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Show Optic Atrophy and a Leigh-Like Syndrome Due to Mutations in the C12orf65 Gene: Report of a Novel Mutation and Review of the Literature Gena Heidary, MD, PhD, Laurel Calderwood, MS, CGC, Gerald F. Cox, MD, PhD, Caroline D. Robson, MBChB, Lisa A. Teot, MD, Jennifer Mullon, MD, Irina Anselm, MD Abstract: Combined oxidative phosphorylation deficiency type 7 (COXPD7) is a rare disorder of mitochondrial metab-olism that results in optic atrophy and Leigh syndrome-like disease. We describe 2 siblings with compound heterozygous mutations in the recently identified C12orf65 gene who pre-sented with optic atrophy and mild developmental delays and subsequently developed bilateral, symmetric lesions in the brainstem reminiscent of Leigh syndrome. Repeat neuroi-maging demonstrated reversibility of the findings in 1 sibling and persistent metabolic stroke in the other. This article high-lights the phenotypic manifestations from a novel mutation in the C12orf65 gene and reviews the clinical presentation of the 5 other individuals reported to date who carry mutations in this gene. Journal of Neuro-Ophthalmology 2014;34:39-43 doi: 10.1097/WNO.0000000000000076 © 2013 by North American Neuro-Ophthalmology Society Combined oxidative phosphorylation deficiency type 7 (COXPD7) was first described in 2010 as a rare dis-order of mitochondrial metabolism caused by mutations in the C12orf65 gene (chromosome 12 open reading frame 65) that may manifest as optic atrophy, external ophthal-moplegia, and Leigh syndrome-like encephalopathy (1). The C12orf65 gene encodes a mitochondrial matrix protein that is critical for the release of newly synthesized proteins from mitochondrial ribosomes. Loss-of-function mutations impair the translation of mitochondrial proteins, with a resul-tant decrease in the protein complexes necessary for effective oxidative phosphorylation (1,2). The COXPD7 phenotype has been described in 2 distinct pedigrees by Antonicka et al (1). A third family has been reported with mutations in the C12orf65 gene with optic atrophy and spastic paraplegia (3). We further delineate the COXPD7 phenotype with the report of 2 siblings who harbor 1 previously reported muta-tion and 1 novel mutation in the C12orf65 gene. CASE REPORTS Case 1 A 7-year-old boy, the third of 9 children born to healthy Caucasian, nonconsanguineous parents, experienced devel-opmental delay, including speech, and decreased energy compared with his siblings. His parents noted the onset of nystagmus by 9 months of age. At 2 years, visual acuity was 20/130 with each eye tested by preferential looking and on examination there was vertical nystagmus and diffuse optic atrophy bilaterally. Brain magnetic resonance imaging (MRI) and spectroscopy were normal. The patient's vision plateaued in the 20/200 range bilaterally by optotype acuity testing and remained stable until 7 years of age. At that time, the patient had a drop in vision in the left eye to 6/200 and subtle abduction limitation of the right eye consistent with a sixth nerve palsy. Neurologic examination was notable for decreased movement of the left side of the face. He had slightly reduced strength in his lower extremities, brisk deep tendon reflexes, and upgoing toes. A lumbering gait along with modified Gowers maneuver was noted. There was bilateral intention tremor and dysmetria. Magnetic resonance imaging revealed areas of T2 prolongation involving the bilateral periaqueductal gray matter, extending inferiorly along the pontine Departments of Ophthalmology (GH, JM), Neurology (LC, IA), Genetics (GFC), Radiology (CDR), and Pathology (LAT), Boston Children's Hospital and Harvard Medical School, Boston, Massa-chusetts; and Clinical Development Program, Genzyme (GFC), A Sanofi Company, Cambridge, Massachusetts. The authors report no conflicts of interest. G. Heidary and L. Calderwood contributed equally to the work. Address correspondence to Irina Anselm, MD, Department of Neu-rology, Boston Children's Hospital, 300 Longwood Avenue, Fegan 11, Boston, MA 02115; E-mail: irina.anselm@childrens.harvard.edu Heidary et al: J Neuro-Ophthalmol 2014; 34: 39-43 39 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. tegmentum and facial colliculi, terminating in the dorsal aspect of the central medulla (Fig. 1). These areas were not associated with brainstem expansion or volume loss. Diffu-sion- weighted imaging (DWI) demonstrated mixed diffu-sion characteristics with