Tips and Tricks for Evaluating Children for Inherited Retinal Degenerations

Novel therapeutics and those in the pipeline are changing how we care for patients with IRDs. Here’s what you need to know.

BY DAVID XU, MD; MICHAEL N. COHEN, MD; MICHAEL A. KLUFAS, MD; AND JOSE S. PULIDO, MD, MS, MBA, MPH

young child referred to a specialist raises has also undergone a revolution, and many concerns. Have they seen a pediatric ophthal- multiplex sequencing has enabled screening for a wide mologist, or is this just a failed vision screening with panel of associated with retinal dystrophies. type A parents? How do I examine an uncoopera- The potential benefits of genetic testing are obvious: tive child in the clinic? How much time will it take It can establish a molecular diagnosis, potentially avoid Ato explain the diagnosis and plan to the parents? electrophysiologic testing, and establish candidacy for gene In this article, clinically useful tips and expert opinion pro- therapy. However, panel testing can also uncover “variants vide a framework to make the clinical approach to young of uncertain significance,” the majority of which represent patients with inherited retinal diseases (IRDs) easier. normal genetic variations rather than a causative mutation. Such a finding can create uncertainty and frustration for the DIAGNOSTIC CHALLENGES physician and family. Historically, IRDs have been classified according to natural history: stationary or progressive, mode of inheritance (auto- somal dominant or recessive, X-linked, or mitochondrial), AT A GLANCE and principal site of dysfunction (retinal pigment epithelium, s Evaluating children for inherited retinal diseases rod or cone photoreceptors, or inner retina). This approach relies on careful and extensive history, clinical examination, (IRDs) involves clinical examination and fundoscopy, multimodal imaging, and, often, electrophysiologic testing. genetic testing, and electrophysiologic testing. Even with this information, the molecular pathophysiol- s Syndromic conditions associated with early- ogy in this clinically and genetically heterogeneous group of dystrophies may not be apparent. In addition, young patients onset IRDs can present with various systemic may be more difficult to examine, may have more subtle manifestations; the key is to home in on patterns of visual complaints, and may have associated disorders. disease to help narrow the differential diagnosis.

Advances in molecular genetics have allowed more s precise classification based on genetic mutations and the A causative mutation can be identified in 60% to 80% associated pathophysiologic defects that lead to retinal of patients with IRDs. dysfunction (Figure).

