History of present illness
We present a case of a 17-year-old male patient with an unremarkable past medical history referred for progressive nyctalopia and tunnel vision first noted at age 2 years. There was no known family history, premature birth, maternal illness during pregnancy, or trauma.
Ocular examination findings
Visual acuity with correction was 20/50 in the right eye and 20/50 in the left eye. Intraocular pressures were 13 and 14 mm Hg in the right and left eye, respectively. Confrontational visual fields showed peripheral constriction. Color plates were 1/14 in both eyes. There was nystagmus and intermittent exotropia of six prism diopters. Anterior segment examination was unremarkable. Dilated fundus examination showed peripapillary atrophy, macular pigment mottling, vascular attenuation, and a blonde peripheral fundus with irregular pigmentation without bone spicules ( Fig. 6.1 ).
Imaging
Optical coherence tomography (OCT) showed peripheral outer retinal atrophy with relative preservation of the subfoveal inner segment/outer segment (IS/OS) junction ( Fig. 6.2 A). Fundus autofluorescence imaging was notable for a lack of the normal autofluorescence pattern and vascular attenuation ( Fig. 6.2 B). Visual field demonstrated significant bilateral constriction ( Fig. 6.3 ). Full-field electroretinogram (ERG) revealed extinguished rod, cone, and combined rod–cone responses ( Fig. 6.4 ).
Questions to ask to aid diagnosis
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At what age did the parents first note visual impairment? Leber congenital amaurosis (LCA) is associated with visual impairment from birth or early life accompanied by nystagmus or roving eye movements.
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Our patient was first noted to have difficulty navigating at night and bumping into objects at age 2 years.
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Does the patient have a family history of ocular conditions? Inheritance patterns can aid in the diagnosis of congenital blindness and are important for genetic counseling.
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The patient has no known family history.
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Does the patient exhibit stereotypical behaviors? Depending on the causative gene, early and severe visual loss may be present. Oculodigital sign consisting of eye poking or rubbing to mechanically stimulate vision may be reported by the parents. The child may stare at lights and be terrified of being in the dark. Rarely, LCA may be associated with developmental delay, cognitive impairment, and oculomotor apraxia with difficulty initiating saccades.
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Our patient reports only difficulty seeing in the dark and bumping into surroundings because of tunnel vision.
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What is the pattern of fundus findings? Clinical phenotype can sometime correlate with the genetic mutation in LCA. GUCY2D, CEP290, CRB1, RDH12, and RPE65 are the most common LCA genotypes. RPE65-associated LCA (5–10% of LCA) typically has a blonde fundus and vascular attenuation. GUCY2D (10–20% of LCA) presents with an essentially normal fundus but is associated with significant photophobia compared with most other LCA genotypes. CEP290 (15–20% of LCA) has a relatively normal fundus in infancy with variable visual acuity progressing to severe vision loss of finger counting or worse within the first decade. CRB1 (approximately 10% of LCA) demonstrates macular atrophy and paraarteriolar sparing of retinal pigment epithelium (RPE). RDH12 (approximately 10% of LCA) typically has widespread RPE and retinal atrophy with minimal pigmentation in early childhood, dense bone-spicule pigmentation by adulthood, and early progressive macular atrophy with pigmentation and yellowing seen as excavation on OCT. Vessel attenuation and disc pallor or drusen may also be present.
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Our patient’s fundus shows no bone spicules and relative preservation of the macula, resembling the RPE65 phenotype.
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Are there any syndromic features? Hearing loss can be associated with Usher and Alström syndromes, with the latter being associated with kidney dysfunction, obesity, diabetes mellitus, and cardiomyopathy. Renal anomalies, obesity, and diabetes are also seen in Bardet-Biedl syndrome; however, the presence of postaxial polydactyly, cognitive impairment, and hypogonadism differentiate Bardet-Biedl from Alström. Renal dysfunction is also observed in Joubert, Senior-Loken, and Saldino-Mainzer syndromes. Joubert syndrome is associated with abnormal development of cerebellar vermis and brainstem resulting in the molar tooth sign on magnetic resonance imaging, whereas Saldino-Mainzer syndrome is associated with cone-shaped epiphyses of the hands, which can be seen on x-rays.
