2023.09.26 | Questions 65-66
Ophthalmic genetics 👁️ (1/3) - An infant with vision loss
Hello,
This is the 1st in a series of 3 posts related to ophthalmic genetics. This week’s questions focus on an infant with vision loss. I also uploaded a YouTube video related to the topic of this post.
Please feel free to reach out with any feedback or ideas for future posts (daniel@studyrare.com).
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Have a great week!
-Daniel
Questions
Question 65
A 5-month-old boy presents with abnormal eye movements. He is not tracking objects or making eye contact and is otherwise meeting developmental milestones. Physical exam shows horizontal nystagmus and intermittent rubbing of the eyes. Height and weight are within normal limits. Fundoscopic exam is normal, and an electroretinogram shows near-absent electrical activity in the retina. Laboratory analysis including plasma amino acids and very long chain fatty acids are normal. What is the most likely diagnosis?
Question 66
Follow up testing reveals homozygous pathogenic variants in the gene RPE65. Which of the following would be indicated to help slow the progression of disease?
Explanation
Question 65: Leber congenital amaurosis
Question 66: Subretinal gene therapy
The patient in question 65 has Leber congenital amaurosis (LCA), a disorder associated with early-onset, non-syndromic, and progressive vision loss. The word “amaurosis” means “loss of sight without an externally perceptible change in the eye,” which describes the LCA phenotype well. LCA typically manifests in infancy, often within the first few months of life, with nystagmus and delayed developmental milestones related to vision, as seen in this patient. This infant also presents with the oculodigital sign, which is characteristic of severe, early-onset visual impairment and consists of the infant rubbing or pressing their eyes. Fundoscopic exam in patients with LCA may be normal on presentation (as was the case with this patient), though patients eventually develop progressive retinal pigmentary abnormalities. The electroretinogram (ERG) is classically "nondetectable" or severely subnormal, as it was in this patient. LCA falls under the broader category of non-syndromic retinitis pigmentosa, a class of disorders associated with progressive vision loss due to retinal abnormalities and without involvement of other organ systems.
💡Infants with LCA likely rub their eyes in an attempt to stimulate their visual pathways, which are receiving minimal input due to retinal dysfunction. Rubbing your eyes generates the sensation of flashes of light without light actually entering the eye (try it yourself!)
Molecular basis of LCA
Most cases of LCA are caused by loss-of-function variants in genes expressed in the cells responsible for vision (rods and cones) or in the cells that support them. RPE65 encodes for retinoid isomerohydrolase, an enzyme that plays a key role in the retinoid cycle, which is a biochemical process in the retina that is important for vision. In addition to RPE65 (~10% of all cases of LCA), there are at least 20 different genes that have been implicated in LCA. LCA is thus an example of locus heterogeneity, meaning that pathogenic variants in different genes can each cause the same disease. Most cases of LCA are inherited in an autosomal recessive manner, though there are a few rare subtypes that are inherited in an autosomal dominant manner.
💡Genetic testing sponsored by the pharmaceutical industry and patient advocacy organizations is available at no charge for patients with suspected retinal dystrophies in the U.S. (a list of sponsored genetic tests can be found here). The diagnostic yield of genetic testing in this scenario (infant with vision loss due to a suspected retinal dystrophy) is also relatively high compared to other common indications for genetic testing (e.g. non-syndromic autism).
Management
In this case, knowing the affected gene is important, as there is a gene replacement therapy available with for RPE65-related LCA (but not yet for the other LCA subtypes). Voretigene neparvovec (Luxturna) is a subretinal gene replacement therapy (Question 66) approved by the FDA in 2017 that was shown to slow the progression of retinal degeneration in patients with RPE65-associated LCA. Of note, Luxturna was the first FDA-approved gene therapy to target a monogenic disorder. While patients should also be enrolled in low vision rehabilitation and may need minus-power lenses (as many patients with LCA also have myopia, or nearsightedness), these measures are largely supportive and would not slow or reverse the progression of disease (Question 66).
💡Though the generic name looks confusing (voretigene neparvovec?!), there is actually a standardized 2-word naming scheme for gene therapies that describes the components of the therapy. For example, because of the suffix “-parvovec” in the 2nd word, we know that this therapy uses a parvovirus vector to deliver the RPE65 transgene.
Incorrect answers
Gyrate atrophy of the choroid and retina (GACR) is characterized by progressive degeneration of the choroid and retina, leading to visual impairment. GACR is caused by deficiency of the enzyme ornithine aminotransferase (OAT), which converts ornithine into glutamate semialdehyde. Onset of OAT is usually in childhood or later, rather than in infancy. Fundoscopic exam would show concentric rings of atrophy. Patients would also have elevated ornithine levels (this patient’s plasma amino acid profile was normal). A diet low in protein and/or arginine (a precursor to ornithine) can help improve vision in some patients with GACR.
Red-green color blindness, also known as protanopia or deuteranopia, is a type of color vision deficiency caused by specific genetic variants affecting the photoreceptor cones in the retina. This condition, which is inherited in an X-linked recessive manner, primarily leads to difficulty distinguishing between red and green colors and does not present with severe visual impairment or nystagmus in infancy.
Zellweger spectrum disorder (ZSD) are characterized by dysfunction of peroxisome biogenesis. While some subtypes of ZSD can present with retinal abnormalities, ZSD typically involves a range of systemic and neurological abnormalities, including impaired liver function, global developmental delay, and craniofacial dysmorphism. In contrast, LCA primarily affects vision and does not affect organ systems outside of the eye.
Learning objective
Leber congenital amaurosis (LCA) is an infantile-onset, non-syndromic, and progressive retinal disorder that is typically inherited in an autosomal recessive manner. Infants with LCA often present with nystagmus, delayed vision-related developmental milestones, and the oculodigital sign. Biallelic variants in one of approximately 20 genes can result in LCA. There is an FDA-approved gene replacement therapy for RPE65-related LCA, and clinical trials are underway for additional LCA subtypes.
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → d. Single Gene Disorders → vii) Ophthalmic genetic disorders
2023 ABGC Exam Content Outline | Domain 1. Clinical Information, Human Development, and Genetic Conditions → C. Genetic Conditions → 1. Clinical features, 4. Treatment options, & 7. Mode of inheritance
References
Leber congenital amaurosis / Early-onset severe retinal dystrophy overview
Nonsyndromic retinitis pigmentosa overview