in the left eye 65.01 µV) and worsening at follow-up (A1–B1 amplitude in the right eye 53.28 µV and in the left eye 42.95 µV and ISO-B1 amplitude in the right eye 28.87 µV and in the left eye 25.65 µV).At last examination, after 7-year follow-up, the patient complained of no visual function deterioration, but BCVA reduced to 20/320 in both eyes. OCT revealed a progressive RNFL thinning (the mean thickness in the right eye was 55 nm and in the left eye was 52 nm) (Fig. 1). The central hypoautofluorescence turned out to be stable at last examination as well as the ONL and IS/OS in the subfoveal region (Fig. 2C, D). On the other hand, full-field ERG testing unveiled the amplitude reduction in both photopic and scotopic responses (Fig. 2G, H). We performed the genetic analysis by a custom next generation sequencing panel of optic atrophy–related genes. Library was built using a Nextera Rapid Capture Custom Enrichment Kit and sequenced on MiSeq Instrument (Illumina). This analysis revealed the presence of compound heterozygous mutations affecting the RTN4IP1 gene: a nonsense (c.432 G>A, p.W144X) inherited by the father and a missense (c.646 G>A, p.G216R) by the mother (RefSeq NM_032730.5). The first mutation is pathogenic; the second is likely pathogenic and previously reported as a compound heterozygous mutation with another nonsense variant (c.1162C > T, p.R388X) (4). According to the public database GnomAD (http://gnomad.broadinstitute.org), these variants are reported in 1 and 2 alleles, respectively, but never in homozygosity. The missense variant is predicted to be pathogenic (DANN 0.9993). Furthermore, to exclude the presence of pathogenic variants explaining the retinal dystrophy phenotype in our patient, a whole exome sequencing (WES) with the IDT xGen Exome Research Panel targeting kit was performed. An ad hoc in silico analysis of genes causing rod–cone dystrophy (See Supplemental Digital Content, Table E1, https://links.lww.com/WNO/A444) revealed the presence of 3 likely benign heterozygous variants (See Supplemental Digital Content, Table E2, https://links.lww.com/WNO/A445) and the absence of likely pathogenic alleles. DISCUSSION The present case report describes the clinical characteristics of a patient affected by recessive optic neuropathy due to compound heterozygous RTN4IP1 mutations (OPA10), associated with rod–cone dystrophy, having reasonably excluded other genetic causes of rod–cone dystrophy. Optic atrophy had childhood onset and further progression in adult age with the addition of retinal pathology, a previously undescribed feature. Autosomal recessive optic neuropathies (arONs) due to mitochondrial dysfunction are rare neurodegenerative disorders affecting the optic nerve and, frequently, the central nervous system (4). Currently, besides RTN4IP1 other genes have been implicated in mitochondrial arONs, including OPA3 (Costeff syndrome), TMEM126A, ACO2, and YME1L. Despite the mechanistic implication of both RTN4IP1 and TMEM126A with complex I function being unclear, recessive mutations in both genes lead to defective complex I function (3). This fits with the phenotypic expression of optic atrophy as Leber hereditary optic neuropathy and dominant optic atrophy (4). However, the macular involvement shown in the present Italian patient was previously unrecognized in OPA10 patients, and it was clinically characterized by severe involvement of outer retinal layers in the macula contributing to the global loss of vision. Somewhat similar to this report, a new clinical entity combining early or congenital optic atrophy with evolving macular involvement in young-adult age has been recently reported because of dominant mutations in the mitochondrial single-strand binding protein 1 (SSBP1) (5). In this disorder, the impaired replication of mtDNA leads to reduced amounts of mitochondrial genomes and a clinical ocular phenotype of optic atrophy and retinal dystrophy. A further example of optic atrophy associated with retinal pathology comes also from ACO2 recessive mutations, which affect the Kreb's cycle. In conclusion, the phenotypic overlap of optic atrophy with retinal pathology further expands the genetic landscape of ocular phenotypes because of mitochondrial dysfunction, with key mechanistic roles played by complex I, mtDNA maintenance, and Kreb's cycle, ultimately reflecting as impaired oxidative phosphorylation. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: P. Barboni, M. Battaglia Parodi, and V. Carelli; b. Acquisition of data: M. P. Manitto, F. Palombo, L. Caporali, A. Grazioli, V. Starace, A. Arrigo, M. L. Cascavilla, and C. La Morgia; c. Analysis and interpretation of data: M. P. Manitto, F. Palombo, L. Caporali, A. Grazioli, V. Starace, A. Arrigo, M. L. Cascavilla, and C. La Morgia. Category 2: a. Drafting the manuscript: P. Barboni, M. Battaglia Parodi, V. Carelli, and F. Rajabian; b. Revising it for intellectual content: P. Barboni, M. Battaglia Parodi, V. Carelli, and F. Bandello. Category 3: a. Final approval of the completed manuscript: P. Barboni, M. Battaglia Parodi, V. Carelli, and F. Bandello.