Leber hereditary optic neuropathy (LHON), a maternally inherited mitochondrial disorder, results from point mutations in mitochondrial DNA (mtDNA), primarily affecting the MT-ND4 gene. To date, no animal model harboring authentic LHON mutations has been available, limiting therapeutic development. However, when we attempted to generate such models using mitochondrial base editors, we found that activity-enhanced DddA11-based cytosine base editors (DdCBEs) induce off-target mtDNA mutations and developmental arrest in embryos. Using a high-fidelity DdCBE (Hifi-DdCBE), we successfully generate mice carrying the pathogenic MT-ND4 G11778A mutation, the most common LHON variant. These mice exhibit hallmark phenotypes, including retinal ganglion cell loss and impaired visual function. Intravitreal delivery of adeno-associated virus encoding TALE-linked deaminases (TALEDs) restores both phenotype and genotype in these mice. Furthermore, optimized TALEDs corrects the ND4 mutation with minimal off-target effects in LHON patient-derived cells, highlighting the potential of mitochondrial base editing as a therapeutic strategy for mtDNA-associated diseases.

Digital health is becoming increasingly powerful and available but is frequently not effectively integrated into daily practice. A hybrid programme was developed to provide holistic diagnostic and therapeutic patient care in atrial fibrillation. Patients (n = 68) were recruited at the electrophysiology centre following successful interventional restoration of sinus rhythm. The 12-month programme consists of the key modalities: (i) self-recording of one-lead electrocardiograms (ECGs), (ii) short-term remote ECG diagnosis and medical advice by video consultation, and (iii) App-based education on lifestyle and risk factor optimization with video consultation. Patients recorded 29 092 ECGs, averaging 1.42 ECGs/day. Recurrent arrhythmia was found and confirmed in 39 patients. In all cases, arrhythmia was first diagnosed based on wearable ECG over the platform, rather than by standard in-office ECG/Holter. No false positive occurred. Patients with recurred arrhythmia were treated by pulmonary vein isolation (n = 17), electric cardioversion (n = 17), antiarrhythmic medication (n = 5), or other interventional procedures (n = 1). Most patients (n = 30) scheduled a video consultation over the App as the first medical touchpoint after arrhythmia occurrence. In 21 patients with arterial hypertension, systolic blood pressure was reduced by 8.0 ± 8.6 mmHg (mean ± SD), P < 0.01. In 25 patients with obesity (body mass index ≥ 30), body weight was reduced by 3.6 ± 5.5 kg (mean ± SD), P < 0.01. This real-world analysis indicates that the hybrid holistic programme is applicable in daily practice and is actively followed by patients and improves diagnostic and therapeutic outcomes. These promising data need to be confirmed in a controlled randomized study.

Non-syndromic Inherited Retinal Dystrophies (IRDs) are a set of degenerative retinal diseases that vary clinically and genetically, including Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). IRDs are a significant cause of vision loss in young adults globally. To date, more than 280 genes have been associated with IRD pathogenesis. This study aims to investigate the genetic basis of non-syndromic IRD in the Qatari population and to assess the diagnostic yield of various genetic tests through a retrospective cohort study. Our study identified 49 eligible patients with IRD, 61.2% of whom were Qatari. Rod-dominated phenotypes accounted for 51% of the hereditary retinal diseases in this cohort. Whole-exome sequencing with mitochondrial genome testing (WES Plus) was the most frequently utilized genetic test. A total of 55 variants were identified across 32 IRD-associated genes. Of the 49 cases, 34 (69.4%) were initially classified as solved, and an additional five were likely to be solved based on familial segregation analysis. Variants in the ABCA4 gene were the most commonly observed, present in eight patients, with the c.5882G>A variant being the most recurrent, identified in three of these cases. Specific genes exhibited recurrent variations, including pan-ethnic variants that are common across multiple populations. These variants merit prioritization in testing due to their global prevalence. WES is recommended as a first-tier test for non-syndromic IRD cases, as it accelerates diagnosis, facilitates earlier interventions, and provides a comprehensive genetic picture by incorporating information from family members. Moreover, our study highlighted the significance of performing family segregation analyses in identifying possible causative variants. This is the first genetic study of IRD in Qatar, laying the groundwork for further research on the epidemiology and genetics of non-syndromic IRD in this understudied region.

Leber hereditary optic neuropathy (LHON) is characterized by vision loss due to the degeneration of retinal ganglion cells. LHON-Plus refers to LHON with additional extraocular findings. Neurological conditions observed in LHON-Plus include seizures, encephalopathy, movement disorders, neuropathy, and myopathy. Herein, we present a case with atypical LHON-Plus caused by a novel DNAJC30 disease-causing gene variant. A 15-year-old boy presented with acute headache, and blurred and decreased vision in both eyes. Although initial evaluation pointed toward idiopathic intracranial hypertension, the subsequent diagnostic process revealed unusual features like area postrema syndrome and T2 hyperintensity in brain magnetic resonance imaging. Consequently, antibody-negative neuromyelitis optica spectrum disorder (NMOSD) was diagnosed and treatment was commenced. Recurrent episodes of elevated intracranial pressure necessitated the insertion of a ventriculoperitoneal shunt. Exome sequencing (ES) revealed a novel homozygous variant in the DNAJC30 gene 2 years after symptom onset. Atypical LHON presentations due to nuclear gene mutations may mimic other neuroinflammatory conditions like NMOSD, necessitating thorough clinical evaluation and genetic testing. ES plays a crucial role in diagnosing complex neurological cases, enabling the identification of novel genetic variants associated with LHON and related disorders.