Wolfram syndrome (WFS) is an uncommon autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, diabetes insipidus, optic nerve degeneration, hearing impairment, and other abnormalities. Additionally, a portion of individuals experience neurological, endocrine, behavioral, and urinary tract disorders that make management more challenging. Here, we present a 22-year-old male who was diagnosed with type 1 diabetes at the age of 4 and received treatment with basal-bolus insulin therapy. He had blurring of vision and hearing loss at 13 years of age, and our evaluation revealed optic atrophy and sensorineural hearing loss. He had polydipsia and polyuria (intake/output of 5-6 L/day) despite a fairly controlled blood glucose level. Serum anti-diuretic hormone (ADH) was done, which confirmed the diagnosis of central diabetes insipidus. His sonogram and urinary flow studies revealed bilateral hydroureteronephrosis with reflux uropathy. We diagnosed him with neurogenic bladder disorder with detrusor sphincter dyssynergia. This patient had an early onset urological disorder with involvement of eyes and ears, with diabetes mellitus and diabetes insipidus, which satisfied the criteria of WFS. The genetic test confirmed the diagnosis. He is currently being managed with insulin and desmopressin.

OBJECTIVE: To define the ophthalmic manifestations in KIF1A-associated neurologic disorder (KAND), a rare, progressive neurodegenerative disorder caused by pathogenic variants in the KIFA1 gene.
METHODS: Cross-sectional study.
METHODS: Clinical ophthalmic examination and multimodal imaging were performed for 24 participants enrolled in the KIF1AOutcome measures, Assessments, Longitudinal And endpoints (KOALA) Study. Visual evoked potentials (VEPs) were performed on select participants.
RESULTS: The average central visual acuity in pediatric participants was 20/43 (logMAR 0.329, range 0.0-1.0) and 20/119 (logMAR 0.773, range 0.471-1.351) in adults. Ninety-five percent of participants examined had some degree of optic nerve atrophy detected by clinical examination and/or optical coherence tomography (OCT). Almost 40% had strabismus. Color vision, visual fields, and stereopsis were impaired in most participants who were able to participate in testing. VEP showed varying degrees of signal slowing and diffuseness.
CONCLUSIONS: Optic nerve atrophy is the primary ocular finding in individuals with KAND and is present at higher prevalence than previously reported. The degree of the atrophy is likely dependent on the severity of the pathogenic variant and possibly the age of the patient. Adults had worse vision on average than children, suggesting possible decline in vision with age. Strabismus in this cohort was common. VEPs showed findings consistent with optic neuropathy and visual dysfunction even in the absence of obvious structural changes on OCT. Families should be counseled regarding visual impairment in KAND patients, so as to obtain appropriate support and assistance to maximize safety, functionality, and learning.

Meningiomas are benign tumors of the central nervous system (CNS) that usually result in compression to adjacent structures and rarely cause pathology on their own. Meningiomas can affect the visual pathways originating from perineural or optic nerve sheath meningioma (ONSM), sellar, or clinoid, to the frontal-temporal-parietal-occipital lobes. Frontal meningiomas have an indolent presentation with frequent behavioral changes (i.e., personality or emotional changes, visual hallucinations), but they rarely present with visual disturbances. We present a case of a giant frontal meningioma causing progressive visual field loss despite preserved visual acuity and no behavioral changes. We aim to highlight the diagnostic value of performing a detailed ophthalmologic evaluation with confrontation visual field (CVF) testing and interpretation in aiding the discovery and diagnosis of intracranial tumors.

Optic nerve atrophy is a pathomorphological consequence of diseases of the peripheral neuron of the visual pathway, manifested as atrophy of nerve fibers of varying severity. The toxic effect of methanol is mainly associated with formic acid and formaldehyde, which suppress the cytochrome system, inhibit oxidative phosphorylation, and thereby cause a deficiency of adenosine triphosphoric acid, to which brain and retinal tissues are especially susceptible. When formiate accumulates, tissue respiration is disrupted, leading to pronounced tissue hypoxia. As a result of such methanol metabolism, metabolic acidosis occurs. Tissue hypoxia develops in the first few hours as a result of the action of formic acid on the respiratory enzyme chain at the cytochrome oxidase level. Hypoxia and, as a consequence, a decrease in energy supply lead to a disruption of biological oxidation and the development of apoptosis in the optic nerve fibers. Understanding the process of optic nerve atrophy development at the pathogenetic level in methyl alcohol intoxication will help make a correct early diagnosis and prescribe timely treatment.
Атрофия зрительного нерва — это патоморфологическое последствие заболеваний периферического нейрона зрительного пути в виде атрофии нервных волокон различной степени выраженности. Токсическое действие метанола главным образом связано с муравьиной кислотой и формальдегидом, которые подавляют систему цитохрома, ингибируют окислительное фосфорилирование и тем самым вызывают дефицит аденозинтрифосфорной кислоты, дефициту которой особенно подвержены ткани мозга и сетчатка. На фоне накопления формиата происходит нарушение тканевого дыхания, что приводит к выраженной тканевой гипоксии. Вследствие такого метаболизма метанола формируется метаболический ацидоз. Развитие тканевой гипоксии происходит уже в первые часы в результате воздействия муравьиной кислоты на цепь дыхательных ферментов на уровне цитохромоксидазы. Гипоксия и, как следствие, снижение энергетического обеспечения приводят к нарушению биологического окисления и развитию апоптоза в волокнах зрительного нерва. Понимание процесса развития атрофии зрительного нерва на патогенетическом уровне при метил-алкогольной интоксикации позволит вовремя поставить правильный диагноз и назначить своевременное лечение.

