Recessive ACO2 variants as a cause of isolated ophthalmologic phenotypes.

The mitochondrial aconitase gene (ACO2) encodes an enzyme that catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid cycle. Biallelic variants in ACO2 are purported to cause two distinct disorders: infantile cerebellar-retinal degeneration (ICRD) which is characterized by CNS abnormalities, neurodevelopmental phenotypes, optic atrophy and retinal degeneration; and optic atrophy 9 (OPA9), characterized by isolated ophthalmologic phenotypes including optic atrophy and low vision. However, some doubt remains as to whether biallelic ACO2 variants can cause isolated ophthalmologic phenotypes. A review of the literature revealed five individuals from three families who carry biallelic ACO2 variants whose phenotypes are consistent with OPA9. Here, we describe a brother and sister with OPA9 who are compound heterozygous for novel missense variants in ACO2; c.[487G>T];[1894G>A], p.[(Val163Leu)];[(Val632Met)]. A review of pathogenic ACO2 variants revealed that those associated with OPA9 are distinct from those associated with ICRD. Missense variants associated with either OPA9 or ICRD do not cluster in distinct ACO2 domains, making it difficult to predict the severity of a variant based on position alone. We conclude that biallelic variants in ACO2 can cause the milder OPA9 phenotype, and that the OPA9-related ACO2 variants identified to date are distinct from those that cause ICRD.

De novo mutations of TUBB2A cause infantile-onset epilepsy and developmental delay.

We analyzed our two new cases of infantile-onset epilepsy with developmental delay with de novo variant in TUBB2A and review the related literatures. Our two probands were both girls with infantile-onset epilepsy and global developmental delay. Case 1 had a novel de novo heterozygous missense variant: c.728C>T [p.Pro243Leu] (NM_001069.2). Her brain magnetic resonance imaging (MRI) showed nonspecific white matter myelination delay and slightly enlarged anterior horn of lateral ventricle. Her epilepsy had been controlled by TPM monotherapy. Case 2 had a reported de novo variant c.743C>T [p.Ala248Val] (NM_001069.2). Her brain MRI showed bilateral microgyria and corpus callosum dysplasia. A total of seven TUBB2A mutations cases had been published previously in five papers, therefore, until now, there were nine patients with TUBB2A mutations. All patients had developmental delay, among them seven cases also with infantile-onset epilepsy, one case with abnormal EEG but without clinical seizures. There are six cases that have different degree of cortical dysplasia, one case with cerebellar vermis atrophy and brainstem sacsinopathy, the rest two cases have no obvious brain structural abnormalities. There was one case with variant c.1249G>A (p.D417N) that had atypical clinical presentation, including prominent progressive spastic ataxia, sensory motor axonal neuropathy, and bilateral optic macular dystrophy, but relatively mild intellectual disability, his MRI showed cerebellar atrophy, thinning of the corpus callosum and pons sacsinopathy, but no cortical malformation. The p.A248V mutation was the most common mutation occurred in three patients (3/9). The clinical phenotypes of these three patients were similar, all of them had global developmental delay with no language and corpus callosum dysplasia, two cases with epilepsy and the other one only have EEG epileptic discharges without clinical seizure, two cases with cortical dysplasia and the other one without obvious brain malformation. In brief, global developmental delay was the most common phenotype of TUBB2A mutation-related disease, most cases also had infantile-onset epilepsy and cortical dysplasia and corpus callosum dysplasia. The region between seventh and eighth alpha-helix of TUBB2A may be a "hot spot" mutation domain.

Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report.

A 38-year-old female patient experienced recurrent episodes of neurological deterioration during febrile illness at the age of 7 and 8 months, and 2, 4, and 37 years. Acute symptoms comprised unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disorders. Each episode of neurological deterioration was followed by partial recovery with residual symptoms of progressive disturbance of visual acuity with optic atrophy and hearing loss, moderate intellectual disability, strabismus, ophthalmoplegia, as well as fluctuating degree of gait ataxia, chorea, tremor, and myoclonus. In addition, electrocardiography revealed incomplete right bundle branch block. The genetic testing revealed a de novo heterozygous mutation of c.2452G > A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome. Here we discuss the significance of clinical features of a patient, overlapping with those of alternating hemiplegia of childhood, along with a literature review.