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No
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Assessment
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This is a case of a 17-year-old male patient with progressive nyctalopia, nystagmus, bilateral visual field constriction, extinguished photopic and scotopic ERG amplitudes, and diffuse outer retinal and RPE atrophy.
Differential diagnosis
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LCA, which can be caused by multiple genes
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LCA, nonsyndromic
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LCA with nephronophthisis
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Joubert syndrome
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Senior-Loken syndrome
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Saldino-Mainzer syndrome
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Alström syndrome
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Severe early childhood–onset retinal dystrophy (SECORD): better visual function compared with LCA despite early, progressive loss
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Early-onset retinitis pigmentosa (RP): considered a milder form of LCA
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Congenital stationary night blindness
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Achromatopsia: typically presents with day blindness, reduced visual acuity, photophobia, and nystagmus
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Blue-cone monochromatism: X-linked
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Metabolic
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Abetalipoproteinemia/Bassen-Kornzweig syndrome
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Zellweger syndrome
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Neonatal adrenoleukodystrophy
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Infantile Refsum disease
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Hyperthreoninemia
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Infections (i.e., rubella or syphilis)
Working diagnosis
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LCA: retinal pigment epithelium–specific 65 kDa protein (RPE65) phenotype given diffuse RPE atrophy, vascular attenuation, and lack of autofluorescence
Multimodal testing and results
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Fundus photographs
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In LCA, fundus findings can range from initially normal to a diffuse pigmentary retinopathy. Our patient demonstrated significant vascular attenuation, extensive peripheral retinal depigmentation, and relative central macular preservation.
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OCT
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Our patient’s OCT was notable for diffuse outer retinal atrophy with relative preservation of the IS/OS junction in the central macula, a finding that can be seen in RPE65-associated LCA with great variability depending on the severity of the causative mutation and the age of the patient. No clear relationship exists between the age of the patient and the genotype-phenotype correlation, as is common for inherited retinal diseases in general. GUCY2D may present with relatively preserved outer retinal structure and photoreceptor-associated layers on OCT with subfoveal cone loss. CRB1 is associated with retinal thickening and loss of normal lamination, as well as cystoid macular edema. RDH12 shows marked retinal thinning and excavation of the macula.
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Autofluorescence
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Findings vary depending on the mutation. For example, our patient demonstrated lack of normal autofluorescence pattern, a common finding in the RPE65 phenotype caused by interruption of the visual cycle and lack of lipofuscin within the RPE cells. The GUCY2D gene results in normal fundus autofluorescence early with the appearance of areas of hypoautofluorescence and hyperautofluorescence as RPE degeneration progresses. Meanwhile, the CRB1 phenotype has been described as hypoautofluorescence sparing paraarteriolar areas corresponding to preserved RPE along the arterioles. ,
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ERG
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ERG was obtained, which showed nearly extinguished scotopic and photopic responses, suggesting LCA or advanced RP and commonly seen with RPE65-associated retinal dystrophy. Interestingly, GUCY2D patients often show relatively preserved rod function (cone–rod disease) with a minority of patients showing reduced but detectable cone function.
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Genetic testing
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Important in diagnosis, prognosis, and identifying gene therapy candidates. Our patient had genetic testing confirming compound heterozygous mutations in the RPE65 gene (paternally inherited p.Tyr431Cys:c1292A>G and maternally inherited p.Glu364Lys: c1090G>A).
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Management
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Given our patient’s biallelic RPE65 mutation–associated LCA2, our patient underwent gene therapy with subretinal injection of the U.S. Food and Drug Administration–approved voretigene neparvovec-rzyl (Luxturna Spark Therapeutics, Inc., Philadelphia, PA). The surgical procedure is shown in Fig. 6.5 .