areas of low and high diffusivity. Magnetic resonance spectroscopy showed nonspecific mildly elevated choline-N-acetylaspartate ratio within the region of signal abnormality of the right midbrain. This constellation of findings was suggestive of Leigh syndrome. Plasma and cerebrospinal fluid (CSF) lactate levels were normal, as was pyruvic acid in whole blood and plasma creatine kinase levels. Lumbar puncture revealed decreased glucose of 56 mg/dL (normal: 60-80 mg/dL) and low pro-tein of 13.8 mg/dL (normal: 15.0-45.0 mg/dL), with nor-mal CSF amino acids, neurotransmitters, sialic acid, and 5-methyltetrahydrofolate. Mitochondrial DNA analysis showed 2 nonpathogenic homoplasmic Leber heredity optic neuropathy secondary mutations: m.4216T.C and m.13708G.A, but was otherwise normal. Testing of a 16-gene panel for optic atrophy and progressive external ophthalmoplegia (GeneDx, Gaithersburg, MD) demon-strated 2 frameshift mutations in the C12orf65 gene that were predicted to be pathogenic: c96_99dupATCC (p.Pro34IlefsX25) and c.210delA (p.Gly72AlafsX13), confirming the diagnosis of COXPD7. These 2 mutations are known to be on separate C12orf65 alleles (in trans) because the initial testing revealed that both were present in the same amplicon by Next Generation sequencing. No sequence or deletion/duplication mutations were identi-fied in the AUH, C10ORF2, CISD2, NDUFSI, OPA1, OPA3, POLG1, POLG2, RRM2B, SLC25A4, SPG7, TIM-M8A, TMEM126A, TYMP, and WFS1 genes. The patient was prescribed multivitamins and ubiquinol. Follow-up ophthalmic examination showed resolution of the esotropia and subsequently an intermittent left exotropia. The patient eventually regained normal ocular alignment over several months. Visual acuity remained unchanged at 20/200, right eye, and 6/200, left eye. Examination at 8 years of age demonstrated moderate improvement of facial asymmetry. Repeat brain MRI 6 months later showed a decrease in the extent of the T2 prolongation previously identified within the midline medulla, ventral pons, and periaqueductal regions, with extension into the midbrain around the red nucleus. The optic nerve sheaths remained dilated bilaterally (Fig. 2). Case 2 The younger sister of Case 1, and the fifth of 9 children in the sib-ship had ophthalmic evaluation at 4 years of age and was found to have 20/200 vision in each eye and diffuse bilateral optic atrophy. She had no history of nystagmus. The birth and developmental history were similar to her affected brother with developmental and speech delay and decreased energy. Brain MRI revealed only prominent CSF spaces surrounding each optic nerve. Neurologic testing demonstrated full and symmetric facial movements and normal strength throughout. One year later, the patient developed acute, external ophthalmoplegia characterized by bilateral sixth nerve palsies and a precipitous decline in vision of the right eye to 4/200. Neurologic examination was notable for facial asymmetry and a deviated tongue. All deep tendon reflexes were brisk, with right greater than left in the upper extremities. There was a positive Babinski sign. Romberg was positive. Tone was noted to be increased in the lower extremities. There was a decrease in energy, stamina, and appetite and a remarkable decline in the patient's expressive language abilities. Magnetic resonance imaging revealed symmetric para-median T2 prolongation in both cerebral peduncles extending inferiorly into the midbrain, dorsal pons, superior and inferior colliculi, and superior aspect of the medulla FIG. 1. Case 1. Fat-suppressed axial T2 magnetic resonance imaging (1.5 T) obtained at 7 years of age. A. There is a rounded area of high signal intensity within the central, posterior aspect of the medulla (arrow). B. The abnormal signal intensity extends cephalad to involve the dorsal pons (arrows). There is prominent cerebrospinal fluid signal around the thinned optic nerves consistent with optic atrophy. C. Abnormal signal extends asymmetrically around the periaqueductal region of the midbrain (arrows) with more ventral extension into the right cerebral peduncle. 