Ocular injury during fetal endoscopy surgery.

A premature infant born at 31 weeks' gestational age was evaluated for periocular laceration and retrobulbar hematoma secondary to injury during a percutaneous fetal procedure. He later developed optic nerve atrophy.

OCT-documented optic atrophy in nonsyndromic craniosynostosis and lacunar skull.

We report the case of 6-year-old boy who presented with mild redness in the left eye. On fundus examination, disk pallor was noted in both eyes. He did not complain of headache, vomiting, or blurred vision. Three-dimensional computed tomography (CT) imaging was suggestive of craniosynostosis and lacunar skull (lückenschädel). Magnetic resonance imaging findings were suggestive of intracranial hypertension. HD-OCT imaging revealed optic neuropathy in both eyes. The patient underwent sutural release and expansion cranioplasty surgery.

Atrofia coroidea relacionada con la edad en pacientes hispanos: serie de casos / Age-related choroidal atrophy in hispanics patients: a case series

Propósito: describir los hallazgos y la medición del grosor coroideo subfoveal utilizando tomografía óptica coherente de imagen de profundidad mejorada (EDI OCT), en paciente hispanos con sospecha clínica de atrofia coroidea relacionada con la edad (ARCA). Métodos: estudio descriptivo y trasversal en 17 pacientes con impresión clínica de ARCA, basados en: disminución de la agudeza visual de reciente aparición, alteraciones pigmentarias en la macula, apariencia de fondo de ojo atigrado y atrofia peripapilar a pesar de no ser miope. A todos se les realizó examen oftalmológico completo, que incluía: Agudeza visual mejor corregida (BCVA), biomicroscopía con lámpara de hendidura y evaluación del fondo de ojo bajo dilatación. A estos pacientes se les realizó fotografía digital del fondo de ojo y tomografía óptica coherente de imagen de profundidad mejorada (EDI OCT). Se realizó un total de 5 mediciones del grosor coroideo en el área macular en cada ojo. Resultados: se evaluaron 26 ojos de 14 pacientes, con una edad media de 70,86 años (DS± 8,46 años). El 57.14% fueron mujeres y el 42.86% hombres. El promedio de la agudeza visual fue 20/47 (0,38 LogMAR), el 80.2% presentaron manifestación binocular. La media del grosor coroideo fue 119,53 µm (DS±49,68µm). No hubo correlación estadísticamente signifi cativa entre la BCVA y grosor coroideo (P=0.407). Conclusión: la atrofia coroidea relacionada con la edad es una condición que puede presentarse en pacientes hispanos de edad avanzada. Afecta igualmente a hombres y mujeres, es usualmente bilateral y el grado de adelgazamiento de la coroides no predice la agudeza visual final.

Purpose: to describe the findings and measure the subfoveal choroidal thickness with Enhanced Depth Imaging (EDI) OCT in hispanics subjects with clinical impression of age-related choroidal atrophy (ARCA). Methods: a descriptive and cross-sectional study of 17 subjects with clinical impression of ARCA: based on recently decreased visual acuity, pigmentary alterations in the macula, a tessellated fundoscopic appearance, and peripapillary atrophy despite being not myopic. All patients had a comprehensive ocular examination, including BCVA, biomicroscopic and fundus examination. They underwent color fundus photography and EDI OCT. A total of 5 measurements were took of each eye. Results: twenty six eyes were included from 14 patients, with a mean age 70,86 years (SD ± 8,46 years). The 57,14% were female and 42.86% male. The mean visual acuity was 20/47 (0,38 LogMAR Equivalent), 80.2% had bilateral disease. The mean choroidal thickness was 119,53 µm (SD ± 49,68 µm). There was no statistically significant correlation between BCVA and choroidal thickness (p =0,407). Conclusions: the ARCA is a condition that can be present in elderly Hispanics subjects. Affects equally male and female, it is usually bilateral and the degree of choroidal thinning does not predict the final visual acuity.

Bilateral choroidal osteoma with optic atrophy.

