Showing papers by "Byron L. Lam published in 2023"
TL;DR: In this article , a post hoc analysis of the XIRIUS and XOLARIS studies investigates how changes in visual function associated with cotoretigene toliparvovec gene therapy in participants with RPGR-variant X-linked retinitis pigmentosa compare with those of untreated individuals.
Abstract: This post hoc analysis of the XIRIUS and XOLARIS studies investigates how changes in visual function associated with cotoretigene toliparvovec gene therapy in participants with RPGR-variant X-linked retinitis pigmentosa compare with those of untreated individuals.
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TL;DR: The authors explored the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.
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TL;DR: In this article , the authors reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy.
Abstract: Abstract Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D , encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or “primed” by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.
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TL;DR: Pelentsov et al. as mentioned in this paper investigated how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed and found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search.
Abstract: Abstract The “diagnostic odyssey” describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identified factors motivating a family to begin searching, but there is limited information about the decision-making process in a prolonged search and how the affected child impacts a family’s decision. This study aimed to understand how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed. Parents who applied to the Undiagnosed Disease Network (UDN) at the National Institutes of Health (NIH) were recruited to participate in semi-structured interviews. The 2015 Supportive Care Needs model by Pelenstov, which defines critical needs in families with rare/undiagnosed diseases, provided a framework for interview guide development and transcript analysis (Pelentsov et al in Disabil Health J 8(4):475–491, 2015. https://doi.org/10.1016/J.DHJO.2015.03.009 ). A deductive, iterative coding approach was used to identify common unifying themes. Fourteen parents from 13 families were interviewed. The average child’s age was 11 years (range 3–18) and an average 63% of their life had been spent searching for a diagnosis. Our analysis found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search. When needs and desires align, reevaluation of a decision to pursue a diagnosis is limited. However, when there is conflict between parent and child desires, there is reevaluation, and often a pause, in the search. This tension is exacerbated when children are adolescents and attempting to balance their dependence on parents for medical care with a natural desire for independence. Our results provide novel insights into the roles of adolescents in the diagnostic odyssey. The tension between desired and realistic developmental outcomes for parents and adolescents impacts if, and how, the search for a diagnosis progresses.
TL;DR: Camburu et al. as mentioned in this paper presented a case of transient monocular heterochromia and transient multinocular vision loss (TMVL) associated with uveitis-glaucoma-hyphaema (UGH) syndrome.
Abstract: Uveitis-glaucoma-hyphema (UGH) syndrome occurs because of contact between the iris or ciliary body and the intraocular lens (IOL). This contact results in mechanical irritation and erosion of uveal tissues, leading to the release of pigment from the iris pigment epithelium.1Durr GM Ahmed IIK. Intraocular lens complications: decentration, uveitis-glaucoma-hyphema syndrome, opacification, and refractive surprises.Ophthalmology. 2021; 128: e186-e194Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Additionally, the breakdown of the blood–aqueous barrier results in the release of blood cells and proteins into the anterior chamber causing secondary glaucoma.2Zemba M Camburu G. Uveitis-glaucoma-hyphaema syndrome: general review.Rom J Ophthalmol. 2017; 61: 11-17Crossref PubMed Google Scholar We present a case of transient monocular heterochromia and transient monocular vision loss (TMVL) associated with UGH syndrome. A 66-year-old white female presented to the ophthalmology clinic with 7 episodes of TMVL of the left eye over a duration of 6 months. During each episode, the patient had a gradual onset of partial to complete vision loss that lasted from 2 to 6 hours and then recovered gradually. She also noted a change of her left iris color during these episodes from green to brown (Fig. 1). Two years prior to presentation, the patient underwent bilateral cataract surgery with multifocal IOL implantation, and there was a history of ocular hypertension in the left eye controlled with 2 topical antiglaucoma medications. Our patient presented to the local