Monoallelic pathogenic HMBS variants are a well-established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS-related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8-year-old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had no epilepsy but sleep electroencephalogram showed paroxysmal changes in the right hemisphere with secondary generalizations. Brain magnetic resonance imaging was unremarkable apart from a few small white matter hyperintensities. Exome sequencing (ES) initially prioritized a SCN3A c.3822G>A de novo variant whose sole causative role was eventually questioned as not fully compatible with symptoms. ES reanalysis revealed a homozygous c.674G>A HMBS variant. In the monoallelic form this variant is a known cause of AIP, whereas in trans with another HMBS pathogenic variant it was associated with the HMBS-related leukoencephalopathy in four individuals. Despite lack of signs/symptoms of porphyria, literature analysis suggested that HMBS c.674G>A likely contributed to the disease either as the sole cause or together with SCN3A c.3822G>A as a part of blended phenotype. Our report adds to the relatively small number of described cases of HMBS-related leukoencephalopathy and emphasizes that autosomal recessive form of HMBS disease can be present in the absence of porphyria symptoms.

GABAA receptor subunit gene (GABR) mutations are significant causes of epilepsy, including syndromic epilepsy. This report for the first time, describes intractable epilepsy and blindness due to optic atrophy in our patient, who has a microdeletion of the GABRA1 and GABRG2 genes. We then characterized the molecular phenotypes and determined patho-mechanisms underlying the genotype-phenotype correlations in a mouse model who is haploinsufficient for both genes (Gabra1+/-/Gabrg2+/- mouse).
Electroencephalography was conducted in both human and mice with the same gene loss. GABAA receptor expression was evaluated by biochemical and imaging approaches. Optic nerve atrophy was evaluated with fundus photography in human while electronic microscopy, visual evoked potential and electroretinography recordings were conducted in mice.
The patient has bilateral optical nerve atrophy. Mice displayed spontaneous seizures, reduced electroretinography oscillatory potential and reduced GABAA receptor α1, β2 and γ2 subunit expression in various brain regions. Electronic microscopy showed that mice also had optic nerve degeneration, as indicated by increased G-ratio, the ratio of the inner axonal diameter to the total outer diameter, suggesting impaired myelination of axons. More importantly, we identified that phenobarbital was the most effective anticonvulsant in mice and the patient\'s seizures were also controlled with phenobarbital after failing multiple anti-seizure drugs.
This study is the first report of haploinsufficiency of two GABR epilepsy genes and visual impairment due to altered axonal myelination and resultant optic nerve atrophy. The study suggests the far-reaching impact of GABR mutations and the translational significance of animal models with the same etiology.

Wolfram syndrome (WS) is a rare genetic disorder typically characterized by juvenile onset diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, and neurodegeneration. There would be a high index of clinical suspicion for WS when clinical manifestations of type 1 diabetes and optic atrophy present together. Genetic analysis is often required to confirm the diagnosis. We describe a pair of Chinese siblings diagnosed with WS at ages 20 and 24 years, respectively. DNA sequencing of the WFS1 gene which encodes for Wolframin ER Transmembrane Glycoprotein identified a heterozygous nonsense variant NM_006005.3: c.1999C>T p.(Gln667*) and a heterozygous missense variant c.2170C>T p.(Pro724Ser) in exon 8 of the gene for both siblings. There is no curative treatment for WS and management of this debilitating disease is aimed at treating individual clinical manifestations, slowing disease progression, and improving quality of life. Treatment with liraglutide, a glucagon-like-peptide-1 receptor agonist, and tauroursodeoxycholic acid was started for the younger sibling, the proband. There was reduction in insulin requirements and improvement in glycemic control. The other sibling was not offered liraglutide due to her complex treatment regimen for end-organ failure. Genetic testing is a valuable tool to detect WS early to allow precise and prompt diagnosis, thereby facilitating the coordinated care from a multidisciplinary team of clinicians.

Pneumosinus dilatans is an abnormal expansion of the air-filled paranasal sinuses. Usually found incidentally on radiology, it does rarely present in the form of cosmetic, neurological, ocular or rhinological pathologies. We report a case of a young male with complaints of bilateral gradual vision loss, diagnosed as pneumosinus dilatans with optic nerve atrophy. He underwent bilateral optic nerve decompression. A review of all cases of pneumosinus dilatans, reported over the last 100 years in English literature is presented.

Oxidative stress is mainly caused by intracellular reactive oxygen species (ROS) production, which is highly associated with normal physiological homeostasis and the pathogenesis of diseases, particularly ocular diseases. Autophagy is a self-clearance pathway that removes oxidized cellular components and regulates cellular ROS levels. ROS can modulate autophagy activity through transcriptional and posttranslational mechanisms. Autophagy further triggers transcription factor activation and degrades impaired organelles and proteins to eliminate excessive ROS in cells. Thus, autophagy may play an antioxidant role in protecting ocular cells from oxidative stress. Nevertheless, excessive autophagy may cause autophagic cell death. In this review, we summarize the mechanisms of interaction between ROS and autophagy and their roles in the pathogenesis of several ocular diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and optic nerve atrophy, which are major causes of blindness. The autophagy modulators used to treat ocular diseases are further discussed. The findings of the studies reviewed here might shed light on the development and use of autophagy modulators for the future treatment of ocular diseases.

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.