Retinopathy and optic atrophy in a case of COQ2-related primary coenzyme Q10 deficiency.

PURPOSE: To describe a case of primary coenzyme Q10 deficiency in a child manifesting as early-onset renal failure, retinal dystrophy, and optic atrophy leading to progressive vision loss. METHODS: Clinical presentation and workup including visual fields, electroretinogram, and optical coherence tomography are presented. Genetic testing was performed. RESULTS: An eight-year-old female with nephropathy requiring renal transplantation subsequently developed progressive cone-rod dystrophy and optic atrophy. The patient had negative results on a targeted next-generation sequencing retinal dystrophy panel but whole-exome sequencing revealed two variants in COQ2 (likely biallelic), consistent with a diagnosis of primary coenzyme Q10 deficiency. CONCLUSIONS: Primary coenzyme Q10 deficiency is a rare disorder with variable systemic and ocular findings; there is also genetic heterogeneity. Genetic testing aids in the diagnosis of this condition, and variants in the COQ2 and PDSS1 genes appear to have the strongest association with ocular manifestations. Oral supplementation of coenzyme Q10 may slow progression of disease. This case highlights the utility of whole-exome sequencing in the diagnosis of a rare syndromic form of ocular disease and reports a novel phenotypic association for this condition.

Neuropatía óptica en un caso de paquimeningitis hipertrófica idiopática recurrente sin respuesta a esteroides e inmunosupresores / Optic neuropathy in a case of recurrent idiopathic hypertrophic pachymeningitis unresponsive to steroids and immunosuppressants

CASO CLÍNICO: Mujer de 38 años con pérdida visual en ojo izquierdo y papiledema bilateral. La resonancia magnética nuclear (RMN) mostraba engrosamiento de la duramadre y la presión intracraneal estaba elevada. Se descartó enfermedad infecciosa, tumoral y autoinmune. DISCUSIÓN: La respuesta inicial a corticoides fue satisfactoria con desaparición del edema de disco óptico, mejoría de la agudeza visual y mejoría radiológica. Después de un año sin tratamiento presentó un nuevo brote, desarrollando una neuropatía óptica izquierda con pérdida irreversible de visión a pesar del retratamiento con corticoides y azatioprina

CASE REPORT: A 38-year-old female patient with bilateral papilledema who presented with loss of vision in her left eye. The Magnetic Resonance Imagining (MRI) showed thickening of the dura mater, and the intracranial pressure was elevated. A cancer, infectious, and autoimmune origin was ruled out. DISCUSSION: The initial response to high doses of corticoids was satisfactory, with disappearance of the optic disc enema, with visual acuity and an improvement in the MRI. However, after one year without treatment she had a new outbreak of the disease. Despite renewed treatment with corticoids and azathioprine, the patient developed a left optic neuropathy and irreversible visual loss

Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induces visual loss and optic atrophy in mice.