emergency department after her initial episode. The patient had computed tomography of the head and chest, carotid ultrasound, magnetic resonance imaging of the brain, magnetic resonance angiography of the head and neck, an echocardiogram, and Holter monitoring. Blood work-up was ordered and included hemoglobin A1C, a lipid panel, erythrocyte sedimentation rate, C-reactive protein, complete blood count, a complete metabolic panel, and a coagulopathy panel. Her extensive laboratory and imaging work-up revealed only mildly elevated levels of cholesterol, for which treatment was initiated. Patient also was started on clopidogrel by her cardiologist given the nature of her symptoms, but the intermittent episodes continued. On examination, the patient's best-corrected visual acuity was 20/15 in each eye, and intraocular pressures were 13 mm Hg OD and 10 mm Hg OS. Pupillary examinations were normal with full extraocular muscles movements. Slit-lamp examination showed symmetrically appearing light-coloured irises with a multifocal intraocular lens bilaterally. Detailed examination of the anterior segment of the left eye revealed superior iris transillumination defects without iris neovascularization (Fig. 2) and a 1-piece IOL with the inferior haptic within the capsular bag and the superior haptic in the ciliary sulcus (Supplementary Fig. 1, available online). Gonioscopy demonstrated open angles with extensive pigmentation of the trabecula meshwork (TM) in the left eye and no evidence of trabecular cleft or angle neovascularization (Supplementary Fig. 2, available online). Fundus examination of both eyes was normal. A review of the patient's cell phone photographs was performed and showed a small layered hyphema inferiorly in the left eye during an episode of transient vision loss (Supplementary Fig. 3, available online). Humphrey visual field testing and optical coherence tomography of the optic nerve of both eyes were normal. A diagnosis of UGH syndrome was established as the cause of the TMVL episodes. Intraocular lens repositioning was performed, resulting in complete resolution of TMVL and transient iris heterochromia in the left eye after 36 months of postoperative follow-up. Our patient developed transient monocular heterochromia, which is a rare ophthalmic entity that to our knowledge that has not been reported previously in association with UGH syndrome. We believe that the recurrent iris heterochromia and TMVL likely were due to the associated hyphema and IOL malposition. In UGH syndrome, the persistent uveal–IOL contact can lead to mechanical irritation and erosion of uveal tissues and anterior-chamber angle. This leads to release of pigment, red blood cells and hyphema formation, white blood cells, and protein into the anterior chamber, producing iritis. Glaucomatous optic neuropathy can develop due to multifactorial mechanisms, including blockage of the TM by released pigment, red or white blood cells, ghost cell glaucoma from vitreous hemorrhage, or synechial angle closure.1Durr GM Ahmed IIK. Intraocular lens complications: decentration, uveitis-glaucoma-hyphema syndrome, opacification, and refractive surprises.Ophthalmology. 2021; 128: e186-e194Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar UGH syndrome may present with various manifestations, including ocular hypertension, microhyphema or hyphema, anterior uveitis, iris transillumination defects, iris neovascularization, and cystoid macular edema.2Zemba M Camburu G. Uveitis-glaucoma-hyphaema syndrome: general review.Rom J Ophthalmol. 2017; 61: 11-17Crossref PubMed Google Scholar Gonioscopy evaluation can demonstrate blood within the anterior-chamber angle, increased pigmentation of the TM, and visualization the IOL haptic. Ultrasound biomicroscopy is often helpful to visualize malposition of the IOL and contact with uveal tissue.2Zemba M Camburu G. Uveitis-glaucoma-hyphaema syndrome: general review.Rom J Ophthalmol. 2017; 61: 11-17Crossref PubMed Google Scholar There are many causes of MTVL, including amaurosis fugax, retinal migraine, intermittent angle-closure glaucoma, papilledema, anemia and hypercoagulopathies, UGH syndrome, and hypotension.3Ahmed R Foroozan R. Transient monocular visual loss.Neurol Clin. 2010; 28: 619-629Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Vision loss due to amaurosis fugax typically occurs suddenly, starts as a curtain covering the visual field, and recovers rapidly over seconds or minutes. Patients sometimes experience complete loss of light perception. However, UGH syndrome can cause diminution of vision that starts over a few minutes, recovers over hours to days, and occasionally is associated with red vision. Patients with TMVL due to UGH syndrome are unlikely to lose light perception during attacks.4Cates CA Newman DK. Transient monocular visual loss due to uveitis-glaucoma-hyphaema (UGH) syndrome.J Neurol Neurosurg Psychiatry. 