Healthcare recommendations for Joubert syndrome

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan

Recent developments in the field of superior oblique palsies

PURPOSE OF REVIEW: The superior oblique muscle is a complex structure that evidences considerable variation in its anatomy as well as its rotational effects upon the eye. Our understanding and treatment of patients with superior oblique dysfunction are complicated by our incomplete, though developing, understanding of the sensory and motor adaptations to these dysfunctions. We review articles published over the previous year, which further our understanding of these issues. RECENT FINDINGS: A thought-provoking three-part series, using monkeys this past year, may provide some insights into time-dependent changes after superior oblique palsy as well as stimulate some interesting conjecture about what, if any, role proprioception may have in strabismus patients. There are some studies, which further our understanding of the torsional effects in superior oblique palsy, the fusional capabilities of normal and palsied patients, and the changes that our surgeries create in the torsional state of the eye. Another case of an ocular torticollis associated with plagiocephaly is presented this year. This past year also saw continuing attempts to determine the best methods for surgically correcting a superior oblique palsy. SUMMARY: Superior oblique muscle dysfunction continues to stimulate research into its complex and varied clinical manifestations. © 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

Evolution of focal choroidal excavation in ABCA4-related retinopathy

Purpose: To report long-term evolution of unilateral focal choroidal excavation in a patient with ABCA4-related retinopathy. Observations: A 51-year-old female with ABCA4-related retinopathy developed a small juxtafoveal defect in Bruch's membrane in a region of macular atrophy in her left eye. In follow-up, the defect widened and subsequently developed into a focal choroidal excavation. Over the next 8 years, serial optical coherence tomography imaging illustrated the conversion of the focal choroidal excavation from conforming subtype into non-conforming subtype with eventual macular hole formation. Conclusions and importance: The long-term follow-up of a patient with serial imaging highlights the potential dynamic nature of focal choroidal excavation in ABCA4-related retinopathy. Progressive retinal degeneration may influence focal choroidal excavation morphology and may promote macular hole formation

Applying next generation sequencing with microdroplet PCR to determine the disease-causing mutations in retinal dystrophies

Abstract Background Inherited Retinal dystrophy (IRD) is a broad group of inherited retinal disorders with heterogeneous genotypes and phenotypes. Next generation sequencing (NGS) methods have been broadly applied for analyzing patients with IRD. Here we report a novel approach to enrich the target gene panel by microdroplet PCR. Methods This assay involved a primer library which targeted 3071 amplicons from 2078 exons comprised of 184 genes involved in retinal function and/or retinal development. We amplified the target regions using the RainDance target enrichment PCR method and sequenced the products using the MiSeq NGS platform. Results In this study, we analyzed 82 samples from 67 families with IRD. Bioinformatics analysis indicated that this procedure was able to reach 99% coverage of target sequences with an average sequence depth of reads at 119×. The variants detected by this study were filtered, validated, and prioritized by pathogenicity analysis. Genotypes and phenotypes were correlated by determining a consistent relationship in 38 propands (56.7%). Pathogenic variants in genes related to retinal function were found in another 11 probands (16.4%), but the clinical correlations showed inconsistencies and insufficiencies in these patients. Conclusions The application of NGS in IRD clinical molecular diagnosis provides a powerful approach to exploring the etiology and pathology in patients. It is important for the clinical laboratory to interpret the molecular findings in the context of patient clinical presentations because accurate interpretation of pathogenic variants is critical for delivering solid clinical molecular diagnosis to clinicians and patients and improving the standard care of patients

Clinical Features of Optic Disc Drusen in an Ophthalmic Genetics Cohort

Background/Aims. Optic disc drusen (ODD) are calcified deposits of proteinaceous material in the optic disc, and their burden in ocular conditions is unknown. As ODD can be associated with visual field defects further compromising already degenerating visual function in patients with retinal degenerations, it is important to further our knowledge of ODD in inherited eye disease. The present study aims to evaluate prevalence, demographic features, and optic disc parameters of eyes with superficial ODD in inherited eye conditions. Materials and Methods. Electronic medical records of patients evaluated in the Ophthalmic Genetics clinic at the National Eye Institute (NEI) between 2008 and 2018 were searched for a superficial ODD diagnosis. Color fundus and autofluorescence images were reviewed to confirm ODD, supplemented with optical coherence tomography (OCT) in uncertain cases when available. Demographic information, examination, and genetic testing were reviewed. Disc areas and disc-to-macula distance to disc diameter ratios (DM : DD) were calculated. Results. Fifty six of 6207 patients had photographically confirmed ODD (0.9%). Drusen were predominantly bilateral (66%), with a female (62%) and Caucasian (73%) predilection. ODD prevalence in our cohort of patients with inherited retinal degenerations was 2.5%, and ODD were more prevalent in the rod-cone dystrophy subgroup at 2.95% (OR = 3.3 [2.1–5.3], P<0.001) compared to the ophthalmic genetics cohort. Usher patients were more likely to have ODD (10/132, 7.6%, OR = 9.0 [4.3–17.7], P<0.001) and had significantly smaller discs compared to the rest of our ODD cohort (disc area: P=0.001, DM : DD: P=0.03). Discussion. While an association between ODD and retinitis pigmentosa has been reported, this study surveys a large cohort of patients with inherited eye conditions and finds the prevalence of superficial ODD is lower than that in the literature. Some subpopulations, such as rod-cone dystrophy and Usher syndrome, had a higher prevalence than the cohort as a whole