Choroidal osteoma is a rare, yellowish-white lesion of the choroid that predominantly affects young women in the second decade of life. Subretinal neovascularization or collection of subretinal fluid may occur in 50 % or more patients in the long run. A 15-year-old girl presented to our practice with bilateral choroidal osteoma associated with advanced bilateral optic atrophy. The underlying cause for optic atrophy is unclear; possible explanations include mechanical pressure effect and ischemic damage.

GAPO syndrome: a report of two siblings and a review of literature.

Growth retardation, alopecia, pseudoanodontia, optic atrophy (GAPO) syndrome is a rare autosomal recessive disorder. The molecular nature of the disease is not fully understood and is considered to be one of the ectodermal dysplasia defects. In this report, we describe clinical, histologic, and ultrastructural features in two siblings born to consanguineous parents with a brief review of the literature.

Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly.

BACKGROUND: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. AIMS: To identify a causative gene for SOPH syndrome. METHODS: Genomewide homozygosity mapping was conducted in 33 patients in 30 families. RESULTS: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. CONCLUSION: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.

Reversal of optic canal stenosis in osteopetrosis after bone marrow transplant.

PURPOSE: To describe a patient with infantile osteopetrosis and optic atrophy secondary to optic canal stenosis who demonstrated optic canal enlargement after bone marrow transplant. METHODS: Case report. A 3-month-old infant with infantile "malignant" osteopetrosis underwent ophthalmic examination, including visual evoked potentials, electroretinogram, and computed tomography (CT). Bone marrow transplant was performed at 8 months of age. RESULTS: Examination revealed visual loss and optic atrophy, left eye greater than right eye, secondary to optic canal stenosis. Flash visual evoked potentials revealed a normal waveform in both eyes with increased latency in the left eye. Electroretinogram was normal in both eyes. CT after bone marrow transplant showed enlargement of the optic canals. Vision remains stable 43 months after bone marrow transplant. CONCLUSIONS: Bone marrow transplant in infantile osteopetrosis may be followed by reversal of optic canal stenosis and preservation of vision.

Orbital hydrocephalus: a proven cause for optic atrophy.

A 4-year-old boy with bilateral optic sheath enlargement and progressive optic atrophy and blindness is presented. Computed tomography demonstrated hydrocephalus and enlargement of the optic nerve sheath complex. The child died during an attempted repair of hypoplastic atrioventricular valves. Autopsy demonstrated a patulous perioptic subarachnoid space and optic atrophy. This condition has been described in the literature but has not had radiologic-pathologic correlation. With the availability of magnetic resonance imaging, this diagnosis may be made prospectively, thus, it is important for the radiologist to be aware of this entity because optic atrophy and blindness may be prevented by early diagnosis and surgery.

Intracranial calcifications, epilepsy, and optic atrophy associated with metaphyseal dysplasia: a case report.

A 15-year-old boy presenting with epilepsy, optic atrophy and intracranial calcifications was diagnosed as having metaphyseal dysplasia by bone X-ray examinations. The patient had no laboratory data suggesting other metabolic or endocrinologic disorders. In addition, CT scans showed unique intracranial calcifications of the corpus callosum and periventricular and subcortical white matter, which were distinct from those of previously reported disorders. This case may represent a unique subset or a new type of metaphyseal dysplasia associated with intracranial calcifications and central nervous system symptoms.

GAPO syndrome: first Egyptian case with ultrastructural changes in the gingiva.

We report on a 3-year-old boy with growth retardation, alopecia, pseudoanodontia, and optic atrophy. This is the 18th known and the first Egyptian case of GAPO syndrome. Electron microscopic examination of gingival biopsy showed excessive collagen fibres and endothelial vacuolisation, suggesting involvement of extracellular pathological collagenosis.

[Causes of progressive optic nerve dystrophy in patients with primary open-angle glaucoma after antiglaucoma surgery performed at the early stages]. / Prichiny progressirovaniia atrfii zritelnykh nervov u bolnykh pervichnoi otkrytougolnoi glaukomoi posle antiglaukomatoznikh operatsii, proizvedennikh v nachalnoi stadii.