1998; 65: 131-132Crossref PubMed Scopus (19) Google Scholar Ophthalmic evaluation during attacks may reveal microscopic hyphema that sometimes clears rapidly, making the diagnosis of UGH syndrome more difficult, as was noted in our patient. IOP spikes in UGH syndrome might lead to decreased ocular perfusion and subsequently transient retinal ischemia and TMVL.4Cates CA Newman DK. Transient monocular visual loss due to uveitis-glaucoma-hyphaema (UGH) syndrome.J Neurol Neurosurg Psychiatry. 1998; 65: 131-132Crossref PubMed Scopus (19) Google Scholar Treatment of UGH syndrome includes topical corticosteroid eye drops to control uveitis and IOP-lowering medications for ocular hypertension. In patients with hyphema, head elevation and topical cycloplegic and steroid drops are recommended. In eyes with recurrent hyphema or chronic inflammation with cystoid macular edema, surgical interventions may be required. A recent study showed that IOL surgeries (including IOL exchange, IOL suturing to the iris or sclera, haptic amputation, and IOL rotation) resulted in resolution of UGH syndrome in 77% of treated patients. There was a statistically significant IOP reduction and best-corrected visual acuity improvement in the operated cases compared with the conservative treatment group.5Iftikhar M Mir T Seidel N et al.Epidemiology and outcomes of hyphema: a single tertiary centre experience of 180 cases.Acta Ophthalmol. 2021; 99: e394-e401Crossref PubMed Scopus (6) Google Scholar Our patient did not develop any TMVL or heterochromia episodes during a 3-year follow-up after IOL repositioning. In summary, our case underscores the importance of maintaining a high index of suspicion for UGH syndrome as the cause of MTVL and transient iris heterochromia in patients with prior cataract surgery and signs of IOL malposition. IOL repositioning was successful in eradicating recurrence episodes with 36 months of postoperative follow-up. Exclusion of other mechanisms of transient vision loss is critical. The authors have no proprietary or commercial interest in any materials discussed in this correspondence. This work was supported by a National Institutes of Health Center Core Grant (P30EY01480) and a Research to Prevent Blindness Unrestricted Grant (GR004596). Download .jpg (.49 MB) Help with files Download .jpg (.39 MB) Help with files Download .jpg (.55 MB) Help with files
TL;DR: In this article , the authors evaluated the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma.
Abstract: To assess the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma.Open-label, prospective, phase I clinical trial.A total of 11 participants were diagnosed with primary open-angle glaucoma (POAG). One eye of each patient was assigned as the study (implant) eye.The study eye was implanted with a high-dose CNTF-secreting NT-501 implant, whereas the other eye served as a control. All patients were followed up for 18 months. Analysis was limited to descriptive statistics.Primary outcome was safety through 18 months after implantation assessed by serial eye examinations, structural and functional testing, and adverse events (AEs) recording. Parameters measured included visual acuity (VA), Humphrey visual field (HVF), pattern electroretinogram, scanning laser polarimetry with variable corneal compensation (GDx VCC), and OCT. These parameters were also used for secondary analysis of efficacy outcome.All NT-501 implants were well tolerated with no serious AEs associated with the implant. The majority of AEs were related to the implant placement procedure and were resolved by 12 weeks after surgery. Foreign-body sensation was the most commonly reported AE and was self-limited to the postoperative period. The most common implant-related AE was pupil miosis; no patients underwent explant. Visual acuity and contrast sensitivity decreased more in fellow eyes than in study eyes (VA, -5.82 vs. -0.82 letters; and contrast sensitivity, -1.82 vs. -0.37 letters, for fellow vs. study eyes, respectively). The median HVF visual field index and mean deviation measurements worsened (decreased) in fellow eyes (-13.0%, -3.9 dB) and improved (increased) in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer thickness measured by OCT and by GDx VCC (OCT, 2.66 ÎĽm vs. 10.16 ÎĽm; and GDx VCC, 1.58 ÎĽm vs. 8.36 ÎĽm in fellow vs. study eyes, respectively).The NT-501 CNTF implant was safe and well tolerated in eyes with POAG. Eyes with the implant demonstrated both structural and functional improvements suggesting biological activity, supporting the premise for a randomized phase II clinical trial of single and dual NT-501 CNTF implants in patients with POAG, which is now underway.Proprietary or commercial disclosure may be found after the references.
TL;DR: In this paper , a 75-year-old man presented with a 6-week history of left eye acute vision loss first noticed while driving his boat and underwent a yttrium aluminum garnet (YAG) laser capsulotomy of the left eye at the onset of the blurry vision.
