RESUMO
This case report presents a 26-year-old female patient diagnosed with fundus albipunctatus (FAP), a rare form of congenital stationary night blindness. The patient's clinical history and retinal findings spanning 23 years are consistent with FAP. The patient has profound night blindness, photophobia, and mild color vision changes with preserved best-corrected visual acuity (BCVA). Small white dots are present throughout the fundus, sparing the central macula. Electroretinograms (ERG) are consistent with congenital stationary night blindness (CSNB) and suggest a lack of rod response. Ophthalmic imaging has remained stable over time. Genetic testing revealed two biallelic missense mutations in the LRAT gene, c.197G>A (p.Gly66Glu) and c.557A>C (p.Lys186Thr). LRAT mutations are known to contribute to other retinal conditions but have not been previously associated with FAP. While there are currently no available treatments for FAP, this report expands our understanding of the genetic landscape of FAP to include LRAT and provides clinical data to support this finding.
RESUMO
Blue cone monochromacy (BCM) is a congenital vision disorder characterized by complete loss or severely reduced long- and middle-wavelength cone function, caused by mutations in the OPN1LW/OPN1MW gene cluster on the X-chromosome. BCM patients typically suffer from poor visual acuity, severely impaired color discrimination, myopia, and nystagmus. In this review, we cover the genetic causes of BCM, clinical features of BCM patients, genetic testing, and clinical outcome measurements for future BCM clinical trials. However, our emphasis is on detailing the animal models for BCM and gene therapy using adeno-associated vectors (AAV). We describe two mouse models resembling the two most common causes of BCM, current progress in proof-of-concept studies to treat BCM with deletion mutations, the challenges we face, and future directions.
Assuntos
Defeitos da Visão Cromática , Animais , Camundongos , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/terapia , Mutação , Terapia Genética , Células Fotorreceptoras Retinianas Cones , Opsinas de Bastonetes/genéticaRESUMO
Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities and dysmorphic facies. RMNS is caused by de novo heterozygous mutations in the histone linker gene H1-4; however, mechanisms underlying impaired neurodevelopment in RMNS are not understood. All reported mutations associated with RMNS in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.4 protein that is both truncated and possessing an abnormal C-terminus frameshifted tail (H1.4 CFT). To expand understanding of mutations and phenotypes associated with mutant H1-4, we identified new variants at both the C- and N-terminus of H1.4. The clinical features of mutations identified at the C-terminus are consistent with other reports and strengthen the support of pathogenicity of H1.4 CFT. To understand how H1.4 CFT may disrupt brain function, we exogenously expressed wild-type or H1.4 CFT protein in rat hippocampal neurons and assessed neuronal structure and function. Genome-wide transcriptome analysis revealed ~ 400 genes altered in the presence of H1.4 CFT. Neuronal genes downregulated by H1.4 CFT were enriched for functional categories involved in synaptic communication and neuropeptide signaling. Neurons expressing H1.4 CFT also showed reduced neuronal activity on multielectrode arrays. These data are the first to characterize the transcriptional and functional consequence of H1.4 CFT in neurons. Our data provide insight into causes of neurodevelopmental impairments associated with frameshift mutations in the C-terminus of H1.4 and highlight the need for future studies on the function of histone H1.4 in neurons.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Animais , Transtorno do Espectro Autista/genética , Mutação da Fase de Leitura/genética , Histonas/genética , Histonas/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Neurônios/metabolismo , RatosRESUMO
BACKGROUND: A right-sided pneumonectomy after induction therapy for non-small cell lung cancer (NSCLC) has been shown to be associated with significant perioperative risk. We examined the effect of laterality on long-term survival after induction therapy and pneumonectomy using the National Cancer Data Base. METHODS: Perioperative and long-term outcomes of patients who underwent pneumonectomy after induction chemotherapy, with or without radiotherapy, from 2004 to 2014 in the National Cancer Data Base were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis. RESULTS: During the study period, 1,465 patients (right, 693 [47.3%]; left, 772 [52.7%]) met inclusion criteria. Right-sided pneumonectomy was associated with significantly higher 30-day (8.2% [57 of 693] vs 4.2% [32 of 772], p < 0.01) and 90-day mortality (13.6% [94 of 693] vs 7.9% [61 of 772], p < 0.01), and right-sided pneumonectomy was a predictor of higher 90-day mortality (odds ratio, 2.23; p < 0.01). However, overall 5-year survival between right and left pneumonectomy was not significantly different in unadjusted (37.6% [95% confidence interval {CI}, 0.34 to 0.42] vs 35% [95% CI, 0.32 to 0.39], log-rank p = 0.94) or multivariable analysis (hazard ratio, 1.07; 95% CI, 0.92 to 1.25; p = 0.40). A propensity score-matched analysis of 810 patients found no significant differences in 5-year survival between the right-sided versus left-sided groups (34.7% [95% CI, 0.30 to 0.40] vs 34.1%, [95% CI, 0.29 to 0.39], log-rank p = 0.86). CONCLUSIONS: In this national analysis, right-sided pneumonectomy after induction therapy was associated with a significantly higher perioperative but not worse long-term mortality compared to a left-sided procedure.