Analysis of the results of follow-up of patients operated on at the initial stages of open-angle glaucoma revealed that, if the hemodynamic parameters of the orbital artery are lowered, the process progresses in the presence of normal intraocular pressure. The linear bloodflow velocity (LBV) in the orbital and suprablock artery varies within a wide range in patients with the initial stages of open-angle glaucoma, this indicating the heterogeneity of hemodynamic disorders at the beginning of the disease. Low values of LBV in the supratrochlear or orbital arteries during the first stage of open-angle glaucoma may be regarded as a risk factor for the progress of glaucomatous atrophy of the optic nerves, despite the normalization of ophthalmic tone.

Childhood fibrous dysplasia presenting as blindness: a skull base approach for resection and immediate reconstruction.

Fibrous dysplasia is an abnormal fibroosseous process of bone of unknown cause. The incidence of skull involvement varies, painless enlargement being the most common presenting symptom. Change in vision is a rare but recognized finding. We report a 3-year-old boy with extreme fibrous dysplasia involving the skull base, who presented with blindness. He underwent exposure osteotomies of the frontal bones and orbits to provide access for skull base tumor removal. The orbital roofs were reconstructed with microplate-fixed cranial grafts. One and one half years after tumor excision followed by immediate reconstruction, the boy retains facial symmetry, and his ocular function has not deteriorated.

Unilateral optic atrophy presumed secondary to schistosomiasis of the optic nerve.

BACKGROUND: Schistosomiasis, a parasitic disease, is endemic in many parts of the world. Schistosomal eggs may be found in almost any organ or tissue in the body, including the eye. The presence of schistosomal eggs in the eye can produce granuloma formation and inflammatory sequelae. METHODS: A 63-year-old male had contracted schistosomiasis 40 years earlier while on active military service in the Philippines. Schistosoma japonicum eggs were isolated from his stools and military records indicated that the disease responded well to treatment with antimony potassium tartrate. The patient has gradually lost vision with his left eye over 15 years without the benefit of a complete optometric and medical diagnosis. RESULTS: CT scan suggested the likelihood of "subtle changes in the left optic nerve medially, possibly related to tumor invasion." Further evaluation and coordinated clinical thinking with other eye and medical practitioners led to the suspected diagnosis of schistosomal granuloma in the left optic nerve. In addition, the patient was legally blind from the consequences of glaucoma and its surgical intervention in his fellow eye. CONCLUSIONS: Although over 200 million people are infected with schistosomiasis, the United States is not an area where schistosomiasis is endemic. It is, however, endemic in parts of South America, Africa, Asia and the Caribbean Islands. Patients who have been in endemic areas with unexplained ophthalmic findings or systemic findings that could be related to granuloma formation or inflammatory sequelae of disease should have schistosomiasis included in their differential diagnosis.

Optic atrophy.

A young woman became suddenly aware of visual loss in her left eye. She was found to have optic atrophy giving chronicity to the disease process. A hypopigmented macule on her face along with neuroimaging studies suggested an inflammatory process. A biopsy of the skin lesion was compatible with sarcoidosis. The patient responded to corticosteroid therapy.

[Prospects of the use of decompression surgery of the optic nerve in atrophy of vascular etiology]. / Perspektivy primeneniia dekompressivnykh operatsii na zritel'nom nerve pri atrofiiakh sosudistogo geneza.

The technique of decompression surgery on the optic nerve in vascular atrophy has been developed. Optic disk staining grew more intensive, visual field widened, and vision acuity improved after such surgery. Results of fluorescent angiography of the fundus oculi and ultrasonic dopplerography evidence an essential improvement of the blood stream in the central retinal artery after the operation. The positive effect of surgery persisted over the entire follow-up period (8 months). The authors consider that enlargement of the inner diameter of the posterior scleral ring permits a more loose disposition of the vessels and fibers of the optic nerve in this ring, this being conducive to better circulation in the optic disk and retina.

Optic neuropathies: diagnostic role of standardized echography.

While large excavation, elevation and drusen of the optic disc are best detected with contact B-scan examination, standardized A-scan echography is needed to investigate properly and to differentiate optic nerve disease. Increased subarachnoidal fluid within the retrobulbar optic nerve, optic nerve atrophy and optic nerve tumors (glioma and meningioma) can be evidenced with standardized echography. Techniques and examples of ultrasound diagnosis of optic nerve disease are presented and discussed.