SID/SIEDP expert consensus on optimizing clinical strategies for early detection and management of wolfram syndrome.

Wolfram Syndrome (WFS) is a rare, multisystemic, degenerative disease leading to premature death. Clinical and genetic heterogeneity makes WFS diagnosis and management challenging. The Italian Society of Diabetes (SID) and the Italian Society for Pediatric Endocrinology and Diabetology (SIEDP) convened an expert panel of professional healthcare practitioners to provide up-to-date knowledge about the pathophysiology, clinical presentation and treatment of WFS, and recommendations for the earlydetection and optimal disease management.

Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis.

Gene therapy for Leber hereditary optic neuropathy.

Introduction: Leber hereditary optic neuropathy (LHON) is among the most frequent inherited mitochondrial disease, causing a severe visual impairment, mostly in young-adult males. The causative mtDNA variants (the three common are m.11778 G>A/MT-ND4, m.

Cardiac Wolframinopathies: A Case Report of Myocarditis and a Literature Review of Cardiac Involvement in Wolfram Syndrome 1.

: Myocarditis is frequently a sporadic disease, but may also occur in the context of genetic disorders which may increase susceptibility to cardiac inflammation. Cardiac involvement in Wolfram syndrome type 1 (WS1) has been scarcely characterized. To our knowledge, no cases of virus-negative myocarditis have been reported in the WS1 pediatric population.

AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients.

Purpose: Heterozygous mutations in the AFG3L2 gene (encoding a mitochondrial protease indirectly reflecting on OPA1 cleavage) and ACO2 gene (encoding the mitochondrial enzyme aconitase) are associated with isolated forms of Dominant Optic Atrophy (DOA). We aimed at describing their neuro-ophthalmological phenotype as compared with classic OPA1-related DOA.

Design: Cross-sectional study.

Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.

Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous.

Sectorial Ganglion Cell Complex Thickness as Biomarker of Vision Outcome in Patients With Dominant Optic Atrophy.

Purpose: Dominant optic atrophy (DOA) is an inherited condition caused by autosomal dominant mutations involving the OPA-1 gene. The aim of this study was to assess the relationship between macular ganglion cell and inner plexiform layer (GC-IPL) thickness obtained from structural optical coherence tomography (OCT) and visual outcomes in DOA patients.

Methods: The study recruited 33 patients with confirmed OPA-1 heterozygous mutation and DOA.

Association of Circulating Antiretinal Antibodies With Clinical Outcomes in Retinitis Pigmentosa.

Purpose: To determine if circulating antiretinal antibodies (ARAs) differ between patients affected by retinitis pigmentosa (RP) and control participants and to assess whether ARAs are associated with clinical outcomes in patients with RP.

Methods: Cross-sectional study involving a group of patients clinically diagnosed with RP and a control group of healthy participants. Serum autoantibodies against enolase, heat shock protein 70 (HSP70), and carbonic anhydrase II (CAII) were tested in all participants using Jess capillary Western blot.

Recessive pathogenic variants cause an LHON-like optic neuropathy.

Background: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial DNA, LHON was recently described in patients carrying biallelic variants in nuclear genes , and . MCAT is part of mitochondrial fatty acid synthesis (mtFAS), as also MECR, the mitochondrial trans-2-enoyl-CoA reductase.

PREVALENCE AND MORPHOLOGIC BIOMARKERS OF METAMORPHOPSIA IN EYES WITH "RESOLVED" CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

Purpose: To assess relationships between demographics, clinical characteristics, and optical coherence tomography characteristics with persistence of metamorphopsia after resolution of subretinal fluid in eyes with chronic central serous chorioretinopathy.

Methods: One-hundred participants with "resolved" (absence of subretinal fluid) chronic central serous chorioretinopathy were retrospectively analyzed. Patients underwent a complete ophthalmologic evaluation, including assessment of the presence of metamorphopsia.

Capturing the Transition From Intermediate to Neovascular AMD: Longitudinal Inner Retinal Thinning and Factors Associated With Neuronal Loss.

Purpose: To estimate the impact of transition from intermediate to exudative neovascular age-related macular degeneration (AMD) on the inner retina and to assess the relationship of clinical characteristics and optical coherence tomography (OCT) findings with inner retinal changes.

Methods: A total of 80 participants (80 eyes) with intermediate AMD at baseline who developed neovascular AMD within 3 months were included in the analysis. OCT scans at follow-up visits (after transition to neovascular AMD) were compared with values at the latest visit with evidence of intermediate AMD to quantify longitudinal inner retinal changes.