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature.

Two patients diagnosed with DYRK1A Syndrome in the Undiagnosed Diseases Program with ophthalmologic abnormalities not previously described

CNGB3-Achromatopsia Clinical Trial With CNTF: Diminished Rod Pathway Responses With No Evidence of Improvement in Cone Function

PURPOSE. Ciliary neurotrophic factor (CNTF) protects rod photoreceptors from retinal degenerative disease in multiple nonhuman models. Thus far, CNTF has failed to demonstrate rod protection in trials for human retinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canine CNGB3 achromatopsia model. This study explores whether this finding translates to humans with CNGB3 achromatopsia. METHODS. A five-subject, open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/d) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for 1 year. RESULTS. Pupil constriction in treated eyes gave evidence of intraocular CNTF release. Additionally, scotopic ERG responses were reduced, and dark-adapted psychophysical absolute thresholds were increased, attributable to diminished rod or rod pathway activity. Optical coherence tomography revealed that the cone-rich fovea underwent structural changes as the foveal hyporeflective zone (HRZ) became diminished in CNTF-treated eyes. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold, or the photopic ERG. Careful measurements of color hue discrimination showed no change. Nonetheless, subjects reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, which may trace to decreased effective ambient light from the pupillary constriction; further they noted slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors. CONCLUSIONS. Ciliary neurotrophic factor did not measurably enhance cone function, which reveals a species difference between human and canine CNGB3 cones in response to CNTF. (ClinicalTrials.gov number, NCT01648452.) Keywords: CNTF, human clinical trial, CNGB3, achromatopsia, cone photoreceptor, rod photoreceptor, ECT implant, CNTF-releasing implant C iliary neurotrophic factor (CNTF) was discovered as a neurotrophic factor that supported ciliary neurons and hence was named as such. 1,2 Shortly thereafter, LaVail and colleagues 3 showed that CNTF promotes the rod photoreceptor survival, and as reviewed by Wen and colleagues, 4 the CNTF neuroprotective effects on rods was subsequently demonstrated in many animal models across several species. This raised hope that CNTF might act to protect rods in human retinal degenerations. The concurrent development of encapsulated cell technology (ECT) in the form of intraocular implantable microcapsules, that allowed delivery of physiologic levels of CNTF to the vitreous over extended periods of time, made it feasible to mount human CNTF clinical trials. 5-8 The first CNTF human phase I clinical trial was conducted in 10 patients with advanced retinitis pigmentosa (RP)

CNGB3-Achromatopsia Clinical Trial With CNTF: Diminished Rod Pathway Responses With No Evidence of Improvement in Cone Function CNGB3-Achromatopsia Clinical Trial With CNTF

PurposeCiliary neurotrophic factor (CNTF) protects rod photoreceptors from retinal degenerative disease in multiple nonhuman models. Thus far, CNTF has failed to demonstrate rod protection in trials for human retinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canine CNGB3 achromatopsia model. This study explores whether this finding translates to humans with CNGB3 achromatopsia.MethodsA five-subject, open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/d) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for 1 year.ResultsPupil constriction in treated eyes gave evidence of intraocular CNTF release. Additionally, scotopic ERG responses were reduced, and dark-adapted psychophysical absolute thresholds were increased, attributable to diminished rod or rod pathway activity. Optical coherence tomography revealed that the cone-rich fovea underwent structural changes as the foveal hyporeflective zone (HRZ) became diminished in CNTF-treated eyes. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold, or the photopic ERG. Careful measurements of color hue discrimination showed no change. Nonetheless, subjects reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, which may trace to decreased effective ambient light from the pupillary constriction; further they noted slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors.ConclusionsCiliary neurotrophic factor did not measurably enhance cone function, which reveals a species difference between human and canine CNGB3 cones in response to CNTF. (ClinicalTrials.gov number, NCT01648452.)