Title | Novel Mitochondrial Translation Optimizer-1 Mutations as a Cause of Hereditary Optic Neuropathy |
Creator | Emily Li; Valentina Emmanuele; Francine Testa; Cristiane De Araujo Martins Moreno; Michio Hirano; Robert L. Lesser |
Affiliation | Department of Ophthalmology and Visual Science (EL, RLL), Yale University School of Medicine, New Haven, Connecticut; Department of Neurology (VE, CDAMM, MH), Columbia University Irving Medical Center, New York, New York; and Department of Neurology (FT, RLL), Yale University School of Medicine, New Haven, Connecticut |
Abstract | Mitochondrial diseases encompass a wide spectrum of inherited disorders associated with dysfunction of mitochondrial oxidative phosphorylation. They can arise at any age and can involve virtually any organ system, often leading to multisystem presentations (1). The birth prevalence is 6.2 in 100,000 and significantly higher in consanguineous communities (2). Mitochondrial diseases have been ascribed to numerous mutations both in nuclear and mitochondrial DNA. Mitochondrial tRNA translation opt-mization 1 (MTO1) gene is a nuclear gene required for mitochondrial protein translation. Biallelic mutations in this gene were initially described in 2012 in patients with infantile onset cardiomyopathy and lactic acidosis (3). Since then, 35 patients from 27 unrelated families have been reported (4-11). Of these, 11 cases (31%) were associated with optic neuropathy (4,5,7,9,10). We report 2 novel MTO1 mutations, one of which is the first nonsenseMTO1mutation known to cause human disease, associated with hereditary optic neuropathy in our patient but not in his brother, who had the same mutations. |
Subject | Adolescent; DNA Mutational Analysis; DNA, Mitochondrial / genetics; Humans; Male; Mutation; Optic Atrophy, Hereditary, Leber / genetics; Optic Atrophy, Hereditary, Leber / metabolism; RNA-Binding Proteins / genetics; RNA-Binding Proteins / metabolism |
OCR Text | Show Clinical Correspondence Novel Mitochondrial Translation Optimizer-1 Mutations as a Cause of Hereditary Optic Neuropathy Emily Li, MD, Valentina Emmanuele, MD, PhD, Francine Testa, MD, Cristiane De Araujo Martins Moreno, MD, Michio Hirano, MD, Robert L. Lesser, MD M itochondrial diseases encompass a wide spectrum of inherited disorders associated with dysfunction of mitochondrial oxidative phosphorylation. They can arise at any age and can involve virtually any organ system, often leading to multisystem presentations (1). The birth prevalence is 6.2 in 100,000 and significantly higher in consanguineous communities (2). Mitochondrial diseases have been ascribed to numerous mutations both in nuclear and MTO1 mutation known to cause human disease, associated with hereditary optic neuropathy in our patient but not in his brother, who had the same mutations. A 17-year-old boy with an extensive systemic medical history presented with bilateral painless, progressive visual decline over the preceding several months causing difficulty with seeing the blackboard, reading, and writing at school. Concurrently, his parents noted associated decline FIG. 1. Color photographs of the optic nerve in the (A) right eye and (B) left eye. There is demonstration of normal macula, temporal optic nerve pallor, and circumpapillary telangiectasias bilaterally. mitochondrial DNA. Mitochondrial tRNA translation optimization 1 (MTO1) gene is a nuclear gene required for mitochondrial protein translation. Biallelic mutations in this gene were initially described in 2012 in patients with infantile-onset cardiomyopathy and lactic acidosis (3). Since then, 35 patients from 27 unrelated families have been reported (4-11). Of these, 11 cases (31%) were associated with optic neuropathy (4,5,7,9,10). We report 2 novel MTO1 mutations, one of which is the first nonsense Department of Ophthalmology and Visual Science (EL, RLL), Yale University School of Medicine, New Haven, Connecticut; Department of Neurology (VE, CDAMM, MH), Columbia University Irving Medical Center, New York, New York; and Department of Neurology (FT, RLL), Yale University School of Medicine, New Haven, Connecticut. The authors report no conflicts of interest. Address correspondence to Emily Li, MD, Department of Ophthalmology and Visual Science, Yale University School of Medicine, 40 Temple Street, Suite 3D, New Haven, CT 06510; E-mail: emily.li@yale.edu 406 in cognitive function. His medical history was notable for cardiomyopathy characterized by left ventricular hypertrophy and pulmonary stenosis diagnosed at 2 weeks of age; developmental delay with acquisition of sitting at 9 months, ability to walk independently at 19 months, and delayed speech; failure to thrive in infancy; and exercise intolerance and anxiety during childhood. At age 17, he had his first generalized seizure, which responded to treatment and has remained stable. An ophthalmic examination at age 12 showed a baseline visual acuity of 20/20 and no abnormal findings in both eyes. He did not use alcohol, tobacco, or illicit drugs. Treatment included ascorbic acid, vitamin B complex, multivitamin, ubidecarenone (coenzyme Q10), levocarnitine, and lamotrigine. He had a 19-year-old brother with a similar but milder phenotype characterized by congenital cardiac defects, developmental delay, epilepsy, and milder intellectual disability, but no vision loss. His parents were in good general health without eye problems. Li et al: J Neuro-Ophthalmol 2020; 40: 406-410 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Optical coherence tomography of the retinal nerve fiber layer (A) at presentation and (B) at 2 years of follow-up showing bilateral temporal thinning. At the time of presentation, the patient's neurological examination showed impaired memory, sparse speech, hypotonia, and brisk tendon reflexes. His visual acuities were 20/400 on the right and 20/200 on the left. Examination was remarkable for optic nerve temporal pallor and circumpapillary telangiectasias in both eyes (Fig. 1A, B). Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) demonstrated bilateral temporal thinning (Fig. 2A). Serologic testing for sarcoidosis, Lyme antibodies, and aquaporin-4 antibodies, MRI of the brain with and without contrast, and cerebrospinal fluid analysis were all negative. Blood lactate was elevated (4.6 mmol/L, normal ,2 mmol/L). Skeletal muscle histology was unremarkable. Respiratory chain enzyme activities (RCA) in skinderived fibroblasts from the proband and the brother assessed as previously described (12) showed combined deficiencies and elevation of citrate synthase, a marker of mitochondrial mass (Table 1). Genetic evaluation for Leber hereditary optic neuropathy (LHON) commonly associLi et al: J Neuro-Ophthalmol 2020; 40: 406-410 ated mutations m.11778 G . A, m.14484T . C, and m.3460 G . A was negative (13). Whole exome sequencing revealed the presence of 2 novel heterozygous mutations in MTO1 gene (ENST00000498286): p.R484W and p.R488*. The missense mutation was predicted to be pathogenic by in-silico analyses (PROVEAN, SIFT, and PolyPhen-2) (14,15). The brothers carried both mutations, TABLE 1. Respiratory chain enzyme activities normalized to citrate synthase Controls Proband Sibling COX/CS I + III/CS II + III/CS II/CS 0.87 ± 0.08 0.38 0.38 1.38 ± 0.38 0.47 0.32 0.41 ± 0.14 0.18 0.18 1.95 ± 0.17 1.34 1.61 Activities are expressed as ratios. Controls are means ± SDs (n = 4). COX, cytochrome c oxidase; CS, citrate synthase; I + III, NADHcytochrome c reductase; II + III, succinate-cytochrome c reductase; II, succinate dehydrogenase. 407 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence TABLE 2. Published cases of optic neuropathy in patients with at least one identified MTO1 mutation Publication Current report Family History Cardiac defects, developmental delay, epilepsy, and mild intellectual disability (brother) Sex, Age at the Last Follow-up (yrs) Male, 19 Intellectual disability (maternal uncle), speech delay, and hyperactivity (maternal first cousin) None Female, 16 None Female, 19 None Female, 16 Yes*, brother (see below) Female, 30 Yes*, sister (see above) Male, 28 Baruffini et al (5) None Male, 20 Ghezzi et al (4) None Male, 19 O'Byrne et al (10) Martin et al (9) Charif et al (7) Male, 16 Ocular Features Additional Clinical Features MTO1 Mutation Homozygous Visual acuities of 20/400 on Developmental delay, p.R484W and hypertrophic the right and 20/200 on p.R488* cardiomyopathy, and the left, bilateral optic intellectual disability, nerve pallor and epilepsy circumpapillary telangiectasias, and bilateral temporal RNFL thinning on OCT Bilateral optic neuropathy Developmental delay, atypical Heterozygous p.R484Q and with "good visual acuity" febrile seizures, hypotonia, p.G425R and bilateral ptosis lactic acidosis, ataxia, intention tremor, and dysarthria Hypotonia, developmental Bilateral visual acuity of delay, intellectual 20/200 and optic atrophy, disability, hypertrophic bilateral GCL, and RNFL cardiomyopathy, lactic thinning on OCT acidosis, and ataxia, epileptic seizures Visual acuity 20/40 OD and Developmental delay, intellectual disability, lactic 20/30 OS, bilateral optic acidosis, dysmetria, atrophy, bilateral GCL and scoliosis, fatigability, and RNFL thinning on OCT, and hypertrophic palpebral tics cardiomyopathy Visual acuity 10/10 OD and Slight developmental delay, fatigability, hypertrophic 8/10 OS, slight bilateral cardiomyopathy, epileptic optic atrophy, and bilateral seizures, and lactic RNFL thinning on OCT acidosis Visual acuity 20/100 OD and Mild intellectual disability, hypertrophic 20/70 OS, bilateral optic cardiomyopathy, epileptic atrophy, bilateral RNFL seizures, and thinning on OCT, kyphoscoliosis cecocentral scotoma OD and enlarged blind-spot OS on visual field testing, normal photopic ERG, reduced P100 amplitude, and subnormal latency on VEP Bilateral visual acuity 20/20 Intellectual disability, fatigability, hypertrophic and cardiomyopathy, asthma, temporal optic atrophy, and kyphosis bilateral RNFL thinning on OCT, normal photopic ERG, reduced P100 amplitudes, and normal latencies on VEP Lack of ocular fixation and Weakness, hypertrophic bilateral optic atrophy cardiomyopathy with sinus bradycardia, and lactic acidosis Bilateral optic atrophy and Hypertrophic cardiomyopathy, increased P100 latency on lactic acidosis, and VEP reduced fine-motor skills Homozygous p.R504C and p.V557M Homozygous p.R504C and p.V557M Homozygous p.R504C Homozygous c.1510C.T Homozygous c.1510C.T Homozygous p [A428T] Homozygous p [A428T] The remaining 3 cases (11 total identified by O'Byrne et al) have not been reported in the literature. *The 2 patients are related and have no additional siblings. FHx, family history of mitochondrial disorder; GCL, ganglion cell layer; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer; VEP, visual-evoked potential. 