Abstract: A 75-year-old man presented with a 6-week history of left eye acute vision loss first noticed while driving his boat. The patient denied any headache, pain with eye movement, or eye trauma. He had bilateral uneventful cataract extraction 7 years before presentation and underwent a yttrium aluminum garnet (YAG) laser capsulotomy of the left eye at the onset of the blurry vision with no improvement. He has a history of diabetes mellitus, atrial fibrillation, and prostate cancer. Medication included metformin, apixaban, tadalafil, and multivitamins. The patient is a former smoker who quit smoking at the age of 35 years and is a mild social alcohol drinker. The best-corrected visual acuity (BCVA) was 20/50 in the right eye and 20/400 in the left eye. Ishihara color plates showed 10/10 in the right eye and 0/10 in the left eye with a left relative afferent pupillary defect (RAPD). Slitlamp examination revealed moderate opacification of the right posterior capsule and normal-looking optic discs. The visual field (VF) showed a cecocentral scotoma in the left eye. Brain and orbital MRI with contrast showed no optic nerve enhancement or atrophy of the left eye. Blood workup was negative for anti-myelin oligodendrocyte glycoprotein (MOG), anti-aquaporin-4 antibody (AQP4-Ab), rapid plasma reagin (RPR), fluorescent treponemal antibody test absorption test (FTA-ABS), angiotensin-converting enzyme (ACE), lysozyme, and nutritional and toxic blood panel. Despite the negative workup, the patient was started on 1-g intravenous methylprednisolone (IVMP) daily for 5 days, with some improvement in right eye color vision and brightness, without any changes in the left eye. Three weeks later, the BCVA was 20/100 in the right eye and 20/400 in the left eye. Ishihara color plates were 3/10 in the right eye and 0/10 in the left eye with trace left RAPD. Fundus examination showed bilateral optic disc pallor. Visual fields showed cecocentral scotoma, the left eye worse than the right eye. YAG capsulotomy right eye was performed without any improvement in vision. At that point, it was a case of unexplained sequential vision loss of 9-week duration. Full-field electroretinography (ffERG) and serum paraneoplastic antibody panel were unremarkable. Leber hereditary optic neuropathy (LHON) testing panel (Athena Diagnostics) came back positive for T14484C ND6 mitochondrial mutation. The patient was started on off-label use idebenone 300 mg 3 times daily.1 Six months later, his BCVA was 20/300 in the right eye and 20/350 in the left eye with bilateral cecocentral scotomas. Optical coherence tomography (OCT) of the optic nerve head revealed temporal thinning of the retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) analysis showed diffuse thinning of the ganglion cell complex. After 5 years of annual follow-up, the patient reported stable vision. The BCVA remained at 20/300 in the right eye and 20/350 in the left eye. Repeated visual field testing (Fig. 1) showed central scotoma in the right eye and cecocentral scotoma in the left eye; RNFL (Fig. 2A) and GCL thicknesses (Fig. 2B) were unchanged. Fundus examination showed temporal pallor of the optic disc in both eyes (Fig. 2C).FIG. 1.: Automated visual field testing (AVF) showing central scotoma in the right eye and centrocecal scotomas in the left eye at the last follow-up visit.FIG. 2.: A. RNFL thickness shows mostly temporal loss. B. Diffuse GCL thinning. C. Fundus photographs showing temporal pallor of both optic nerves. GCL, ganglion cell layer; RNFL, retinal nerve fiber layer.To the best of our knowledge, our case is one of the most delayed onsets of patients with T14484C LHON and underscores that LHON should be considered in the differential diagnosis of subacute blindness, even in older patients. The 3 most common mutations responsible for 90% of LHON are G11778A, T14484C, and G3460A. LHON usually affects male patients more than female patients and presents in the second to fourth decade of life but can present at any age.2 The oldest reported ages of onset of visual loss were a 76-year-old man with 11778 mutation,3 a 75-year-old man with 3460 mutation,3 and a 57-year-old man with 14484 mutation associated with longitudinal extensive myelitis.4 The inciting factors for visual loss in patients with one of the typical mutations for LHON are not fully known. Apart from alcohol and smoking, for which a correlation was demonstrated,2,5 many other nonspecific triggers have been described in some case reports. Except for the very late age of onset, our case has typical sequential subacute vision loss of LHON with typical clinical findings in the clinical examination and ancillary testing. In addition, there were no triggering factors other than the very remote smoking history and social alcohol consumption which could cause a cumulative effect on the optic nerves.
TL;DR: In this article , a healthy 27-year-old woman with biallelic mutations in the RPE65 gene, who underwent bilateral sequential gene therapy with subretinal administration of voretigene neparvovec-rzyl, reported panuveitis with exudative retinal detachments.
TL;DR: In this paper , the authors report a case of a 74-year-old male with progressively painful unilateral proptosis caused by a thrombosed varix of the inferior ophthalmic vein in the left inferior intraconal space.