40 Heidary et al: J Neuro-Ophthalmol 2014; 34: 39-43 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Fig. 3). On DWI, these areas exhibited mildly decreased diffusion. The optic nerves, chiasm, and optic tracts were mildly atrophic but without signal abnormality. Magnetic resonance spectroscopy over the midbrain revealed a small lactate peak. Plasma lactate and pyruvate levels were normal. Creatine kinase was mildly elevated at 189 U/L (normal: 4-150 U/L). Chemistry panel and liver function tests were normal. The patient also was positive for the same mutations in the C12orf65 gene (c.96_99dupATCC and c.210delA) and she was started on the multivitamins and ubiquinol. Although the patient's bilateral external opthalmoplegia remained stable, she developed cardiomyopathy with mild left ventricular hypertrophy, as well as an irregular breathing pattern. Repeat neuroimaging 4 months later showed brainstem lesions to be unchanged. The patient died from respiratory failure less than 1 year after the onset of her brainstem changes. Autopsy was declined. Both siblings had skin biopsies with testing of cultured skin fibroblasts for electron transport chain enzyme activity. Electron microscopy demonstrated increased numbers and enlargement of mitochondria in essentially all types of cells visualized, including endothelial cells, epithelial cells of the sweat ducts, fibroblasts, myelinated and nonmyelinated nerves, and lymphocytes. The enlarged mitochondria had prominent, often densely packed cristae, including wavy or stacked forms. The mitochondrial matrix was finely granular with scattered, small, electron dense deposits (Fig. 4). Activity of complex IV (cytochrome c oxidase) was reduced to below 40% of normal controls in Case 1 and below 30% in Case 2. Their remaining siblings, with the exception of an infant brother, underwent ophthalmic evaluations that were normal. Genetic testing of other family members has not been performed. There is no family history of metabolic or mitochondrial disorders, seizures, developmental delay, or genetic disorders. FIG. 2. Case 1. Repeat axial T2 magnetic resonance imaging (3T). A. There is a decrease in the size and extent of the previously noted medullary signal abnormality (arrow). B. There are small residual foci of signal abnormality within the dorsal pons (arrows). The appearance of the optic nerves is unchanged. C. The signal abnormality within the midbrain also has decreased in extent (arrows). FIG. 3. Case 2. Axial T2 magnetic resonance imaging (3 T) at 5 years of age. A. There are bilateral symmetric areas of increased signal involving the medulla (arrows). The abnormal signal extends to involve the dorsal pons (B) (arrows) and midbrain (C) with predominantly periaqueductal involvement (arrows). There are also foci of abnormal high signal intensity within the substantia nigra (arrowheads). Prominent cerebrospinal fluid signal surrounds the optic nerves consistent with optic atrophy. Heidary et al: J Neuro-Ophthalmol 2014; 34: 39-43 41 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. DISCUSSION We report the fourth pedigree of patients to harbor mutations in the C12orf65 gene and whose clinical phenotype is consis-tent with a diagnosis of COXPD7. In both siblings, the initial manifestation of the disease was optic atrophy. Later in the disease course, each patient developed neurologic impairment and neuroimaging findings resembling those seen in Leigh syndrome. The appearance of optic atrophy antedating neu-rologic decline distinguishes COXPD7 from typical Leigh syndrome and other similar pediatric neurodegenerative disor-ders in which optic atrophy occurs concomitantly with clinical manifestations of neurologic or systemic disease (4). In the older brother, there was clinical and radiographic improve-ment, but the young sibling's clinical course was characterized by a precipitous decline from which she did not recover. Neither patient had a significant elevation of plasma or CSF lactate, indicating that normal values in these first-tier assess-ments do not exclude the diagnosis of COXPD7. In addition to the neurologic complications from this disease process, Case 2 developed cardiomyopathy, a feature seen in other mito-chondrial diseases. In 2010, Antonicka et al (1) described the first cases of COXPD7 in 3 individuals from 2 families. The first patient was of Turkish descent and born to consanguine-ous parents. She presented with developmental regression after age 1 year and external ophthalmoplegia and ptosis at 18 months. Magnetic resonance imaging at 2 years of age revealed bilateral lesions involving the thalami and brain-stem, and a presumed diagnosis of Leigh syndrome was made. Optic atrophy was confirmed at 5 years of age and the patient died at 8 years of age. Genetic testing revealed a homozygous 1-base pair deletion, c.248delT, causing a frameshift. The