408 Li et al: J Neuro-Ophthalmol 2020; 40: 406-410 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence and each parent carried one of the mutant alleles. The patient was counseled to refrain from alcohol and tobacco use and started on an empiric trial of nicotinamide riboside, an oral precursor to vitamin B3 and nicotinamide adenine dinucleotide, shown to induce mitochondrial biogenesis in cellular and animal models, and used experimentally in the treatment of mitochondrial myopathy and fatty liver disease (16,17). At the last follow-up 2 years after the initial presentation, he had continued bilateral vision loss to hand motion, temporal optic nerve pallor, and stabilized RNFL thinning on OCT (Fig. 2B). His neurological examination was stable as well as his cardiomyopathy. We describe a complex case of developmental delay, hypertrophic cardiomyopathy, intellectual disability, epilepsy, and hereditary optic neuropathy secondary to compound heterozygous novel mutations in MTO1 gene. Mutations in this gene have variable phenotypic expression, including optic neuropathy. Before this report, only 35 patients, from 27 unrelated families, had been described (3-11). The broad phenotypic spectrum encompasses a neonatal onset form, which is usually rapidly progressive and often fatal, and a late-onset slowly progressive or stable form. Early onset is usually associated with unfavorable prognosis (10). Hallmark features include cardiomyopathy, lactic acidosis, and cognitive disability (10). Optic neuropathy has been reported in the minority of patients (11/35 [31%]) with biallelic MTO1 mutations (Table 2) (4,5,7,9,10). These reported cases showed no strong sex predilection with optic atrophy occurring by adolescence or early adulthood. Reported visual acuity ranged from 20/20 to 20/200 bilaterally. All patients displayed bilateral optic atrophy with or without demonstration of RNFL thinning on OCT (4,5,7,9,10). Visual-evoked potential, when reported, had reduced P100 amplitude and varying latency (4,5,7,10). The genotype-phenotype relationship is not well delineated. It was hypothesized that the presence of a frameshift variant might be associated with an early neonatal presentation and a more severe prognosis and that a truncating mutation might not be compatible with survival (10). We describe for the first time a nonsense mutation associated with human disease; our proband with MTO1 mutations presented with late-onset and less severe phenotype than many reported cases, thus demonstrating that a truncating allele does not cause prenatal lethality. Moreover, the proband's brother had identical mutations but did not have any visual problems and had a milder disease course. The only published cases of MTO1-related optic neuropathy with significant family history are 2 related siblings with the p.R504C homozygous mutation. The ophthalmic disease severity differed among the 2 siblings-one had visual acuities of 20/100 in the right eye and 20/70 in the left eye, whereas the other had 20/20 vision bilaterally (7). Diagnosis was achieved by whole exome sequencing but suspected on the basis of the clinical phenotype and elevated Li et al: J Neuro-Ophthalmol 2020; 40: 406-410 lactate, which has been reported in all patients with MTO1 mutations. Pathogenicity was confirmed by detecting impaired RCAs in fibroblasts. Decreased RCAs in skinderived fibroblasts have been reported in 7/11 patients and represent an additional diagnostic tool (10,11). In conclusion, optic neuropathy is an uncommon manifestation of MTO1 mitochondrial disease and can resemble LHON. Genetic evaluation for MTO1 mutations is indicated in patients who test negative for mitochondrial DNA mutations and display systemic manifestations of mitochondrial disease, such as cardiomyopathy, lactic acidosis, and developmental delay/cognitive dysfunction. RCA assessment can be useful, but a negative result does not exclude the diagnosis. Genotype-phenotype correlations are complex and not completely understood. Intrafamilial variability in clinical presentation and severity make prognosis challenging. Better characterization of MTO1 diseases is warranted to facilitate awareness, diagnosis, and potential therapeutic development. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Li, V. Emmanuele, F. Testa, C. D. A. M. Moreno, M. Hirano, and R. Lesser; b. Acquisition of data: E. Li, V. Emmanuele, F. Testa, C. D. A. M. Moreno, M. Hirano, and R. Lesser; c. 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Date | 2020-09 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, September 2020, Volume 40, Issue 3 |
Collection | Neuro-Ophthalmology Virtual Education Library - Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah, 10 N 1900 E SLC, UT 84112-5890 |
Rights Management | © North American Neuro-Ophthalmology Society |
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Setname | ehsl_novel_jno |
ID | 1592978 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s6cs1hsr |