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risks (such as depression of ERG waveforms). Visual field testing can help monitor progression of a rod- cone dystrophy or make a determination of legal blindness or disability. Examination of other family members and doc- umentation of a complete pedigree may provide information on the mode of transmission and illuminate implications for siblings and other family members. SYSTEMIC ASSOCIATIONS Syndromic conditions associated with early-onset retinal degeneration can present with a variety of manifestations. The key is to home in on patterns of disease to help narrow the diagnosis and refer patients for appropriate screenings. Following is a selected list of conditions to look out for.2 Retinal —Usher, Bardet-Biedl, Senior Loken, Joubert, and other syndromes—arise from genetic defects affecting photoreceptors and other cellular cilia, leading to Figure. This 19-year-old woman presented with long-standing vision loss with a VA an RP-like phenotype. Usher syndrome, caused by muta- of counting fingers OD and 20/400 OS. examination (top) showed macular tions in at least 11 known genes, leads to progressive retinal atrophy and pigment hyperplasia, fluorescein angiography (middle) demonstrated degeneration and hearing loss. Bardet-Biedl syndrome pro- hypoautofluorescence with peripapillary sparing, and OCT (bottom) showed bilateral duces a constellation of findings including cone-rod dystro- widespread ellipsoid zone and retinal pigment epithelium attenuation consistent with phy, polydactyly, obesity, and hypogonadism. Senior Loken . Genetic testing of the ABCA4 gene revealed a heterozygous nonsense is a rare autosomal recessive disorder characterized by an RP mutation Q1029X and F418S variant of unknown significance. or Leber congenital amaurosis (LCA) phenotype associated with juvenile nephronophthisis, causing cystic degeneration THE PEDIATRIC EVALUATION of the kidneys. Joubert syndrome can be associated with There are three key elements to consider in the evaluation hypotonia, ataxia, and a characteristic “molar tooth sign” of IRDs in children. on MRI of the brain. Although the manifestations of ciliopa- 1. Clinical examination and fundoscopy; a challenge here thies are quite pleomorphic, it is important to identify pat- is that some IRDs, such as congenital stationary night terns of disease and initiate the appropriate workup.2 blindness (CSNB), pigmentosa (RP) sine pig- Neuronal ceroid lipofuscinoses, such as juvenile CLN3, mento, and others, present with minimal to no retinal are progressive neurodegenerative disorders caused by changes on examination; abnormal accumulation of lipofuscin and lipid deposits. 2. Genetic testing; and Retinal degeneration can predate the other manifestations. 3. Electrophysiologic testing (full-field and/or multifocal Unfortunately, patients develop neurologic decline and loss electroretinogram [ERG] and electrooculogram). of motor coordination and die in their teens or 20s.2 The first objective is to establish a diagnosis and confirm Refsum disease is a peroxisomal storage disorder that that an IRD is responsible for the vision loss. The most com- presents with ichthyosis, ataxia, and RP. Dietary restriction of mon visual complaints, as reported by parents, include nys- phytanic acid and plasmapheresis are standard treatments.2 tagmus, vision loss, and .1 If disease onset is ear- Ocular mitochondrial disorders can affect the lier than 6 months, is often the earliest complaint. or retinal ganglion cells or can lead to a pigmentary retinopa- A thorough medical and ocular history is important for all thy. Those with retinal manifestations include chronic pro- patients, including best available , refraction, and gressive external ophthalmoplegia, Kearns-Sayre syndrome, careful anterior segment examination. Teller acuity or other mitochondrial encephalomyopathy, lactic acidosis, stroke- pediatric vision tests can be performed in preverbal children. like episodes, and others. These can be associated with , Clinicians should also evaluate for systemic abnormali- ophthalmoplegia, cardiac myopathy, and seizure.2 ties such as hearing loss, renal dysfunction, extra digits, and neurologic dysfunction. In uncooperative children, GENETIC TESTING BASICS examination under anesthesia may be necessary for a Testing can play an important role in achieving the cor- complete fundus examination. Fundus photography, fluo- rect diagnosis and determining eligibility for investigational rescein angiography, fundus autofluorescence, and full-field gene therapies. A causative mutation can be identified in ERG can help narrow the differential diagnosis. The benefits 60% to 80% of patients with IRDs, and most often a sali- of a sedated examination should be weighed against the va sample (2 mL) is sufficient for initial panel testing.3 Several

JULY/AUGUST 2021 | RETINA TODAY 35 - , Ital J Ital J Transl Vis Transl Vis CEP290 . 2018;1085:261-268. Adv Exp Med Biol . 2010;50(4):45-56. n International Ophthalmology Clinics . 2018;7(4):6. A 2-year-old girl with infantile nystagmus was referred for possible nystagmus was referred for possible A 2-year-old girl with infantile for decreased vision and was found to A 3-year-old boy was referred . 2019;45(1):168. RAPID-FIRE CASES RAPID-FIRE due to intense photophobia since birth. Low hyperopia was photophobia since birth. Low hyperopia was achromatopsia due to intense Given her age, an ERG would have to be present on cycloplegic refraction. Instead, genetic testing was ordered, revealing obtained under anesthesia. but a positive LCA panel for a negative result for achromatopsia obviating the need for ERG. fundus examination was unremarkable, making have -6.00 D . The condition from other retinal degenerations. it difficult to distinguish his often associated with X-linked and autosomal However, myopia is more should remain recessive variants of CSNB rather than LCA. Visual fields response (initial con stable in CSNB, unlike in RP. A paradoxical pupillary be seen with CSNB. striction of when ambient light is dimmed) may University Hospitals, Philadelphia (Genentech, Regeneron) Vitreoretinal Surgeon, Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson Vitreoretinal Surgeon, Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson [email protected] Financial disclosure: None Financial disclosure: Consultant (Allergan, Keeler) Vitreoretinal Surgeon, Wills Eye Hospital, Mid Atlantic Retina, Philadelphia Assistant Professor of Ophthalmology, Thomas Jefferson University, Philadelphia Retina Chief, Eyetube.net [email protected] Financial disclosure: Consultant (Allergan, Novartis, Genentech); Speaker Clinic, Rochester, Minnesota Professor Emeritus, Departments of Ophthalmology and Molecular Medicine, Mayo Financial disclosure: iPSC-RPE Cell Delivery Patents (Mayo Clinic) Larry Donoso Chair of Translational Ophthalmology, Wills Eye Hospital, Philadelphia   Vitreoretinal Surgeon, Wills Eye Hospital, Mid Atlantic Retina, Philadelphia Vitreoretinal Surgeon, Wills Eye Hospital, Mid Atlantic University, Philadelphia Assistant Professor of Ophthalmology, Thomas Jefferson         DAVID XU, MD XU, DAVID MICHAEL N. COHEN, MD COHEN, N. MICHAEL MD KLUFAS, A. MICHAEL MPH MBA, MS, MD, PULIDO, S. JOSE n n n n n Sci Technol inherited eye diseases - 2014. Accessed 5. American Academy of Ophthalmology. Recommendations for genetic testing of June 3, 2021. www.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d n n n n n n n n n advances in genetic testing and better understanding ofadvances in genetic testing and better understanding hope forpathogenic variants will continue to provide patients with these orphan diseases. to diagnosis for pediatricians. 1. Suppiej A, Marino S, Reffo ME, et al. Early onset retinal dystrophies: clinical clues Pediatr 2. Fasiuddin A. Inherited retinal degenerations. 3. Tsang SH, Sharma T. Genetic testing for inherited retinal dystrophy: basic understanding. landscape and knowledge gaps. 4. Duncan JL, Pierce EA, Laster AM, et al. Inherited retinal degenerations: current ------

