Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.

OBJECTIVE: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. METHODS: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. RESULTS: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. INTERPRETATION: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.

MP1 AND MAIA FUNDUS PERIMETRY IN HEALTHY SUBJECTS AND PATIENTS AFFECTED BY RETINAL DYSTROPHIES.

PURPOSE: To compare retinal sensitivity obtained with MP1 and MAIA microperimeters in patients affected by retinal dystrophies (RD) and in healthy subjects. METHODS: Thirty-six patients affected by RD and 25 healthy subjects were considered for the study. All patients and controls underwent a complete ophthalmic examination including fundus-related perimetry, performed by means of two microperimeters, the MP1 (Nidek Technologies) and the MAIA (CenterVue). Main outcome of the study was the comparison of retinal sensitivity. Such comparison was performed converting the MP1 decibel (dB) values to their MAIA equivalent dB values. RESULTS: Mean retinal sensitivity in patients affected by RD was 5.68 ± 6.08 dB (mean ± SD) on MP1 (9.66 ± 10.06 dB converted to their equivalent MAIA values) and 14.66 ± 9.37 dB on MAIA (P < 0.0001). Mean retinal sensitivity in healthy subjects was 18.46 ± 3.10 dB on MP1 (22.44 ± 7.08 dB on their converted equivalent MAIA values) and 28.52 ± 1.12 dB on MAIA (P < 0.0001). Thirty eyes affected by RD (41%) showed retinal areas characterized by sensitivity under 1 dB on MP1, whereas the MAIA examination of the same areas revealed a mean retinal sensitivity of 4.7 dB. Moreover, 28 of these eyes disclosed also areas of absolute scotoma on MP1, but examining the same areas on MAIA, just 13 of these eyes (46%) disclosed an absolute scotoma. In addition, in a subgroup of 6 eyes affected by RD (8%) showing a retinal sensitivity of 20 dB on MP1, the corresponding value on MAIA varied from 26.3 dB to 30.0 dB, with a mean value of 27.8 ± 1.3 dB. CONCLUSION: The MAIA microperimeter provides a more accurate characterization of functional impairment in RD with respect to the MP1 system, especially in cases with low and high retinal sensitivity. MAIA microperimeter could reveal particularly useful in precisely identifying and monitoring subtle changes in retinal sensitivity, especially in view of the availability of therapies aiming at a functional rescue in patients with RD.

Impact of intravitreal dexamethasone implant (Ozurdex) on macular morphology and function.

PURPOSE: To investigate the impact of intravitreal dexamethasone implant (Ozurdex) on macular morphology and function in eyes with macular edema secondary to central retinal vein occlusion. METHODS: Twelve treatment-naive patients with decreased visual acuity because of central retinal vein occlusion-related macular edema were enrolled in this prospective uncontrolled study. Patients were treated with intravitreal Ozurdex and followed up at 1 month and 3 months for the evaluation of morphologic and functional outcomes, by means of best-corrected visual acuity, microperimetry, multifocal electroretinography, and customized high-resolution enhanced depth imaging spectral-domain optical coherence tomography scans. RESULTS: Twelve eyes of 12 patients (10 men, 2 women; mean age 56.2 ± 13.0 years) were included for analysis. At 1 month, mean best-corrected visual acuity, retinal sensitivity (microperimetry), multifocal electroretinography parameters, central macular thickness, and specific neurosensorial retinal measurements improved significantly. We found a significant negative correlation between retinal sensitivity and central macular thickness at 1 month and 3 months (r = -0.831, P = 0.001; r = -0.881, P = 0.001; respectively). Moreover, retinal sensitivity was negatively related to both outer and inner retinal thickness in all four intervals from the fovea. From baseline to Month 1, change in outer retinal thickness was positively related to multifocal electroretinography N1R1 amplitude change (r = 0.698, P = 0.012), whereas change in central macular thickness was negatively related to multifocal electroretinography P1R1 amplitude change (r = -0.701, P = 0.011). At 3 months, improvement of mean retinal sensitivity and central macular thickness slightly decreased. CONCLUSION: In eyes with macular edema secondary to central retinal vein occlusion, intravitreal dexamethasone provides functional benefits that correlate well with ultrastructural macular changes.

Intravitreal bevacizumab for extrafoveal choroidal neovascularization secondary to pathologic myopia.

PURPOSE: To assess the effects of intravitreal bevacizumab injections in the treatment of extrafoveal choroidal neovascularization (CNV) associated with pathologic myopia. METHODS: Patients diagnosed with pathologic myopia complicated by extrafoveal CNV were considered in this prospective, open-label interventional study. All patients underwent a complete ophthalmologic examination, including Early Treatment Early of Diabetic Retinopathy Study (ETDRS) visual acuity measurement, optical coherence tomography, and fluorescein angiography. The protocol treatment included a first injection, followed by repeated injections over a 24-month follow-up period on the basis of optical coherence tomography and angiographic features, monitored monthly. Primary outcomes were the mean changes in best-corrected visual acuity and the proportion of eyes gaining at least 15 letters at the 24-month examination. Secondary outcomes included central macular thickness, size of the CNV, and extension to the fovea. RESULTS: Fifteen patients were included in the study. Mean best-corrected visual acuity changed from 0.47 logarithm of the minimum angle of resolution (20/60 Snellen equivalent) at baseline to 0.22 logarithm of the minimum angle of resolution (20/30 Snellen equivalent) at the 24-month examination. An improvement of at least 3 ETDRS lines was achieved by 7 eyes (46.6%) at the 24-month examination. Mean central macular thickness changed from 313 µm to 254 µm at the 24-month examination (P = 0.008). Mean CNV size decreased from 348 µm2 to 251 µm2 at 24 months (P = 0.029). CONCLUSION: Intravitreal bevacizumab injection is a beneficial treatment for extrafoveal CNV associated with pathologic myopia.