PURPOSE: Although mutated G11778A NADH ubiquinone oxidoreductase subunit 4 (ND4) mitochondrial DNA (mtDNA) is firmly linked to the blindness of Leber hereditary optic neuropathy (LHON), a bona fide animal model system with mutated mtDNA complex I subunits that would enable probing the pathogenesis of optic neuropathy and testing potential avenues for therapy has yet to be developed. METHODS: The mutant human ND4 gene with a guanine to adenine transition at position 11778 with an attached FLAG epitope under control of the mitochondrial heavy strand promoter (HSP) was inserted into a modified self-complementary (sc) adeno-associated virus (AAV) backbone. The HSP-ND4FLAG was directed toward the mitochondria by adding the 23 amino acid cytochrome oxidase subunit 8 (COX8) presequence fused in frame to the N-terminus of green fluorescent protein (GFP) into the AAV2 capsid open reading frame. The packaged scAAV-HSP mutant ND4 was injected into the vitreous cavity of normal mice (OD). Contralateral eyes received scAAV-GFP (OS). Translocation and integration of mutant human ND4 in mouse mitochondria were assessed with PCR, reverse transcription-polymerase chain reaction (RT-PCR), sequencing, immunoblotting, and immunohistochemistry. Visual function was monitored with serial pattern electroretinography (PERG) and in vivo structure with spectral domain optical coherence tomography (OCT). Animals were euthanized at 1 year and processed for light and transmission electron microscopy. RESULTS: The PCR products of the mitochondrial and nuclear DNA extracted from infected retinas and optic nerves gave the expected 500 base pair bands. RT-PCR confirmed transcription of the mutant human ND4 DNA in mice. DNA sequencing confirmed that the PCR and RT-PCR products were mutant human ND4 (OD only). Immunoblotting revealed the expression of mutant ND4FLAG (OD only). Pattern electroretinograms showed a significant decrement in retinal ganglion cell function OD relative to OS at 1 month and 6 months after AAV injections. Spectral domain optical coherence tomography showed optic disc edema starting at 1 month post injection followed by optic nerve head atrophy with marked thinning of the inner retina at 1 year. Histopathology of optic nerve cross sections revealed reductions in the optic nerve diameters of OD versus OS where transmission electron microscopy revealed significant loss of optic nerve axons in mutant ND4 injected eyes where some remaining axons were still in various stages of irreversible degeneration with electron dense aggregation. Electron lucent mitochondria accumulated in swollen axons where fusion of mitochondria was also evident. CONCLUSIONS: Due to the UGA codon at amino acid 16, mutant G11778A ND4 was translated only in the mitochondria where its expression led to significant loss of visual function, loss of retinal ganglion cells, and optic nerve degeneration recapitulating the hallmarks of human LHON.

Optic atrophy as a sign of wolfram syndrome.

BACKGROUND: The hallmark of Wolfram syndrome -- an extremely rare autosomal recessive disorder -- is the association of juvenile onset diabetes mellitus with optic atrophy. Additional symptoms such as deafness and diabetes insipidus may develop. HISTORY AND SIGNS: An 18-year-old man suffered progressive visual loss over the last seven years. Severe optic atrophy with extensive cupping and slightly elevated intraocular pressure in both eyes were found. Perimetry revealed peripheral defects with paracentral scotomas. ERG results excluded tapetoretinal degeneration; visual evoked responses were delayed. At the age of nine the patient had been diagnosed with diabetes mellitus type I and neurosensory deafness, seven years later a beginning hypogonadism was found. THERAPY AND OUTCOME: Wolfram syndrome is a progressive degenerative disorder with reduced life expectancy. Treatment is symptomatic. CONCLUSIONS: Wolfram syndrome should be considered in every patient who presents with optic atrophy and juvenile onset diabetes mellitus.

Progressive optic atrophy associated with juvenile diabetes mellitus: report of two cases among first cousins.

Two first cousins both suffering from insulin dependent diabetes mellitus since early childhood developed progressive optic atrophy from the age of 5 and 9 years respectively. They had similar ophthamological features which include optic atrophy with cupping, paracentral scotomata, and total achromatopsia. One patient also had stunted growth, delayed puberty and psychiatric disorder. Neither had diabetes insipidus and deafness. It is suggested that they may be a variant of DIDMOAD (Diabetes Insipidus, Juvenile Diabetes Mellitus, Optic Atrophy, Deafness).

Leber's optic atrophy with myopia masquerading as glaucoma: case report.

In recent years there has been much discussion in the literature regarding the proper approach to the patient who presents with apparent "low tension" glaucoma. In addition to a complete workup and proper management of such a patient, careful consideration must be given to the differential diagnosis of clinical conditions presenting with optic disc cupping and visual field changes. We present an interesting clinical situation in which a patient with severe myopia and Leber's optic atrophy was referred for surgery for treatment of apparent progressive "low tension" glaucoma.