Abstract: Background: Orbital varices are rare, accounting for only 0–1.3% of orbital masses. They can be found incidentally or cause mild to serious sequelae, including hemorrhage and optic nerve compression. Case Description: We report a case of a 74-year-old male with progressively painful unilateral proptosis. Imaging revealed the presence of an orbital mass compatible with a thrombosed orbital varix of the inferior ophthalmic vein in the left inferior intraconal space. The patient was medically managed. On a follow-up outpatient clinic visit, he demonstrated remarkable clinical recovery and denied experiencing any symptoms. Follow-up computed tomography scan showed a stable mass with decreased proptosis in the left orbit consistent with the previously diagnosed orbital varix. One-year follow-up orbital magnetic resonance imaging without contrast showed slight increase in the intraconal mass. Conclusion: An orbital varix may present with mild to severe symptoms and management, depending on case severity, ranges from medical treatment to escalated surgical innervation. Our case is one of few progressive unilateral proptosis caused by a thrombosed varix of the inferior ophthalmic vein described in the literature. We encourage further investigation into the causes and epidemiology of orbital varices.
TL;DR: The Undiagnosed Diseases Network (UDN) is a clinical research study funded by the National Institutes of Health (NIH) that aims to provide answers for patients with unddiagnosed conditions and generate knowledge about underlying disease mechanisms as mentioned in this paper .
Abstract: Abstract Introduction The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possible in clinical settings. While medical and research outcomes of UDN evaluations have been explored, this is the first formal assessment of the patient and caregiver experience. Methods We invited UDN participants and caregivers to participate in focus groups via email, newsletter, and a private participant Facebook group. We developed focus group questions based on research team expertise, literature focused on patients with rare and undiagnosed conditions, and UDN participant and family member feedback. In March 2021, we conducted, recorded, and transcribed four 60-min focus groups via Zoom. Transcripts were evaluated using a thematic analysis approach. Results The adult undiagnosed focus group described the UDN evaluation as validating and an avenue for access to medical providers. They also noted that the experience impacted professional choices and helped them rely on others for support. The adult diagnosed focus group described the healthcare system as not set up for rare disease. In the pediatric undiagnosed focus group, caregivers discussed a continued desire for information and gratitude for the UDN evaluation. They also described an ability to rule out information and coming to terms with not having answers. The pediatric diagnosed focus group discussed how the experience helped them focus on management and improved communication. Across focus groups, adults (undiagnosed/diagnosed) noted the comprehensiveness of the evaluation. Undiagnosed focus groups (adult/pediatric) discussed a desire for ongoing communication and care with the UDN. Diagnosed focus groups (adult/pediatric) highlighted the importance of the diagnosis they received in the UDN. The majority of the focus groups noted a positive future orientation after participation. Conclusion Our findings are consistent with prior literature focused on the patient experience of rare and undiagnosed conditions and highlight benefits from comprehensive evaluations, regardless of whether a diagnosis is obtained. Focus group themes also suggest areas for improvement and future research related to the diagnostic odyssey.
TL;DR: In this paper , a 69-year-old male with a history of cardiac transplantation presented with progressive, sequential, and painless vision loss after years of treatment with sirolimus.
Abstract: Objective To describe a case of optic neuropathy after prolonged sirolimus therapy in the setting of cardiac transplant. Background Sirolimus is an immunosuppressant that inhibits Mechanistic Target of Rapamycin (mTOR) and blocks T-cell activation and B-cell differentiation by preventing response to Interleukin-2 (IL-2). Tacrolimus is another immunosuppressive agent, one of the known but uncommon side effects of which is bilateral optic neuropathy years after taking the medication. To the best of our knowledge, this is the first report of sequential optic neuropathy after years of treatment with sirolimus. Case Presentation A 69-year-old male with a history of cardiac transplantation presented with progressive, sequential, and painless vision loss. Visual acuity was 20/150 OD and 20/80 OS, with impaired color vision in both eyes (Ishihara 0/10) and bilateral disc pallor and mild optic disc edema in the left eye. Visual field was constricted in both eyes. The patient was on prolonged sirolimus therapy for over 7 years. Orbital MRI revealed bilateral chiasmatic thickness and FLAIR hyperintensity, without optic nerve enhancement post gadolinium. After extensive work up, other etiologies such as infectious, inflammatory, and neoplastic lesions were ruled out. Subsequently, sirolimus was substituted with cyclosporin that led to gradual improvement of vision and visual fields bilaterally. Conclusion Optic neuropathy is a rare side effect of tacrolimus, which has been seen as sudden, painless, and bilateral vision loss in post-transplant patients. Other concurrent medications influencing the cytochrome P4503A enzyme complexes may alter the pharmacokinetics of tacrolimus and increase the likelihood of toxicity. Discontinuation of offending agent has been shown to improve visual defects. We presented a rare case of optic neuropathy in a patient on sirolimus, whose visual defects improved upon discontinuation of sirolimus and switching to cyclosporin.
TL;DR: The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNas, telomeric RNAs and protein-coding mRNAs as mentioned in this paper .
Abstract: The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development. The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.