second pedigree involved 2 brothers of nonconsanguineous Dutch origin. Both developed nystag-mus within the first 2 years of life and both developed optic atrophy. Each had normal MRI of the brain, as was the case for our 2 siblings. Between 3 and 8 years of age, each of the Dutch children suffered from progressive cognitive and neurologic decline. The brothers were homozy-gous for a 1-base pair deletion, c.201delA, causing a frameshift. More recently, Shimazaki et al (3) reported a consanguin-eous Japanese family with homozygous nonsense mutation c.C394T (p.R132X) in C12orf65 that manifested clinically as optic atrophy and spastic paraplegia. In this family, 2 affected brothers showed loss of visual acuity by 7 years of age, with the onset of peripheral neuropathy and spasticity of the lower extremities by 10 years of age, which progressed into adulthood. Final reported vision was in the range of legal blindness for each brother. To date, all the mutations associated with the COXPD7 phenotype have been homozygous loss-of-function mutations involving either frameshifts or nonsense mutations. One of the 2 mutations identified in our cases was c.210delA, a frameshift mutation that was previously observed in the homozygous state in 2 Dutch siblings with a similar phenotype (1). It is predicted to cause a loss of normal protein function through protein truncation. The second mutation found in our sib-lings, c.96_99 dupATCC, is a novel one. It is predicted to cause a frameshift at codon 34, changing the proline to iso-leucine and creating a premature stop codon at position 25 of the new reading frame (p.Pro34IlefsX25). It may cause a loss of normal protein function either through protein truncation or nonsense-mediated messenger RNA decay. Electron transport chain activity in patients in these cohorts has been previously described as abnormal with severe assembly defects in complexes I, III, IV, and V (1,3). Kogure et al (2) found that knockdown of the C12orf65 protein in cell culture assays resulted in an increase in reactive oxygen species and apoptosis. Mitochondrial dysfunction was demonstrated by impaired cytochrome c oxidase activity. To date, the ultrastructural features of mitochondria have not been reported in patients with C12orf65 muta-tions. In our 2 patients, electron microscopy revealed enlarged mitochondria engorged by an abnormal number of densely packed cristae. The features identified are similar to the ultrastructural findings described to be present in Leber hereditary optic neuropathy (5-7). FIG. 4. Electron photomicrographs of skin biopsies. A. Case 2. Abnormal mitochondria vary in size (black arrows) with enlarged forms (white arrow). Cristae in many mitochondria are decreased in number, irregularly spaced, and haphazardly oriented. Tubular (black arrowhead) and curved (white arrowhead) cristae are present. Stacked cristae, which were found in some mitochondria, are not present in this illustration. B. Case 1. Increased number of abnormal mitochondria are present. Small, electron dense bodies (arrows), but no crystalline structures, are present. 42 Heidary et al: J Neuro-Ophthalmol 2014; 34: 39-43 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Our cases have characteristics similar to previously reported patients with COXPD7 deficiency but also have several unique features. All cases demonstrated optic atrophy pre-ceding the development of other neurological symptoms. Leigh-like disease features on brainMRI previously reported in the literature are reminiscent of those seen in our patients. Reduced activity of complex IV of the electron transport chain noted in a previous report (1) was also demonstrated in our patients. We add 2 new observations. One of our 2 patients experienced significant improvement in neurological symp-toms and almost complete reversal of MRI abnormalities. His sibling developed abnormal breathing and cardiomyopa-thy that seem related to the underlying disease. Our report suggests that in pediatric patients with acquired optic atrophy, clinicians should probe the clinical history for other neurological symptoms and consider the need for broad genetic testing. Genotype confirmation will guide appropriate management and treatment from the limited options currently available as well as provide important information regarding the recurrence risks of optic atrophy and other medical concerns for the affected families. REFERENCES 1. 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