5 -associated RPE65 -associated LCA. Numerous clinical Single gene analysis with traditional Single gene analysis 4 RPE65 | JULY/AUGUST 2021 JULY/AUGUST | IRDs are a heterogeneous group of degenerative disor Management of IRDs has traditionally been limited toManagement of IRDs has traditionally been Segregation analysis with a familial pedigree can help toSegregation analysis with a familial pedigree The potential outcome of genetic testing should be con The potential outcome of genetic testing Next-generation sequencing methods have enabled theNext-generation sequencing However, hereditary dystrophies are quite heterogeneous;However, hereditary Achieving a diagnosis can be challenging, especially in young patients, but it is key to successful management. Careful clinical examination and history-taking, genetic testing, and ERG evaluation all play important roles. Diagnosis now opens the door to for those with LCA and for clinical trial elibility for many others. Continued targeted therapies, the therapeutic armamentarium will hopefully evolve. TAKEAWAYS ders that negatively impact patients’ autotomy and vision. systemic associations, and educational or occupational ther systemic associations, and educational or apy. But the era of gene-based ocular therapy for IRDs began with the FDA approval of voretigene neparvovec (Luxturna, Spark) to treat trials are evaluating therapeutic candidates for X-linked RP, Stargardt disease, achromatopsia, choroideremia, X-linked , and others. With increased genetic testing and have important consequences for families considering addi have important consequences for families future.tional children and for their children’s reproductive ADVANCES TREATMENT ofgenetic counseling, low-vision referral, management sive, or be negative for all tested genes. Referral to a geneti sive, or be negative for all tested genes. Referral in the child’s workupcist or genetic counselor can be helpful purposes.and treatment, and also for family planning when more thanclarify the inheritance pattern and establish This canone copy of a gene is in cis or trans configuration. eases or when only a specific gene or set of genes is believedeases or when only a specific gene or set Genetic Testingto be causative. The AAO’s Task Force on specific test orrecommends that clinicians order the most findings. tests available based on each patient’s clinical example, the resultssidered prior to ordering the panel. For be inconclu could either confirm the suspected diagnosis, creation of IRD panels that can screen a large number ofcreation of IRD panels approximately two-thirds of patientscandidate genes, and of children with IRDs can receiveoverall and up to 85% a genetic diagnosis. for monogenic dis Sanger sequencing is more appropriate ries can also perform testing.ries can also loci have been implicated in retinalmore than 260 genetic mutations of a single gene can bedystrophies, and different phenotypes. For example, RP can beresponsible for different in one of 84 different genes, and cone- caused by mutations caused by mutations in one of 33 genes.rod dystrophy can be commercial retinal dystrophy panels are available in the are available in retinal dystrophy panels commercial laborato gene sequencing and CLIA-approved United States, s DISEASES RETINAL INHERITED AND RARE RETINA TODAY RETINA

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