Choroidal vascularity index in hereditary optic neuropathies.

Purpose: To assess the choroidal vascularity index (CVI) in patients affected by Leber hereditary optic neuropathy (LHON) compared to patients affected by dominant optic atrophy (DOA) and healthy subjects.

Methods: In this retrospective study, we considered three cohorts: LHON eyes (48), DOA eyes (48) and healthy subjects' eyes (48). All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) acquisition.

Visual Outcomes and Optical Coherence Tomography Biomarkers of Vision Improvement in Patients With Leber Hereditary Optic Neuropathy Treated With Idebenone.

Purpose: To assess the relationship of demographics, clinical characteristics and structural optical coherence tomography (OCT) findings to long-term visual outcomes in patients with Leber hereditary optic neuropathy (LHON) treated with idebenone.

Design: Retrospective, interventional, noncomparative clinical cohort study.

Methods: In this study, a total of 17 participants (34 eyes) with LHON treated with idebenone therapy within 1 year after disease onset and 2 years (24 months) of regular follow-ups were retrospectively enrolled.

Capturing the Pattern of Transition From Carrier to Affected in Leber Hereditary Optic Neuropathy.

Purpose: To capture the key features patterning the transition from unaffected mutation carriers to clinically affected Leber hereditary optic neuropathy (LHON), as investigated by optical coherence tomography.

Design: Observational case series.

Methods: Four unaffected eyes of 4 patients with LHON with the first eye affected were followed across conversion to affected, from 60 days before to 170 days after conversion.

The Pattern of Retinal Ganglion Cell Loss in Wolfram Syndrome is Distinct From Mitochondrial Optic Neuropathies.

Purpose: To describe the clinical phenotype of a cohort of patients with Wolfram syndrome (WS), focusing on the pattern of optic atrophy correlated with brain magnetic resonance imaging (MRI) measurements, as compared with patients with OPA1-related dominant optic atrophy (DOA).

Design: Retrospective, comparative cohort study.

Methods: We reviewed 25 patients with WS and 33 age-matched patients affected by OPA1-related DOA.

Retinal vascular impairment in Wolfram syndrome: an optical coherence tomography angiography study.

To evaluate differences in macular and optic disc circulation in patients affected by Wolfram Syndrome (WS) employing optical coherence tomography-angiography (OCTA) imaging. In this retrospective study, 18 eyes from 10 WS patients, 16 eyes of 8 patients affected by type I diabetes and 17 eyes from 17 healthy controls were enrolled. All patients were imaged through OCT and OCTA and vascular parameters, as perfusion density (PD) and vessel length density (VLD) were measured.

Longitudinal Study of Optic Disk Perfusion and Retinal Structure in Leber's Hereditary Optic Neuropathy.

Purpose: The purpose of this study was to evaluate optic disk perfusion and neural retinal structure in patients with subacute Leber's hereditary optic neuropathy (LHON) and LHON carriers, as compared with healthy controls.

Methods: This study included 8 patients with LHON in the subacute stage, 10 asymptomatic carriers of a LHON-associated mitochondrial DNA mutation, and 40 controls. All subjects underwent measurement of the retinal nerve fiber layer (RNFL) thickness, the ganglion cell-inner plexiform layer (GCIPL) thickness using optical coherence tomography and optic disk microvascular perfusion (Mean Tissue [MT]) using laser speckle flowgraphy (LSFG).

Case Report: Off-Label Liraglutide Use in Children With Wolfram Syndrome Type 1: Extensive Characterization of Four Patients.

Wolfram syndrome type 1 is a rare recessive monogenic form of insulin-dependent diabetes mellitus with progressive neurodegeneration, poor prognosis, and no cure. Based on preclinical evidence we hypothesized that liraglutide, a glucagon-like peptide-1 receptor agonist, may be repurposed for the off-label treatment of Wolfram Syndrome type 1. We initiated an off-label treatment to investigate the safety, tolerability, and efficacy of liraglutide in pediatric patients with Wolfram Syndrome type 1.

Impact of Structural Changes on Multifocal Electroretinography in Patients With Use of Hydroxychloroquine.

Purpose: To investigate the relationship between retinal structure and macular function in eyes screened for hydroxychloroquine (HCQ) toxicity.

Methods: Participants referred for hydroxychloroquine retinopathy screening with spectral domain optical coherence tomography (SD-OCT) and multifocal electroretinogram (mfERG) testing were included in the analysis. Amplitude and implicit time of mfERG N1 and P1 responses were included in the analysis.